Off-label Drugs and its potential use against cancer – An Intro by Raymond Chang MD

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The off-label use of a drug is the prescription or taking of a medicine for other than what it was originally intended for as described or approved by the US FDA or similar regulatory body. Simply put, medication usage for what is not on the official label of the drug is “Off-Label”.

Although hardly uncommon, there are distinct reasons why off-label prescribing is not as common as it ought to be if based on scientific evidence of efficacy alone. Firstly, it is unlawful to market, advertise or promote the off-label use of drugs (See an example of the intricacies and complexities as well as the conundrum of off-label regulation by FDA, US Congress and the Courts as evidenced by the recent saga of the Neurontin case in this 2004 paper by Robert Kaufman of the Harvard Law School).

Secondly, the insurance industry frequently invoke the off-label nature of a prescription to decline payment (ie they will not pay if they can find a reason not to pay, why would they? See illustrative story here), although Medicare in recently expanded its coverage of off-label treatments for cancer (See related news here), although it mainly applies to the use of an agent already approved for the coverage of some form of cancer to be covered when used for a different cancer, which is quite different from the drugs presented here ( approved for some other condition than cancer, to be applied for use as an anti-cancer), ie it is off-label use of a cancer drug rather than off-label use of a drug for cancer.

Finally, although the FDA does not regulate the individual physician’s prescription of a drug as long as it has been approved,  the legal liability for the physician is deemed higher especially if harm arises out of the course of its use and if it seems to deviate from “standards of care” which is how physicians are legally judged. Furthermore, physicians may be deemed to be engaged in human experimentation when prescribing drugs off-label (See a balanced discussion by Maxwell Mehlman JD on the legality and bioethics issues of off-label prescribing here)

It is because of potential legal risk on the part of the prescribing physician, limitations of insurance reimbursement, as well as the lack of knowledge about the potential off-label usefulness that limits the broader use of such drugs.  The unlawfulness of pharma related marketing or promotion and their lack of interest in investing in new clinical trials to demonstrate new indications when a drug has already gained FDA approval is often a factor limiting the broader use off-label treatments.

Back to the cancer patient: my purpose here is just to broaden the awareness of the science behind the usefulness of some very common and some not so common drugs that could jointly or otherwise enhance a patient chances of overcoming cancer, and to disentangle the healing process from insurance red-tapes and legal suffocation (See Disclaimer).

More useful info on Off-label Drugs for cancer can be found at the NCI site here.

TOPICS in this blog include:

Introduction to Off-label drugs for cancer

Posts (Publisjed, Most Recent or Recently Updated First)

1. Statins, pleiotropic anti-cancer (6.10)
2. Gamma-delta immunotherapy (2.09, updated 6.10)
3. Urso as chemopreventative (5.09)
4. Noscapine  near perfect (5.09)
5. Naltrexone (2.09)
6. Bisphosphonate (2.09)
7. Clodronate for breast cancer (2.09)
8. Gossypol (11.08)
9. Metformin (10.08)
10. Disulfirim (11.08)
11. Dipyridamole (11.08)
12. Cimetidine (11.08)

Draft Topics (To Be Published)

• Cox-2 inhibitors (e.g. Celecoxib i.e. Celebrex)
• PPAR agonists
• Heparin
• Anti-coagulants
• Coumadin
• Tetracyclines as Anti-angiogenics
• Clarithromycin against lung cancer
• Artesunate and Antimalarials for cancer
• Lithium as immunomodulator
• Anti-depressants against cancer
• Cannabinoids
• Benzodiazepines
• Theophylline for B cell leukemia (CLL) / lymphoma (NHL)

Antimalarial Artesunate’s potential against cancer

Artemisinin or Qinghaosu (青蒿素), derived from the leafy portions of the sweet wormwood plant Artemisia annua L. or qinghao (青蒿), and isolated in 1972 by Chinese chemists, is a potent anti-malarial that has revolutionized modern malaria treatment.  What makes this and related bioactive derivatives super interesting is that they exhibit potent anticancer effects in a variety of human cancers (Expert Rev Mol Med. 2009 Oct 30;11:e32), a fact which has been known for almost three decades but relatively unexplored.

In Vitro and in Vivo Research

One of the most notable semi-synthetic derivative drug from artemisin is artesunate (ART), which was developed for malaria in the 1980′s was noted to have anti-cancer activity along with other artemisinins by the early 1990′s (J Nat Prod. 1993 Jun;56(6):849-56), with Lai and Singh reporting that artemisinin selectively killed MOLT-4 lymphoblastoid leukemia cells in 1995 (Cancer Lett 1995; 91:41-46). Subsequent research by Thomas Efferth’s team in Germany demonstrated artesunate’s in vitro efficacy against multiple tumor lines (Int J Oncol. 2001, 1:767-773) and was most active in vitro against leukemia and colon cancer while modestly effective against melanomas, breast cancer, ovarian cancer, prostate cancer, glioma, and renal cancer. The same research team was also responsible for elucidating much of the molecular mechanisms of efficacy of ART against cancer, which included direct cytotoxicity, anti-angiogenesis as well as induction of apoptosis (See Drug Resist Updat. 2005 Feb-Apr;8(1-2):85-97).

Clinical Studies

Beyond the test-tube, it has been found that ART (as well as artemisinin and other artemisinin derivatives) can successfully treat grafted human tumors in laboratory animals (Biochem Pharmacol 2004 Dec 15;68(12):2359-66), and this lead to Efferth’s group to attempt to treat two uveal melanoma patients after chemotherapy has failed.  Generally, such cases have a median survival of 2-5 months, but with ART treatment, one patient went on to live 24 months and the other patient is alive at 47 months (as of 2007) after initial diagnosis of stage IV melanoma. Other clinical reports include the successful use of artemether, a related compound, in the treatment of a pituitary macroadenoma (Integr Cancer Ther. 2006 Dec;5(4):391-4) and a report of a 72 year old gentleman in India with laryngeal squamous cell cancer, which responded nicely to ART alone with a 70% shrinkage over 2 months (Arch Oncol 2002; 10(4):279-80).  In China, a clinical trial comparing ART + chemo vs. chemo alone against non-small cell lung cancer found a modest improvement of the time to progression in ART treated patients (Zhong Xi Yi Jie He Xue Bao. 2008 Feb;6(2):134-8) despite the fact that lung cancer is one of the least sensitive cell lines to ART when tested in vitro.  Anecdotally, dogs with bone cancer and lymphosarcoma have been reported to rapidly respond to artemisinin, and patients with prostate cancer, brain tumors, pancreas cancer, breast cancer were also anecdotally reported to have been helped by artemisin derivatives. Reportedly, Dr. N. Singh from the U. of Washington mentioned the case of a man with brain cancer who has been in coma for 5 months who came out of the coma after 21 days injections of artemether, a related compound.  (See newsletter article by Christina White, “Cancer Smart Bomb, Part I & II: An Idea from Ancient Chinese Medicine”, New Horizons, Summer & Fall 2002 issues published by the Brewer Science Library -> an online excerpt is available).

In Germany, a trial of ART against breast cancer is currently recruiting at the University of Heidelberg and there was also a phase I trial in the U.K. against colon cancer that was completed but unpublished.

ART availability

ART is largely non-toxic, with related compounds having been administered to over 2 million patients, children and adult, world-wide without significant concern for serious adverse effects reported (Trans R Soc Trop Med Hyg. 1994: 88 (Suppl 1):S3-4.) and ART is cheap compared to conventional cancer drugs, but then why aren’t there more trials or more wide-spread use of ART as an off-label cancer treatment?  The usual combination of ignorance (most conventional oncologists I have spoken with not even unaware of artemisia or artemisinin or ART’s potential against cancer, and some have never heard of a drug called artesunate) and commercial interests (or lack of interest rather) are the culprits here hampering an advance. Furthermore, in the specific case of ART, its highly restricted availability is also contributory (believe it or not, in the USA, it was only in 2007 that the FDA approved investigational new drug (IND) protocol # 76,725 for the use of artesunate in treating “severe malaria”, making it the first time that any of the artemisinins are legally available as a drug in the US.  Currently, the US army (Walter Reed Army Institute of Research) supplies ART to the Center of Disease Control (CDC) which is in turn the only legitimate source of the drug in the US, and even then, it is only available to hospitals, upon request and on an emergency basis, by the CDC ! (See CDC website for  ART availability details).  Worldwide, genuine oral ART is also difficult to obtain due to WHO concerns and constraints secondary to surging malaria resistance to one of the last remaining effective anti-malarials, compounded by a problem of rampant distribution of fake ART in third world countries.

My take

Despite some concern for neurotoxicity based on animal studies, ART and related compounds are some of the least toxic medications on the market for any condition, without clinically relevant toxicity after extensive oral and parenteral use in various populations for the past two decades, except for sporadic and transient cardiac dysrhythmias.  These compounds are also relatively inexpensive, being dispensed mainly in the third world in poor populations where malaria is endemic.  With the demonstrated bioactivity in the laboratory and the promising anecdotal cases, these seem to be perfect compounds to try against cancers , either in combination or when other treatments fail. It is hoped that regulatory authorities could loosen the grip on dispensing of ART and related medicines, especially where malaria or malaria resistance is not a concern in the territory (e.g. in the US or Western Europe, Japan) to allow cancer patients a compassionate avenue to the treatment especially when other treatments have failed.

My research group at the Institute of East West Medicine here in New York have noticed the potential of anti-malarials against cancer in general and we are currently exploring other naturally derived anti-malarials as possible anti-cancer agents with generous support from the Gray Charitable Trust and other private supporters.  Funding permitting, semi-synthetic and synthetic derivatives of artemisinins could also be systematically explored and developed with a use against cancer in mind, and combinations of ART with other anti-cancer agents to achieve synergies should also be urgently investigated.

Anti-HIV’s now also anti-cancer ?

Its been a while since I last updated here, and there are many potential off-label drugs for cancer that should be NEXT written about, but one category that deserves immediate attention are the anti-HIV drugs.  One of them, Nelfinavir, was even called “a magic bullet to annihiltate cancer cells” recently (Cancer Biol Ther. 2009 Feb;8(3):233-5).

Of course, cell signalling pathways as a source for new target therapy drugs against cancer is all the rage now but to develop a new candidate molecule into an approved drug can cost a billion dollars and take over 10 years, so how about looking at established targeted therapies for other diseases such as HIV and see if there are potential off-label drug candidates for cancer there ?  Well, Dr. Phillip Dennis and colleagues did exactly that:  they took existing HIV protease inhibitor drugs and tested 6 of them against cancer cell lines derived from 9 different human tumor types and found that three of the drugs (ritonavir, nelfinavir and saquinavir) reduced the growth of 60 of those cell lines. In the laboratory, nelfinavir or Viracept®, a first generation speific protease inhibitor designed for HIV appeared most potent (Autophagy 4(1):107-9, 2008).

Nelfinavir seems to exercise a broad-spectrum cancer killing effect through multiple pathways: apoptosis, necrosis and autophagy (See Clin Cancer Res 13(17): 5183-94, 2oo7), and is also noted to have antiangiogenic and immunomodulatory ability.  Nelfinavir has also been shown to have radiosensitizing properties (Cancer Res. 2005 Sep 15;65(18):8256-65.) via Akt activation making it a logical addition to radiation therapy and trials using it in this fashion are underway against brain, rectal and pancreas cancers.  One of the ways it works with chemo and radiation may be via disruption of the process by which hypoxia occurs by restoring proper blood flows to tumors ad making them more vulnerable to other therapies according to research by McKenna of Oxford. McKenna’s group also demonstrated as early as 2005 that Nelfinavir radiosensitized cancer cells and a small trial he conducted with nelfinavir + chemoradiation showed dramatically that 6 out of 10 patients with advanced pancreas cancer had their cancer shrank enough to be surgically removed whereas normally it would be only 1 in 10 (J Clin Oncol. 2008 Jun 1;26(16):2699-706) .

Using anti-HIV drugs against cancer is not a novel idea, the grand daddy anti-HIV drug AZT was originally tested against cancer in the ’90s because of laboratory promise, but it did not pan out in human testing.  HIV patients are at increased risk for certain cancers, and those on protease inhibitor treatment have been thought to have reduced kaposi’s sarcomas and lymphomas, this observation was noted early on and trials to test the drugs against HIV related cancers were planned as early on as 2003 in Italy (Lancet Oncol. 2003 Sep;4(9):537-47)

The anti-HIV protease inhibitors have been around since 1993 and their dosage, safety and toxicity in humans are well known.  Currently, multiple phase 1/2 studies are under way to evaluate the potential of nelfinavir in renal cell, rectal, lung, adenocystic, liposarcoma, brain and pancreas cancers, alone, and in combination with chemotherapy and radiotherapy and other targeted agents such as bortezomib or Velcade® and temsirolimus or Torisel®. (See current US trials here)

The usual starting dose for nelfinavir is 1250 mg twice a day (costs about $25/day in the US) but ongoing phase 1/2 trials are testing higher doses.  Its common side-effect is diarrhea, blood lipid abnormalities  (good reason to add a statin as another off-label anti-cancer treatment, see here; but caution must be exercised when adding or selecting a statin due to potential drug-drug interaction via the CYP pathway where the lactone pro-drugs simvastatin and lovastatin should not be used, see here) and redistribution of body fat (64% at 13 months of usage), as well as glucose intolerance (with a diabetes risk of 3% with long-term use) but its side-effects do not overlap with mainstream anti-cancer agents’ and is usually tolerable for long term treatment.

Urso as Chemopreventative

Off-label therapeutic inspirations sometimes come from my patients.

And this one came from Noreen T.  Noreen has advanced metastatic breast cancer refractory to almost all treatments and has just started on an investigational Dendritic vaccine + Zadaxin (thymosin) but her disease is progressing rapidly with rising markers and an obstructive jaundice caused by liver metastases.  External drainage and internal stenting was out of the question and she was offered lactulose as we need to buy time for the immune treatments to work.  In my searches, I came across Ursodiol (Urso) which I am familiar with in its use in preventing gallstones or for primary biliary cirrhosis and other cholestatic conditions.  Its just that its not usually used in oncology.  Researching deeper led to the interesting discovery for me that it is also an anti-cancer (which I doubt that most my hepatology or GI colleagues are aware). Even more interesting was a converse (vis-a-vis this blog) discovery, that Tamoxifen which is traditionally used for breast cancer, may be useful as an off-label treatment for primary biliary cirrhosis (Reddy et al. Liver Int., 2004 Jun;24(3):194-7)!  So thank you Noreen for leading me to a treasure trove of discoveries!

What is Urso?

Ursodiol or Ursodeoxycholic (Actigall, URSO) is a naturally derived bile acid that decreases the amount of cholesterol produced by the liver and absorbed by the intestines. Interestingly, ursodiol is found in large quantities and the major therapeutic ingredient in bear bile, which is an established if controverial member of traditional Chinese medicine’s pharmacopoeia. Ursodiol helps break down cholesterol that has formed into stones in the gallbladder and is also hepatoprotective. Ursodiol also increases bile flow, which is why it is useful in cholestatic conditions such as biliary cirrhosis.  Since the 1980′s, Urso has been in widespread clinical use for biliary conditions. But what surprised me when researching the potential application of Urso for Noreen’s case is the anti-cancer properties of Urso.

Urso and Cancer

Earnest DL et al. from the U. of Arizona reported as early as 1994 that Urso is a potential chemopreventative agent in experimental colon cancer and highlighted a role of bile salts in modulating gastrointestinal cancer development, and it wasn’t long before Urso became a recognized chemopreventative agent against colon cancer in those with inflammatory bowel disease (See Itzkowitz SH, Gastroenterol Clin North Am. 2002 Dec;31(4):1133-44).  In 1997, the Korean team Park YH et al. reported that Urso induced apoptosis (suicide) of liver cancer cells in vitro (Arch Pharm Res. 1997 Feb;20(1):29-33) and the same team further demonstrated derivatives of Urso had efficacy against prostate and breast cancers in later studies. Im and Martinez more recently demonstrated that Urso induced apoptosis in colon cancer partly via modulation of EGFR/Raf-1/ERK signaling (Nutr Cancer. 2005;51(1):110-6.) A most recent review of Urso as an apoptotic is found in a review by Amaral JD et al. in J Lipid Res. 2009 May 5.

Granted, clinical data for Urso as a cancer treatment is not available and its main potential seems to be the use as chemopreventative in those at high risk for colon or liver cancers to reduce the risk, but attempts to synthesize Urso and other bile salt derivatives for cancer treatment is already on the way.

Noscapine near perfect?

Solid science, potential efficacy, minimal toxicity and low cost – that would be a nearly perfect anti-cancer, wouldn’t it?

This is not an entirely new one.  Noscapine (also, see NCI drug dictionary) a naturally derived and existing ingredient of OTC cough medicines in some countries, it has more data backing its usefulness against cancer than its relative Naltrexone (a fellow off-label anti-cancer candidate which is opiate derived) and works like the chemo drug paclitaxel (Taxol) but without many of the nasty side-effects, all of which has been known for some time.

So, what is Noscapine?  It is a non-opiate alkaloid from plants of the poppy family that makes up 1-10% of opium’s alkaloid content, but without significant pain killing properties. This agent is primarily used for its antitussive (cough-suppressing) effects, and is approved for use as such in some countries, but not in the US.

Mechanism of Action

A review by Ye et al. from Emory, where much subsequent in vitro and in vivo research on its anti-cancer effects were done, presented as early as 1998 (Proc Natl Acad Sci, 17;95(4):1601-6.) demonstrated elegantly how Noscapine may inhibit cancer by interfering with microtubular function at the cellular level, thereby arresting cell growth and  inducing cellular suicide or apoptosis, much like taxanes and the vinca alkaloids do. Noscapine binds to tubulin and alters its conformation, resulting in a disruption of the dynamics of microtubule assembly (by increasing the time that microtubules spend idle in a paused state) unlike other tubulin inhibitors such as the taxanes and vinca alkaloids which affect microtubule polymerization. Perhaps more importantly, Noscapine was able to inhibit cancer at doses which produced little or no toxicity, including no adverse effects on the primary immune response (Ke Y et al. Cancer Immunol Immunother. 2000 Jul;49(4-5):217-25).  More recently, Newcomb et al. from New York also demonstrated potential anti-angiogenic activity of Noscapine as an alternate anti-cancer mechanism (Int J Oncol. 2006 May;28(5):1121-30)

In Vitro

Noscapine inhibits paclitaxel resistant ovarian cancer cells (Zhou, J et al. J Biol Chem. 2002 Oct 18;277(42):39777-85); C6 rat glioma when administered alone, (as well as augmented the cytotoxicity of radiation and chemotherapy upon C6 rat glioma cells when administered concomitantly – Surg Neurol. 2006 May;65(5):478-84), HL60 and K562 myelogenous leukemic cells Anticancer Drugs. 2007 Nov;18(10):1139-47),

In Vivo

Noscapine inhibits murine lymphoid tumors,  human breast and bladder in nude mice murine (Ye, 1998), prolonged survival in melanoma (Landen et al. Cancer Res. 2002 Jul 15;62(14):4109-14), crosses the blood brain barrier and inhibited implanted C6 glioma in the rat model (Landen, Clin Cancer Res. 2004 Aug 1;10(15):5187-201), and has potent anti-cancer activity in the non-small cell lung cancer model Cancer Chemother Pharmacol. 2008 Dec;63(1):117-26).

Generating the most buzz was the last year’s demonstration by Dr. Barken of San Diego of Noscapine’s ability to inhibit progression and metastates (60% and 65% respectively) inPC3 human prostate cancer-bearing immunodeficient mice Anticancer Res. 2008 Nov-Dec;28(6A):3701-4.)

Clinical (human) Studies

Unfortunately, although a phase I/II clinical trial of Noscapine (CB3304) for patients with refractory non-Hodgkin’s lymphoma and chronic lymphocytic leukemia at USC / Norris Cancer Center was planned in 2003, it was terminated early because of apparent funding issues.  However, interim results in 2005 on 12 patients recruited thus far suggested that one out of ten patients evaluable did have a partial response, and two other patients demonstrated stable disease.  The research team stated that they were encouraged by the results. Cougar Biotech Inc. currently has a phase I trial of noscapine in patients with multiple myeloma ongoing at the Center for Lymphoma and Myeloma/Weill Cornell Medical College and Columbia University Medical Center, and Dr. Barken of the Prostate Cancer Research and Educational Foundation (PC-REF) in San Diego, California, is planning on facilitating clinical trials with noscapine in prostate cancer.

My Take

Potentially useful against CLL leukemia/lymphoma/myeloma, prostate cancer, non-small cell lung cancer, glioma (administered alone or in combination with chemo and/or radiation to enhance cytotoxicity), hormone resistant breast cancer, or perhaps co-administered with taxanes.

Distinct advantages include i) oral bioavailability, ii) encouraging experimental data, iii) low toxicity, iv) low cost, and v) synergistic potential with other modalities and drugs.

The future lies with more affirmative clinical trials and the development of more potent derivatives such as 9-bromonoscapine (Mol Cancer Ther. 2006 Sep;5(9):2366-77) and to develop other analogs of Noscapine with higher tubulin binding activity  and/or affect tubulin polymerization differently, or able to arrest cell cycle progression at lower concentrations.

Clarithromycin for lung cancer

Advanced comments welcome … In the process of reasearch and writing up, thank you for your patience !

Artesunate and Antimalarials for Cancer

Advanced comments welcome … In the process of reasearch and writing up, thank you for your patience !

Gamma-Delta Immunotherapy

A Preamble

γδ T cells or “gammadelta” T cells are unique to primates and represent a minority white cell in our blood (0.5-5%); yet they play an essential role in sensing ‘danger’ by invading pathogens as they expand dramatically in many acute infections and may be a key fighter in cancer as well.  I want to discuss very exciting findings of how to harness these cells as an anticancer strategy but why does it belong in this blog?

Technically, gammadelta therapy is an immune therapy and is not “off-label” per se, because since these are a patient’s own cells, there is no issue of FDA approval or non-approval, and thus no issue of being on or off-label !   But, the key here are the drugs used to expand gammadelta T cells to use them to fight cancer are approved for other uses and these agents can be used off-label to direct the expansion of gammadelta T cells, hence the mention of this treatment here.

I am not easily excited, having been “in the business” if you will for decades and having seen so many mediocre agents and methods come and go in our “war against cancer” where true advance has been been disappointingly few.  But this time we may be on to something truly special.  The title of a recent review article by N Caccamo of Italy “Amiophosphonate-activated gammadelta T cells in immunotherapy of cancer: Doubt no more” ( Expert Opin Biol Ther 2008 Jul; 8:7, pp. 875-883) sums up the excitement.

Some Background

The background is not necesarily an easy one to understand if you do not have a science or medical background.  There are surprisingly few general introductory books on the topic, but the dated (1992) paperback “The Transformed Cell” by Steven Rosenberg is still a good primer for those who are interested but not necessarily want to earn college credit on the subject. And if you are not much interested at all in how this method works and all the immunology mumbo jumbo, but just want to know the practicalities of the treatment, you may as well skip to the last 2 sections to avoid a headful (and a headache!).

I have also put in BOLD some key concepts here in  order to highlight the key concepts for non-scientist or patients to help understand all this.

We as mammals have two innate immune defense systems:  an adaptive immune system unique to vertebrates in which lymphocytes participate with recognition of peptide antigens and which can be defined by memory of the target; and a more ancient innate immunity which is cell based (macrophages, monocytes, NK cells, NKT cells, dendritic cells) and which has no memory once demobilized.  The gammadelta cells can be thought of as unconventional T cells at the interface between and linking the two immune systems, and contribute to the elimiation of infections or cancers by direct and indirect killing as well as modulation and stimulation of other immune cells (eg macrophages and NK cells) and the secretion of cytokines, notably interferon gamma and TNF-alpha.

Gammadelta T cells were known since the time when I was graduating medical school, in the mid to late ’80s (See Lanier et al. The gamma T cell antigen receptor. J Clin Immunol 1987;7(6):429-40 and Pardoll et al., The unfolding story of T cell receptor gamma, FASEB J, 1987; 1(2):103-9.) and it became known  that gammadelta T cells can kill tumor cells.  However, over the years, these cells received much less attention than Natural Killer (NK) cells, NKT lymphocytes and the much more populous alphabeta T cells in regards to applications in cancer immunotherapy.

The use of killer cells against cancer has been a focus of research for nearly two decades. Since the original descriptions of in vitro lymphocyte-mediated cytotoxicity against cancer, there have been numerous quasi-sucessful attempts to exploit these for therapeutic use in the clinic.  I say “quasi-successful” because there are no mind blowing successes, regretfully.  Most modern research have focused on the role of either natural killer (NK) cells or cytotoxic CD8 + alphabeta T cells , and little attention has been paid to the role of gammadelta T cells due to a lack of understanding of how they work, as well as the practical problem of obtaining enough of them for bedside use.  Our clearer understanding of these cells and their role in infections, cancer and autoimmunity is only surfacing recently (The first world conference on gammadelta T cells only got under way in 2004).

Gammadelta cells share with alphabeta T cells certain functions such as cytokine production and potent cytotoxic (cell killing) activity but gammadelta cells recognize different sets of antigens, usually in a non-MHC-restricted fashion, and cancers are highly susceptible to gammadelta T-cell mediated lysis which led to the proposal that gammadelta T cells can be used for cancer immunotherapy (See Kabelitz D, Potential of human gammadelta T lymphocytes as immunotherapy for cancer, Int J Cancer 2004 Dec 10;112(5):727-32). Unlike conventional T lymphocytes which recognize peptide antigens,  this “alternative” T cell’s ability to recognize tumor cell ligands not seen by conventional alphabeta T cells is one property that makes them intriguing. The other unique property is the way they recognize antigens circumvents to ability to of cancer cells to eventually elide detection.

In Vitro Work

It has long been known that these cells can kill cancers.

Gammadelta T cells are able to kill myeloma (Kunzmann et al. Blood, 2000; 96(2): 384-392, also Clin Exp Immunol, 2006;144(3):528-33) and lymphoma cells (Fisch et al. Europ J Immunol 1997;27:3368-3379)

Human Vgamma9Vdelta2+ gammadelta-T cells found able innately to recognize and kill certain human prostate tumor cell lines (DU-145 and PC-3 but not LNCaP) (Liu et al. J Urol, 2005;173(5):1552-6).

Gammadelta-T cells are able to innately recognize and kill human breast cancer cells in a gammadelta-TCR-dependent manner (Guo BL et al. Breast Cancer Res Treat 2005; 93(2):169-75.).

Freshly prepared gammadelta T cells consisting mainly of Vdelta2 gammadelta T cells showed increased cytotoxicity against bisphosphonate-treated pancreatic carcinoma cells (J Immunother 2007; 30(4):370-7)

Perhaps most exciting is the finding of efficient killing of cancer stem cells by gammadelta T cells (Todaro M, et al. J Immunol. 2009 Jun 1;182(11):7287-96).

In summary, most epithelial tumours (including melanomas, pancreatic adenocarcinomas, squamous cell carcinomas of the head and neck, and lung carcinoma – See Scan J Immunol, 2007;66(2-3):320-8) were susceptible to allogeneic gammadelta T-cell lysis and in the case of an established ovarian carcinoma, to autologous gammadelta T-cell killing

Animal Studies

Early on. Hayday found that mice lacking gammadelta cells were highly vulnerable to skin cancer when exposed to carcinogens.

A ‘St Jude’s regimen” utilizing human gammadelta T-cells from leukapheresis and adoptive transfer of the cells with an anti-GD2 antibody and the cytokine Fc-IL7 demonstrated enhance survival in a mouse model of human disseminated neuroblastoma (Clin Cancer Res 2005;11(23):8486-8491.

In models of mice bearing localized and disseminated prostate cancer treated i.v. with gammadelta T cells developed measurably less disease and superior survival compared with untreated mice (Liu Z, J Immunol, 2008;180(9):6044-53).

Intravesical administration of gammadelta T cells with zoledronic acid demonstrated antitumor activity against bladder cancer cells in the orthotopic murine model and resulted in prolonged survival (Yuasa T et al. Cancer Immunol Immunother 2009;58(4):493-5020

Recently published study ( Jul 2010) out of the U. of Alabama demonstrated efficacy of adoptively transferred gammadelta-T cells in both syngeneic (4T1) and xenogeneic (2Lmp) models of breast cancer, and the treatment was otherwise well-tolerated by treated animals. (Beck BH et al. Breast Ca Res Treat. 2010 Jul;122(1):135-44)

Stimulating and Expanding Gammadelta T Cells is Key.

Just knowing gammadelta T cells can kill cancer cells is not enough.  We and cancer patients all have these cells, but how to harness them to fight cancer in us or our patients? The limitations up until late ’90s has been the difficulties associated with identifying, harvesting, and expanding the cells. Thus the  key is in growing or expanding these cells either in the laboratory and externally applying the cells to the patient ( so-called adpotive therapy) or to stimulate and expand the gammadelta cells in our bodies somehow.  Both have been looked into:

Gammadelta cells is known to be stimulated by a number of non-peptide phosphorylated antigens, including a number of mycobacterial and bacterial derived molecules as when one encounters when one catches one of these infections (eg TB, E.Coli), as reported since the early ’90s.  Reports of gammadelta stimulation and expansion by small phosphorylated metabolites, amino-bisphosphonates (risedronate>alendronat>pamidronate) and synthetic phosphoantigens (defined as small, phosphorus-containing antigenic molecules) followed, openning up the opportunity of clinically applying this as a practical cancer treatment (reviewed by Fourniee and Bonneville in Res Immunol, 1996;147(5):338-47).

Pioneering work by the Italian team Casetti et al. elegantly demonstrated that co-stimulation simply with interleukin 2 plus non-peptide antigens or amino -bisphosphonates induced up to 100-fold increases in the numbers of peripheral blood Vgamma9Vdelta2 T cells in animals and together with a German team led by Wilhelm M et al. (see below, this laid the ground work for subsequent clinical endeavours in this field (Casetti R et al. Drug-Induced Expansion and Differentiation of V9V2 T Cells In Vivo: The Role of Exogenous IL-2, J Immunol 2005;175(3):1593-8).

Exciting Human Observations and Clinical Data

In the past few years, clinical data has been pouring in fast and furious suggesting practicability and efficacy of this unique therapy.

In 2005, Bennouna et al. presented a phase I trial of 18 BrHPP (Phosphostim) and low dose IL-2 treated patients with solid tumors in a poster session at ASCO (JCO, 2005; 2005 ASCO Annual Meeting Proc 23(16S), Pt II of II:2536).

By 2007, Godder KT et al. from the US reported intriguing 5 year follow-up results showing three-fold overall survival advantage in acute leukemics with increased gammadelta cells following partially mismatched allogeneic stem cell transplantation, and postulated a graft versus leukemia effect (Bone Marrow Transplant 2007;39(12):751-7).

One of the earlier trials using gammadelta therapy was carried out by a German team from Wuerzberg utilizing low-dose interleukin 2 (IL-2) in combination with pamidronate in patients with relapsed/refractory low-grade non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). They observed significant in vivo activation/proliferation of gammadelta T cells in 5 out of 9 patients (55%) who had positive in vitro response to pamidronate / IL-2 stimulation and objective responses (PR) were achieved in 3 patients (33%) . And thus the team demonstrated for the first time that this therapy was feasible (Wilhelm M. et al, Gammadelta T cells for immune therapy of patients with lymphoid malignancies, Blood, 2003;102(1):200-6).

Recently, a Japanese team from Tokyo attempted adoptive immunotherapy using in vitro-activated autologous gammadelta T cells against advanced renal cell cancer had found that it was well tolerated and induced anti-tumor effects (kobayashi H. et al, Cancer Immunol Immunother. 2007 Apr;56(4):469-76) . A French team using gammadelta T cells expanded in vivo with BrHPP (IPH1101, Phosphostim) and interleukin 2 (IL-2) at administered by infusion to metastatic renal cell cancer patients resulted in stable disease in 6 patients out of 10 (Bennouna J. et al. Cancer Immunol Immunother 2008;57(11):1599-609).

Almost simultaneously, the Italian team led by Dieli F of Palermo initiated a phase I clinical trial in metastatic hormone-refractory prostate cancer to examine the feasibility of using zoledronate in combination with low-dose interleukin 2 (IL-2) to stimulate gammadelta cells against the cancer and registered 3 partial remissions and five stable diseases out of nine patients (Dieli et al. Cancer Res.2007;67(15):7450-7) .

The same team above from Palermo also reported positive results in a small trial in May of 2010 of using zoledronic acid with low dose IL-2 in 10 “therapeutically terminal, advanced metastatic” breast cancer patients. Treatment was well tolerated and there was a statistically significant correlation of clinical outcome with peripheral Vgamma9Vdelta2 T cell numbers, with three patients who sustained robust peripheral Vgamma9Vdelta2 cell populations after treatment responding with declining cancer markers and partial remission or stable disease (Meraviglia S, et al. Clin Exp Immunol. 2010 May 10 Epub ahead of print), while a Japanese team almost simultaneously reported in Feb of 2010 thr complete remission of a patient with lung metastasis from renal cell carcinoma after six cycles of autologous in vitro-activated gammadelta T-cells followed by low-dose interleukin-2 and zoledronic acid intravenous infusion. Complete remission was achieved which has been maintained for 2 years without any additional treatment (Kobayashi H, et al. Anticancer Res 2010 Feb;30(2):575-9)

At the moment, there has been trials including a study of the use of gammadetla therapy in recurrent non-small cell lung cancer at the U. of Tokyo in Japan and an active phase I trial “Immunotherapy of Hepatocellular Carcinoma With Gamma Delta T Cells” which involves the direct intrahepatic injection of gammadelta cells going on in Rennes, France under the direction of Dr. Jean-Luc Raoul.  Researcher Lamb LS Jr. and team at the U. of Alabama have also been exploring explores graft engineering techniques in the development for the therapeutic use of gammadelta T cells against glioblastoma multiforme (Immunol Res. 2009;45(1):85-95)

My Take

Although we have known about gammadelta cells, but the ability to use fairly straightforward medicines such as the amino-bisphosphonates and interleukin-2 off-label to dramatically expand these cells in a patient without serious side-effects opens the way to a practical immunotherapy.  The fact that there is laboratory data showing efficacy against leukemia/myeloma and also human experience which is positive for some solid tumor (prostate, breast, lung and kidney) cancer types gives hope that this treatment can be broadly deployed against an array of cancers, both hematologic and solid tumors.  Research finding that the therapy can efficiently kill cancer stem cells is also exciting.  Most importantly, that this therapy calls for a protocol that is much more simple (30 minute treatment every month) than the parenteral Vitamin C protocol with much more science behind it than IPT (Insulin Potentiation Therapy) and other “alternative” cancer regimens makes this a very attractive options for patients seeking an alternative to conventional chemotherapy or radiotherapy.  Although NK cells are much more popularly known but there is no practical way to expand NK cells in the patient but this gammadelta therapy is eminently praticable.  My colleague Dr. Thomas Nesselhut at the Institut of Tumortherapie in Duderstadt, Germany is starting to apply this as a part of the Dendritic Cell therapy protocol that we have been collaborating on for the past 5 years and it appears quite promising.  We are currently gearing up to offer this as a viable alternative therapy while working out some of the legal and logistics hurdles to deployment.  All very exciting indeed.  Your comments welcome !

Future Directions

-> Clinical trials covering other cancers beyond prostate, kidney, myeloma. and NHL.

-> Development of more potent gammadelta stimulants or expansion protocols.

-> Exploring naturally-derived gammadelta agonists for dietary preventative therapeutic regimens.

-> Exploring the preventative possibilities of gammadelta therapy

Amino Bisphosphonates as Anti-Cancers

The use of bisphosphonates (eg Aredia, Zometa, Clodronate) for cancer is not new and is not considered off-label, so why this blog? Well, these agents are only applied narrowly and used palliatively in most cases, ie only in certain cancers (notably myeloma, breast, prostate and more recently lung cancers) and only when there is bone metastases.  I have recently discussed the potential for adjuvant use of Clodronate in breast cancer, but I will share here some of the very exciting recent discoveries with newer generation bisphosphonates [so-caled amino bisphosphonates or nitrogen containing bisphosphonates "NBPs", namely Aredia (pamidronate disodium) Zometa (zoledronic acid) Fosamax (alendronate) Actonel (risedronate) and Boniva (ibandronate)] as direct anti-cancers, ie the off-label potential to apply the newer generation NBPs in a combinatorial manner in the treatment of cancers.  So, where as it was originally and previously thought that bisphosphonates are useful in bone metastases because of the ability of these agents to inhibit bone resorption, newer understanding leads us to knowledge that such agents are really direct anti-cancers as well.  Without elaborating on the complex biochemical and molecular pathways (See diagram below, e.g. NBPs are thought to inhibit farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway,  in turn inhibiting the prenylation of small G-proteins such as Ras, Rap1, Rho and Rab, reduces the signals they mediate, and thereby prevents the growth, adhesion/spreading, and invasion of cancer cells) which have been extenstively reviewed, suffice it to say that NBPs cause direct cell cycle disruption and induce cancer cell death (so-called apoptosis), and this direct apoptotic effect of NBPs such as Zometa has now been reported in breast, prostate, myeloma, leukemia, colon cancers. Moreover, NBPs also independently inhibit cancer cell invasiveness, and exert anti-angiogenic effects as well via a variety of potential mechanisms.

(courtesy Caraglia M, et al. Endocrine-Related Cancer (2006) 13 p.14, Fig 2)

Now, back to the clinic.  With all the direct anti-cancer effects of the NBPs, we should then see some survival advantages of patients treated with Zometa or Aredia, but how come that hasn’t been widely reported and only noted in a subset of Zometa treated myeloma patients?  It seems like the problem is with the pharmacokinetics of the drugs themselves.  It turns out that not only are the half-lives of the drugs are very short in the blood ( no more than an hour or two), the maximum concentration achieved is also up to 100 fold less than what was demonstrated to cause cancer apoptosis (self-destruction) in the test tube experiments, although concentrations are adequate for anti-invasive effects.  These drugs tend to concentrate in the bones though, which explains why they are effective for controlling cancer metastatic to the bone.   However, all is not loss: it turns out that it is possible to manipulate the drugs to bring out its anticancer effects via pharmacological manipulations such as encapsulating the NBPs in liposomes and exploiting the NBP’s synergisms with other agents.

NBPs have been reported to be synergistic with various cytotoxic agents, cox-2 inhibitors, imatinib, bortezomib, rapamycin, ATRA (retinoic acid), thalidomide, histone deacetylase inhibitors (HDACs), and interferon beta on growth ihibition.

Perhaps most exciting is the recent finding that NBPs have immunomodulating properties, specifically by stimulating and expanding cytotoxic gammadelta T lymphocytes (See separate blog on this topic). There are very exciting recent reports of NBPs combined use with low dose Interleukin 2 (IL-2) to induce gammadelta T cells as immuotherapy against a variety of cancers.

My Take

NBPs are already in common use, and are quite non-toxic.  I think its use as a direct anticancer can be broadened to more cancer types as primary treatment used in a combinatorial manner if the latest research on gammadelta cell therapy (See my blog on this) is confirmed and its combined use with other potentially synergistic agents should be actively explored.  Based on principles of molecular action, I suspect that MMP inhibitors such as the tetracyclines and HMG Co-A reuctase inhitors (so-called “statins”, see separate blog on statins for cancer) should be synergistic with NBPs as well.  Baulch-Brown from Australia already demonstrated Zometa synergism with Lescol (Fluvastatin) against myeloma in vitro ( Leuk Res. 2007 Mar;31(3):341-52), and similar results were obtained with Zocor by a German group (Anticancer Drugs. 2006 Jul;17(6):621-9). In the future, we may look forward to new agents such as BPH-715 which is 200x more potent as an anti-cancer than current NBPs.  As to the current choice of NBP, current research seems to point to Zometa as being more powerful but it has to be administered parenterally.  Ibandronate (Boniva) is worth exploring for application because it can be given orally and has a better safety profile although less data is available but maybe I will explore this in a separate blog soon!

Adjuvant Clodronate for Breast Cancer

Clodronate is a first generation bisphosphonate (a.k.a. clodronic acid, marketed under the Brand names of Bonefos, Clasteon, Difosfonal, Loron, Mebonat and Ossiten in Europe & the U.K., Canada, and elsewhere, not yet commercially available in the US, where the FDA deems it “approvable” as of 2005 ) that shares with its more famous cousin Fosamax the ability to inhibit bone resorption and is thus used for treating osteoporosis to increase bone mass and reduce fractures. Because of the propensity of these agents to adsorb mineral and inhibit bone resorption, they have also been applied to treat cancer metastases to the bone, as well as to lower cancer associated hypercalcemia since the 1980′s.  So why is it appearing in my blog as an “off-label” treatment for cancer? Well, it can be used in cancer as other bisphosphonates, but usually in a palliative sense to control bone metastases and/or hypercalcemia associated with cancer, but not as a standalone treatment for the cancer itself.  However, there is compelling data for Clodronate’s use as an adjuvant agent, especially in breast cancer.

In a pioneering double-blind controlled study of Clodronate in treating breast cancer metastatic to the bone, Canadian researchers Paterson et al. (1993) noted reduced bone-related morbidity in treated patients and recommended that Clodronate be further investigated for potentially reducing bone metastasis as an adjuvant treatment for those who are at risk.  Not long thereafter, Diel et al. (1998) from the University of Heidelberg published a landmark trial in the New England Journal of Medicine on the subject and found in the 302 patient randomized trial that adjuvant clodronate at 1600 mg a day reduced not only bone metastases in breast cancer, but reduced other organ metastasis as well as the risk of death.  Subsequent, a Finnish study published in 2001 unexpectedly showed a decrease in survival in clodronate treated breast cancer patients, thus confounding the topic.  With accumulating evidence in favor, the FDA issued an approvability letter in 2005 for the use of clodronate as an adjuvant treatment in breast cancer. Finally in 2006, a larger randomized double-blinded placebo controlled multi-center study of over one thousand patients over 5 years confirmed reduced skeletal metastasis as well as possibly favorable survival in breast cancer patients (esp those with Stage II or III disease rather than Stage I) receiving clodronate as adjuvant over the initial 2 years.

There are quite a few discussions and review of the use of clodronate for breast cancer online and there is no doubt remaining controversy based on the earlier Finnish trial and a more recent meta-analysis which found no attributable benefit to the drug.  Furthermore, the drug is not commercially available in the US and not FDA approved despite its approvability, and these all hinder more wide-scaled use of the drug.  Lately, there has also been increasing concern for the risk of osteonecrosis of the jaw as a complication of long-term bisphosphonate use, but unlike other bisphosphonates, the risk of ONJ with clodronate is extremely low at 0 – 0.5% (rare cases reported only) after taking it for 2 years (see Mayo Clin Proc 2007; 82:516-522), and this should not be a major deterrent in those considering its use.

My Take

Given some of the favorable trial results above and the very safe and relatively inexpensive (under $200 per month from Canada) nature of the drug, in addition to its benefit in reducing bone loss in breast cancer patients simultaneously receiving anti-estrogen therapy, I think Clodronate ought to be seriously considered as adjuvant treatment for Stage II and III breast patients, and I have been recommending it for the past 5 years.  It is not available in the US, but can be obtained from Canada, Mexico, Europe and Asia. Newer generation bisphosphonates may have more potent anti-cancer potential (See my more recent blog on gammadelta cell therapy as well as amino bisphosphonates if interested) and may in the future replace Clodronate for this use, so I eagerly await further trials in the area of using bisphonates as adjuvant therapy for breast cancer.

Tetracyclines for cancer

PPAR agonists for cancer

Naltrexone for Cancer

Naltrexone is an opioid receptor antagonist approved and used for management of alcohol and opioid dependency.  Low dose naltrexone or LDN (at 1/10th of the dose used for drug rehab) however has been proposed as an off-label therapy for a broad range of immune disorders such as HIV, MS, autoimmune thyroiditis, and colitis, and is one of the more popular off-label treatments for cancer thanks to some promising trials, low toxicity, relative low cost and much internet publicity such as found on the Low Dose Naltrexone Homepage and a Low Dose Naltrexone Forum.  But if you don’t have a health science degree you might be wondering, what is the connection between cancer and opioids? And most importantly, does it work?

Opiates and Cancer

First some background on opioids and cancer.  Firstly, there is the difference of endogenous opiates (eg endorphins and enkephalins) vs. exogenous opiates (drugs).  The effects of opioids on cell growth is complex and is believed to be mediated through opioid and non-opioid receptor signalling (See Chen YL et al. The Other side of the Opioid Story: Modulation of Cell Growth and Survival Signalling, Curr Med Chem 2008:15(8):772-8), thus opioids directly modulate cell growth and endogenous opiates can directly suppress cancer growth.  On the other hand, exogenous opiates can suppress the immune system, which is not ideal for treating cancer. It has been known for some time from animal studies that opioids interfere with the immune system ( Sacerdote P, Opioids and the Immune System, Palliat Med 2006;20 Suppl 1:s9-15), and that opioid pain killers such as morphine can decrease and depress immunity.  In animal studies for example, morphine causes worsening of cancer, although the effect is different amongst different opioids, with buprenorphine (“Bupe”) perhaps the least immunosuppressive.

Background 1: Zagon

Now back to Naltrexone, an opioid antagonist.  There is no doubt that Dr. Ian Zagon at Penn State is a major pioneer researcher in endogenous opiates and the major bench-side explorer of “off-label” applications of LDN.  In his own words about the journey of discovery of opioid effects on cancer, he said : “When we discovered the effects of opioid antagonists such as naltrexone and naloxone in 1979, this was purely happenstance. Around 1975, we were interested in the effects of opiates… on children who were born to mothers that were addicted. The scientific literature revealed that these babies and children had neurological difficulties and were lower in body weight. We (myself and Dr. Patricia McLaughlin) developed a model to look at this in animals. Along the way, I was doing another project on neuroblastoma, a childhood tumor. When I found that these exogenous opioids altered growth of these developing animals… This started in 1977-1978. We then progressed to injecting cells into mice and creating cancers, and examined whether these exogenous opioids would repress growth of these cancers. In fact, they did…” (as quoted on the LDN forum).

It turns out from Zagon’s research, that the central actor may be one “OGF” or opioid growth factor, or otherwise known technically as [Met5]-enkephalin.  Zagon proposed that OGF is an inhibitory peptide whose action is modulated via an OGF receptor and which modulates cancer cell proliferation and migration, and angiogenesis. Zagon has demonstrated that OGF inhibits pancreatic (BxPC-3), colon (HT-29), renal cell (Caki-2), neuroblastoma, and head and neck (CAL-27) cell lines (Int J Oncol, 2000 Nov;17(5):1053-61). Moreover, OGF also suppressed pancreas cancer in animals (Cancer Lett 1997 Jan 30;112(2):167-75) , and synergistically enhanced the efficacy of chemotherapy against pancreas cancer (Cancer Chemother Pharmacol 2005 Nov;56(5):510-20) and enhanced survival in squamous cell head and neck cancer as well(Cancer Chemother Pharmacol 2005 Jul;56(1):97-104).  Based on such observations, Zagon & McLaughlin filed a patent in 1997 claiming that the administration of an opiate antagonist such as Naltrexone “at an amount sufficient to effect the intermittent blockade of the zeta receptor present in the cancer (and surrounding tissues) thereby producing a subsequent period of elevated endogenous enkephalin levels or receptor numbers to inhibit, arrest and even prevent tumor growth” (US Patent 6136780)

Background 2. Bihari

Almost working in parallel as Zagon, but from the clinical side and not in the laboratory, there is one Dr. Bernard Bihari, who is an addiction specialist who used Naltrexone and claims to have discovered the immunomodulatory benefits of Naltrexone in 1985.   The story goes that Dr. Bihari began noticing in the 1980s that some of his addict patients with immune deficiency (subsequently discovered to be HIV/AIDS) had symptomatic improvement on lower doses of Naltrexone, so he conjectured that Naltrexone somehow upregulated their immune system (See AIDS Patient Care 1995 Feb;9(1):3).  Along this line of thinking and based on some reports that lymphoma responded to endorphin treatment in animals, he had treated a recurrent lymphoma patient with low dose naltrexone and the lymphoma got better.  He subsequently also treated a woman named CP with advanced melanoma and the cancer responded. Then from 1999 onwards, Dr. Bihari investigated the effects of LDN in private patients, using a low dose of 3mg given at night and theorizing that the treatment induced an increase in endorphins, especially metenkephalin, in the pre-dawn hours.  The endorphins would in turn directly suppress cancer growth and upregulate the immune system.  This theory coincided with Zagon’s animal work on how OGF may inhibit cancer and is consistent with the actions of naltrexone.  Unfortunately, there has not been any organized clinical trial or even published case series on this, except for what has been presented in the Low Dose Naltrexone website, that “as of March 2004 … medication by Dr. Bihari in some 450 patients with cancer, almost all of whom had failed to respond to standard treatments, suggests that more than 60% of patients with cancer may significantly benefit from LDN. Of the 354 patients with whom Dr. Bihari had regular follow-up, 86 have shown objective signs of significant tumor shrinkage, at least a 75% reduction. 125 patients have stabilized and/or are moving toward remission” Apparently,  of patients treated, “88 LDN-only group includes five breast cancer patients, one patient who had widespread metastatic renal cell carcinoma, three with Hodgkin’s disease and six with non-Hodgkin’s lymphoma. Reportedly, other cases, some on LDN for as long as four years, included a score of patients with non-small cell lung cancer, as well as patients with ovarian cancer, uterine cancer, pancreatic cancer (treated early), untreated prostate cancer, colon cancer, malignant melanoma, throat cancer, primary liver cancer, chronic lymphocytic leukemia, multiple myeloma and some others” according to another website.  Again reportedly, in June 2002 an oncologist and an oncology physician’s assistant from the National Cancer Institute reviewed some 30 charts of cancer patients at Dr. Bihari’s office, and about half were chosen as appearing to have responded to LDN without question.  Supposedly, copies of these records were sent to the NCI for further data collection on its part for consideration for NCI’s Best Case Series. Four cases of prostate cancers responding to LDN was reported as well in a patent “Method of Treating Cancer of the Prostate” Bihari filed in 2000. But again, regretfully, none of any of these cases ended up being published in the medical literature, and they circulate as quasi-anecdotal mentions online.

How might Naltrexone work in cancer?

In summary, based mainly on Zagon’s work, naltrexone at low dose administered nocturnally could bne postulated to work via 1) a stimulation of endogenous opiates as well as the number and density of opiate receptors on tumor cell membranes making them more responsive to the inhibitory effects of circulating opiates, which in turn suppresses tumor growth directly, 2) an enhancement of cellular immunity as a result of effects of higher levels of endogenous opiates, and 3) metabolites such as methylnaltrexone which exert antiangiogenic effects.

What does the medical literature say?

Bihari had published nothing on LDN and cancer in the medical literature.

Zagon had reported on using naltrexone in a mouse neuroblastoma model showing inhibition of growth and prolonged survival in those mice that develop tumors and protected some mice from developing tumors altogether (Brain Res 1989 Feb 20;480(1-2):16-28).  At a similar dose of 0.1mg/kg, his team was also able to retard implanted human colon cancer in mice (Cancer Lett 1996 Mar 29;101(2):159-64), apparently via an stimulation of metenkephalins, which is in line of his research hypothesis.

Clinically, only two single case reports of 1) a long surviving metastatic pancreas cancer treated with LDN and alpha-lipoic acid (Integr Cancer Ther 2006; 5(1):83-9), and 2) a B-cell lymphoma with clinical reversal using only LDN Integr Cancer Ther 2007; 6(3):293-296) can be found in the medical literature that I can find.

Along these lines, an OGF plus gemcitabine for pancreas cancer trial is on the way (starting this month!) at Penn State, but while there are several trials on LDN for Crohn’s and MS and other conditions on the way, there is nothing on the horizon testing LDN for cancer per se.

My Take

I have been prescribing off-label Naltrexone to my cancer patients for many years.  I remember being asked by organizers from Drs. Bihari’s camp to present at the 1st Annual LDN Conference in 2005 but declined to attend because I had no clear cut cases to report  (Then they asked me to report on the tolerability of the treatment, which is not meaningful, and I didn’t go).  Indeed, over the years, I have not seen any definitive responses that I can attribute to LDN with certainty.  I wish to give some credence to the cases of response found online, but such are anecdotes that cannot strictly be considered admissible evidence in clinical science, only suggestive leads for further investigations. There are inherent limitations for testing LDN of course: not every patient is a candidate (eg if on narcotics for cancer pain) for LDN and most who take it are on at least a few other treatment modalities making a judgement of LDN efficacy difficult.  Then also, the drug itself is cheap and generic and thus there is no industry interest in funding formal trials.  However, I still prescribe LDN to this day since the theoretical background is not unsound, the side-effects are minimal, and the substance is readily available and at such a reasonably low cost that I usually do not mind the addition of LDN to a patient’s treatment, especially if requested and especially in cases of pancreas or colon ca, melanoma, SCCHN where there has been studies or prostate cancer where there has been a patent filed.  Personally, I think LDN may perhaps have greater promise in other conditions such as Crohn’s and MS rather than cancer, and OGF may be a more direct opioid treatment option for cancer in the future.

Your comments welcome.

Cox-2 for Cancer

A big topic with alot of research and active trials ongoing.  I am in the process of writing this up. Your advanced comments and patience appreciated.

Statins for Cancer

This is a VERY LARGE topic to review (just like “cox-2 inhibitors” and “PPAR gamma agonists” because of the abundant data and complexity of the background biology – which is why I haven’t gotten to it sooner, sorry !).

Statins is the nick name for so-called HMG-CoA reductase inhibitors and well established for treating high cholesterol. Statin research started with Japanese researchers Endo and Kuroda in 1971 and within a decade Merck has launched lovastatin (Mevacor), the first statin drug.  Today, statins are the second most common class of drugs prescribed in the US after analgesics, and are commonly used for hyperlipidemia and to reduce the risk of heart attack and stroke. What makes statins intriguing is that these drugs have other biological actions beyond the lowering of cholesterol which makes them potentially useful in a bewildering array of medical conditions such as auto-immune conditions, organ transplantation, polycystic ovarian syndrome (PCOS), arrhythmias, chronic obstructive pulmonary disease (COPD), sepsis, contrast-induced nephropathy, cataract, age-related macular degeneration, sub-arachnoid hemorrhage, osteoporosis, dementia, asthma, thromboembolism, Alzheimer and even cancer.  As a class, statins have diverse biological effects including improving endothelial function, stabilizing atherosclerotic plaques, attenuating oxidative stress and inflammation, immuno-modulation, as well as inhibition the thrombogenic response. Many of these actions are executed via a modulation or inhibition of post-translational protein prenylation (also called isoprenylation). The basic biology behind statin effects is way too large a topic to review here and I would suggest reading articles like “Statins: a new insight into their mechanisms of action and consequent pleiotropic effects” in Pharmacol Rep. 2007 Sep-Oct;59(5):483-99 or the excellent downloadable article in Nature Reviews Immunology “Statin therapy and autoimmune disease: from protein prenylation to immunomodulation” for further insight. For our purposes, it suffices to know that the immunomodulatory, antiangiogenic and anti-inflammatory effects of statins all contribute to its anti-cancer potential (for an overview of “statins in tumour suppression”, also see Sassano and Platanias’s article of this title in Cancer Letters 2008 Feb 18; 260(1-2):11-9), and instead we will focus on the practical applicability of the scientific findings to date.  So, here is the background:

a) In Vitro (cellular evidence):

There is a large body of in vitro evidence demonstrating the potential of statin’s use against cancer, especially of its potential synergies with other agents against cancer.  We will not be able to list them all, but will cite a sample of some recent research in various cancer types to illustrate as follows:

Breast Cancer – Many studies demonstrated in vitro inhibition of breast cancer cells by statins and synergistic effects with other agents as well, an example would be Campbell et al’s Breast cancer growth prevention by statins in Cancer Res., 2006 Sep 1;66(17):8707-14.

Lung Cancer – Inhibition of various lung cancer cell lines have been widely reported (See Maksimova, E. Lung. 2008 Jan-Feb;186(1):45-54) including against small cell lung cancer (Khanzada UK, et al. Oncogene. 2006 Feb 9;25(6):877-87). Moreover, Furthermore, synergism with greentea, cox-2 inhibitors, gamma tocotrienol, chemotherapy, bisphosphonates has been demonstrated in vitro.

Brain Cancer – Statin treatment inhibited proliferation and migration in human U251 and U87 glioma cells in a dose dependent manner.  Statins also induced apoptosis of glioma cells thought to be related to inhibition of the prosurvival PI3K/Akt pathway triggering caspase-3-dependent cell death through the modulation of lipid rafts (Wu H, et al. Neurosurgery. 2009 Dec;65(6):1087-96). Earlier in 2004, it was also reported that simvastatin induced proliferation inhibition and apoptosis in C6 glioma cells via c-jun N-terminal kinase (Neurosci Lett. 2004 Nov 11;370(2-3):212-7).

Colon Cancer – There are many reports of statins inducing apoptosis in human colon cancer cells and preventing its carcinogenesis. Furthermore, synergism with cox-2 inhibitors, gamma tocotrienol, chemotherapy, TRAIL, butyrate has been demonstrated in vitro and studies showing statins ability to reduce inflammation in colon tissue raises the hope that it may be useful in inflammatory bowel diseases as a chemopreventative against colon cancer.

Ovarian Cancer – There is research to establish that statins induces cell death in ovarian cancer. What is interesting is the existence of possible differential effect between lipophilic (eg simvastatin) v. hydrophilic (e.g. pravastatin) statins (Kato et al, J Cell Mol Med. 2009 May 11)

Prostate Cancer – There are many reports of statins inducing apoptosis in prostate cancer (e.g. PC-3) cells via various mechanisms (Hoque A, et al. Cancer Epidemiol Biomarkers Prev. 2008 Jan;17(1):88-94), e.g. Murtola et al’s recent results demonstrating simvastatin to inhibit prostate epithelial cell growth at clinically relevant doses (Prostate. 2009 Jun 15;69(9):1017-23). Furthermore, synergism with cox-2 inhibitors, PPAR agonists, bisphosphonates, HDAC inhibitors, tocotrienols in vitro have all been reported.

Pancreas Cancer – Statins reduce pancreatic cancer growth, invasion and metastasis (Kusama et al. Gastroenterology. 2002 Feb;122(2):308-17). Mistafa and Stenius from the Karolinska Institute in Sweden recently reported that atorvastatin (Lipitor) decreased constitutive- and insulin-induced pAkt in Panc-1 and MIA PaCa-2 cells and also inhibited pAkt in combination with gemcitabine and 5-fluorouracil chemotherapy, and sensitized cells to gemcitabine and 5-fluorouracil induced apoptosis and inhibition of cell proliferation (Biochem Pharmacol. 2009 Nov 1;78(9):1115-2). Czech researchers comparing various statins against pancreas cancer in vitro identified also simvastatin as the most potent (Int J Cancer. 2008 Mar 15;122(6):1214-21)

Comparable research showing the usefulness of statins against cancer cell lines have been published against a wide range of other cancers (liver, sarcoma, leukemia, lymphoma), and as noted above, synergies in vitro with cox inhibitors, green tea polyphenols, HDAC inhibitors, PPAR agonists, gamma tocotrienols, chemotherapeutic agents, bisphosphonates, and even oncolytic viruses etc. have also been documented (also see below section on synergisms).

In Vivo (animal evidence):

There is a similarly large body of evidence that statins are bioactive as anti-cancer agents both in the prevention and suppression of cancer in laboratory animals, and a sampling of such research is as follows:

Cancer Prevention -

A new lipophilic statin pitavastatin attenuates chronic inflammation and improves the imbalance of adipocytokines, thus preventing the development of colonic premalignancies in C57BL/KsJ-db/db (db/db) obese mice (Cancer Sci. 2010 Mar 24).

Atorvastatin inhibits intestinal tumorigenesis especially when given together with low doses of celecoxib in APC(min) rodent model (Cancer Res. 2006 Jul 15;66(14):7370-7)

Studies in severe combined immunodeficiency (SICD) mice show that simvastatin delays the development of EBV-lymphomas in these animals (Br J Cancer. 2005 May 9;92(9):1593-8).

Cancer Treatment -

Low-dose simvastatin increased necrosis and apoptosis in an orthotopic mouse glioblastoma (GL-26) model (Anticancer Res. 2009 Dec;29(12):4901-8.).

Combination of atorvastatin and celecoxib prevented prostate cancer progression from androgen dependence to androgen independence in a mouse model (Cancer Prev Res (Phila Pa). 2010 Jan;3(1):114-24).

Simvastatin exhibited impairment of xenograft K562 chronic myelogenous leukemia (CML) cell growth in nude mice and also blocked cell cycle in G(1) phase (Chemotherapy. 2008;54(6):438-46).

Lovastatin inihibted tumor growth and lung metastasis in a mouse model of metastatic mammary cancer with a p53 mutation demonstrated by inoculating syngeneic BALB/c mice with BJMC3879 cells (Carcinogenesis. 2004 Oct;25(10):1887-98)

Clinical (human evidence):

Unlike the unequivocal in vitro and animal studies demonstrating clear-cut benefit of statins against a wide array of cancers, there is relative few data from the clinical arena.  In the early 2000s, there was actually a concern that statin use may be associated with an increased risk of cancer, but analyses of several large statin studies in cardiovascular diseases dispelled the concern. Human studies can be generally divided into the use of statins as a chemopreventative to prevent cancer or as an adjuvant to treat actual cancer. While a lot of effort in terms of direct studies and meta-analyses have been devoted to finding a correlation of statin use and cancer incidences, and while risk reductions of 48% – 90% were found for breast, colon and prostate cancers in retrospective case-control studies, these are by no means a final reliable statistic.

Breast Cancer - In a review by Kochhar and team of 40,421 females,  statin use was associated with a 51% risk reduction of breast cancer after controlling for age, smoking, alcohol use, and diabetes (J Clin Oncol 23: 7S, 2005 [suppl, abstr 514]). In the same vein, Kwan et al. observed that breast cancer patients who took statins after diagnosis were less likely to have had recurrences than were patients who did not take stains (Breast Ca Res Treat. 2008 Jun;109(3):573-9).  In 2008, Kumar et al. made the interesting observation that women on statins who develop breast cancers develop less aggressive cancers which are of lower grade and less invasive (Cancer Epidemiol Biomarkers Prev. 2008 May;17(5):1028-33.). Subsequently, Garwood et al. from UC San Francisco performed an interesting perioperative window trial of fluvastatin in 40 women with a diagnosis of DCIS or stage 1 breast cancer. Patients were randomized to high dose (80 mg/day) or low dose (20 mg/day) fluvastatin for 3-6 weeks before surgery and the research team found that the short treatment caused measurable favorable biologic changes by reducing tumor proliferation in high-grade, stage 0/1 breast cancer but not DCIS (Breast Ca Res Treat. 2010 Jan;119(1):137-44).

Colorectal Cancer – Researchers from the University of Michigan, collaborating with researchers in Israel, compared the use of statins among 1,953 patients with colorectal cancer and 2,015 other people who did not have the disease. This study specifically associated a 47 percent reduction in the risk of colorectal cancer with statin use (Poynter, JN., et al. New England J Med,. May 26, 2005, 352:2184–92)

Hepatocarcinoma -  A first study showing risk reduction of liver cancer from statin use was reported by El-Serag et al. from Baylor in 2009 where the risk reduction observed with statin use ranged was as high as 40% (Gastroenterology. 2009 May;136(5):1601-8). And as far as statins as an adjuvant therapy for liver cancer, Kawata et al. from Osaka reported their controlled trial in 91 patients with unresectable hepatocarcinoma randomly assigned to standard care v. standard care plus 40mg of daily pravastatin.  The result revealed that survival was doubled ( 18 v. 9 mos) for patients receiving pravastatin (Br J Cancer. 2001 Apr 6;84(7):886-91)

Graf et al. from Germany 183 HCC patients who had been selected for palliative treatment by transarterial chemoembolization (TACE). Fifty-two patients received TACE combined with pravastatin (20-40 mg/day) and 131 patients received chemoembolization alone. Six independent predictors of survival according to the Vienna survival model for HCC were equally distributed in both groups. RESULTS: During the observation period of up to 5 years, 31 (23.7%) out of 131 patients treated by TACE alone and 19 (36.5%) out of 52 patients treated by TACE and pravastatin survived. Median survival was significantly longer in HCC patients treated by TACE and pravastatin (20.9 months, 95% CI 15.5-26.3, p = 0.003) than in HCC patients treated by TACE alone (12.0 months, 95% CI 10.3-13.7) (Digestion. 2008;78(1):34-8)

Lung Cancer – Use of statins for more than 6 months reduced the risk for lung cancer by 55%, according to the results of a large scale case-control study involving almost a half million patients, published in the May 2007 issue of Chest. (Chest, 2007;131:1282-1288). What was intriguing was that longer duration of statin use was associated with enhanced risk reduction, rising from 55% to 77% for those who have been on statins for 4 years or more.

Prostate Cancer – Until only several years ago, only a handful of observational studies found statin use to be associated with reduced prostate cancer risk, though others found no association. By 2008 however, four large prospective studies (e.g. the California Men’s Health Study) have since observed similar reductions in the risk of advanced prostate cancer, although there was no reduction in the risk of overall prostate cancer.  For example, a meta-analysis of 19 studies [6 randomized clinical trials (RCTs), 6 cohort and 7 case-control studies] found that while long-term statin use did not seem to contribute to a reduced incidence of prostate cancer, statins did seemed to confer a protective effect in advanced prostate cancer (RR = 0.77, 95% CI: 0.64-0.93) (Int J Cancer. 2008 Aug 15;123(4):899-904).

As for statin use in patients who have had prostate cancer, a study examining statin use in close to 1000 patients with localized prostate cancer treated with brachytherapy found patients on statins to have lower PSAs and % positive biopsies than controls (Urol Nurs. 2006 Aug;26(4):298-303). The results were corroborated by Zelefsky et al’s recent report from Memorial Sloan-Kettering Cancer Center that high risk prostate cancer patients who have undergone radiotherapy had an improved PSA-relapse free survival and concluded that “data suggest that statins have anticancer activity and possibly provide radiosensitization when used in conjunction with radiotherapy in the treatment of prostate cancer” (Int J Radiat Oncol Biol Phys. 2010 May 6).  A meta-analysis of 19 studies [6 randomized clinical trials (RCTs), 6 cohort and 7 case-control studies] found that while long-term statin use did not seem to contribute to a reduced incidence of prostate cancer, however statins seemed to confer a protective effect in advanced prostate cancer (RR = 0.77, 95% CI: 0.64-0.93) (Int J Cancer. 2008 Aug 15;123(4):899-904). And most recently, a retrospecitive report on 23,320 patients in the Finnish prostate cancer screening trial found lower prostate cancer incidence in statin users (Int J Cancer. 2010 Jan 13)

And the latest study:  in the upcoming Jul 15th 2010 issue of Cancer, data from Duke by Stephen Freedland’s team show that in a series of 1300+ men who had prostatectomy for prostate cancer, there is a 30% lowered chance of recurrence for those patients who took statins.  Intriguingly, men who took the highest doses saw their recurrence risk drop 50%. In 300 men with biochemical recurrences during the follow-up,  16% were on statins vs. 25% who were not.

Myeloma – In a small European phase 2 study involving six myeloma patients refractory to two cycles of bortezomib or bendamustine, simvastatin was concomitantly administered during further cycles. Observation showed reduction of drug resistance by simvastatin (Eur J Haematol. 2007 Sep;79(3):240-3).

Potential synergies with other anti-cancer agents

This is a particularly interesting area. Perhaps because of the pleiotropic effects of statins themselves, it may influence the efficacy of many other anti-cancer or potential anti-cancer agents, either via biological synergism or by affecting the blood levels of some agents.  Although most of the studies represent in vitro work, such insights set a potential foundation for rational planning of a cocktailed approach against cancer.  Some representative research illustrating statin synergy potentials are as follows:

- potentiates sorafenib (Nexavar) cytotoxicity (Cancer Lett. 2010 Feb 1;288(1):57-67)

- synergizes with  , the cox-2 (Celebrex) inhibitor, against colon cancer (Int J Oncol. 2009 Nov;35(5):1037-43; also Int J Cancer. 2010 Feb 15;126(4):852-63)

- synergizes with sulindac (NSAID) against colon cancer (Gastroenterology. 1999 Oct;117(4):838-47)

- synergizes with gamma tocotrienols against breast cancer (Exp Biol Med (Maywood). 2009 Jun;234(6):639-50)

- enhances the all-trans retinoic acid (ATRA)-dependent antileukemic response in acute promyelocytic leukemia (Mol Cancer Ther. 2009 Mar;8(3):615-25)

- synergistic inhibition of lung tumorigenesis with green tea polyphenols (Clin Cancer Res. 2008 Aug 1;14(15):4981-8)

- potentiation of the effects of lenalidomide against myeloma (Leuk Res. 2009 Jan;33(1):100-8), and thalidomide as well (Eur J Clin Pharmacol. 2006 Apr;62(4):325-9)

- synergistic with an m-TOR inhiitor against acute leukemia (Anticancer Drugs. 2008 Aug;19(7):705-12)

- enhances the cytotoxic and apoptotic effects of doxorubicin chemotherapy against human colon cancer cells and in murine tumor models (Oncol Rep. 2008 May;19(5):1205-11)

- enhances the antiproliferative effects of gemcitabine chemotherapy against pancreas cancer in vitro (Br J Cancer. 2005 Aug 8;93(3):319-30)

- synergism with paclitaxel (Taxol) chemotherapy in K52 and HL60 cell lines (Mol Cancer Ther. 2001 Dec;1(2):141-9)

- potentiates cisplatinum against MmB16 melanoma in rodent model (Gastroenterology. 1999 Oct;117(4):838-47)

- potentiation anti-tumor effects of pamidronate (bisphosphonate) in vitro and in vivo (Int J Oncol. 2007 Jun;30(6):1413-25)

- synergizes with zoledronic acid (Zometa, a bisphosphonate) against myeloma (Anticancer Drugs. 2006 Jul;17(6):621-9)

- enhances trastuzumab (Herceptin) in breast cancer cell lines (Breast Cancer Res Treat. 2007 Jul;104(1):93-101)

- potentiates the effect of saquinavir against Daudi and Raji human lymphoma cells (Oncol Rep. 2004 Dec;12(6):1371-5)

- synergism with tamoxifen (Cardiovasc Res. 2004 Nov 1;64(2):346-55)

- synergistic effect with troglitazone (PPAR agonist) in majority of cell lines tested including DBTRG 05 MG (glioblastoma) and CL1-0 (lung) (Int J Cancer. 2006 Feb 1;118(3):773-9).

- synergizes with HDAC inhibitors against mice Lewis lung cancer model (Int J Cancer. 2002 Feb 20;97(6):746-50); and with phenylacetate against human glioma cells (J Neurochem. 1996 Feb;66(2):710-6).

- potetiation of photocytotoxic effect of photofrin II (Bull Acad Natl Med. 1994 Jun;178(6):1177-88)

- synergizes with TNF alpha against MmB16 melanoma (Neoplasma. 1995;42(2):69-74)

… and the list goes on.

My take

Notwithstanding occassional contradictory reports of statins increasing the risk of cancer, I feel strongly that given the safety (simvastatin is available as an OTC in the U.K.) and low cost of statins, plus the wide array of studies and accumulating data showing a protective effect of statins against cancer development and recurrence, statins should be seriously considered as part of a cocktailed approach for primary and secondary cancer prevention (especially for colon, breast, lung and prostate – where the data is strongest).  It should also be seriously considered as a cornerstone ingredient to combine synergistically with other compounds such as gamma tocotrienols, cox-2 inhibitors, bisphosphonates etc for added effects in cancer treatment.  Not all statins are the same however, and some (e.g. lipophilic statins such as simvastatin) may work better against certain cancers than others (e.g. hydrophilic statins such as pravastatin).  Dosage may be important as well.  Unfortunately, because most of the statins have patents that are expired or near expiration, there is a lack of incentive on the part of drug companies to conduct large scale clinical trials using these agents against cancer, so it is not clear that we will gain much more useful clinical insight in the near future, but I believe that these are nearly no-brainer drugs to add to most cancer preventative or treatment cocktails unless side-effects are an issue in an individual patient. Your comments welcome.

Theophylline for Leukemia/Lymphoma

Advanced comments welcome … In the process of reasearch and writing up, thank you for your patience !

Disulfiram (Antabuse) for cancer

Disulfiram (Antabuse) is an old thiocarbamate drug known to support the treatment of alcoholism and cocaine dependency. Unlike Naltrexone which is also used for alcoholism, its potential usefulness is cancer is well researched but curiously little publicized (Naltrexone is conversely little researched and well publicized ! Will discuss in this blog).  I am in fact quite impressed by the numerous documented investigations into Disulfiram’s use as an anti-cancer when I first investigated its potential in this area.

Schirmer and Scott seemed to have been the earliest to notice a relationship of disulfiram and tumor inhibition (Trans Am Assoc Genitourin Surg. 1966;58:63-6.), and subsequently Wattenberg was able to demonstrate that the dietary disulfiram inhibited DMH chemical induction of bowel cancer in mice  (JNCI, 1975 Apr;54(4):1005-6). Eventual research since the 70s have demontrated that disulfiram can block the P-glycoprotein extrusion pump and thus reduce drug-resistance, inhibits the transcription factor nuclear factor-kappaB, reduces angiogenesis, and inhibits tumor growth in cell lines and rodents.

Now where is the evidence?

a) In Vitro (cellular evidence):

Disulfiram inactivates the ability of the Rous sarcoma virus to malignantly transform chick embryo cells.

Disulfiram potentiated the cytotoxicity of nitrogen mustard and 5FU chemotherapy effects on leukemia and colorectal cells respectively.

Disulfiram can potentially reduce P-glycoprotein (P-gp) mediated drug resistance by inhibiting P-gp activity (possibly via cysteine modification) and/or by blocking its maturation (JNCI 2000 Jun 7;92(11):898-902).

Disulfiram induces apoptosis in melanoma cells (Mol Cancer Ther 2002 Jan;1(3):197-204).

Disulfiram inhibited invasion and angiogenesis of both tumor and endothelial cells possibly via interactions with MMP-2 and MMP-9 and inhibiting their proteolytic activity through a zinc related mechanism (Mol Pharmacol 2003 Nov;64(5):1076-84).

Disulfiram, as a member of the metal-chelating group of dithiocarbamate compounds, is able to bind with tumor cellular copper, forming an active complex with proteasome-inhibitory, apoptosis-inducing and anti-cancer activities. (Int J Mol Med 2007 Dec;20(6):919-25)

Disulfiram inhibited expression of metalloproteinases MMP-2 and MMP-9 and suppressed the invasion of human osteosarcoma cells. (J. Biochem Mol Biol 2007 Nov 30;40(6):1069-76)

b) In Vivo (animal evidence)

Dietary disulfiram inhibits chemical induction of intestinal (colon), bladder and breast cancer in rodents.

Disulfiram reduced ifosfamide-induced nephrotoxicity in rodents.

Disulfiram potentiated the cytotoxicity of nitrogen mustard chemotherapy in rodents (Cancer Res. 1989 Dec 1;49(23):6658-61).

c) Clinical (human experiences)

Roemeling et al. reported that human beings given 2 g of oral disulfiram at a particular time of day and high doses of cisplatin had lesser kidney toxicity. Disulfiram administration also apparently does not interfere with the antineoplastic activity of cisplatin (Chronobiol Intl 1986;3(1):55-64). Based on such evidence, a phase I and II study of cisplatinum and disulfiram was carried out which however overturned the hypothesis that disulfiram afforded nephroprotection in platinum chemotherapy (Am J Clin Oncol. 1990 Apr;13(2): 119 -24).

More recently in 2004, a first clinical report using a combination of oral zinc gluconate and disulfiram at approved doses for alcoholism induced >50% reduction in hepatic metastases and produced clinical remission in a patient with stage IV metastatic ocular melanoma, who has continued on oral zinc gluconate and disulfiram therapy for 53 continuous months with negligible side effects.

There is currently ongoing clinical trials of disulfiram with copper gluconate against liver cancer in Utah (ClinicalTrials.gov Identifier: NCT00742911) and of disulfiram as adjuvant against lung cancer in Israel (ClinicalTrials.gov Identifier: NCT00312819).

My take

This drug long known as a treatment for alcoholism found recent revival of interest as an anticancer and this has recently been reviewed by ZE Sauna et al. of the National Cancer Institute (Mol Biosyst 2005 Jul; 1(2): 127-34.  Epub 2005 May 26.)  Although there are no significant completed clinical trials to mention, both in vitro and animal data are supportive of its use, especially in melanoma and in conjunction with certain chemotherapies (eg 5FU), in cases of potential chemo-resistance, and as an anti-angiogenic perhaps in conjunction with Zinc gluconate.

It is not a totally hassle- free drug to prescribe though:

The initial dose is 500 mg for 1 to 2 weeks, followed by a maintenance dose of 250 mg (range 125 mg–500 mg) per day. The total daily dosage should not exceed 500 mg.  It is known to be a drug with moderate side-effects.  Of course, side-effects could be provoked if taken with alcohol, hence its use to support detox for alcohol dependence.  But other significant side-effects include hepatitis (1 case in 30,000 treated/yr), and neurologic. There are rare reports of psychosis and confusional states and peripheral nse effects, tiredness, headache and sleepiness are the most common.  Due to its CNS activity, drug-drug interaction is also an issue:

Drugs that may interact with disulfiram include, but are not limited to:

• Bupropion (Wellbutrin IR/SR/XL, Amfebutamone)
  
• Amphetamines (Adderall, Dexedrine, etc.)
• Methylphenidate (Ritalin, Concerta, Focalin, etc.)
• Cocaine (Occasionally used in dental procedures, and a known substance of abuse.)

The metabolism of other drugs may be inhibited by disulfiram, increasing their potential for toxic effects. Drugs known to have adverse effects when used concurrently with disulfiram include amitriptyline, isoniazid, and metronidazole (all with acute changes in mental state), phenytoin, some benzodiazepines, morphine, pethidine, and barbiturates.

Dipyridamole for cancer

Dipyridamole (Persantine, Persantin), a synthetic derivative of pyrimido-pyrimidine, with antiplatelet properties as a phosphodiesterase inhibitor that inhibits adenosine uptake by platelets and endothelial cells. It is an older, low toxicity and inexpensive drug that is widely used as an anti-thrombotic, with or without aspirin, to prevent recurrent strokes and heart attacks, as well as clotting associated with artificial heart valves.  It works as an anti-aggregating agent against platelets. It has other off-label potentials as a drug for schizophrenia, mania and arthritis.  It has long been researched against cancer and is has potential clinical anticancer properties. It is in fact listed on the NCI website as an agent which enhances chemotherapy cytotoxicity againt cancer but it remains seldom known or used in cancer.  Why it is not more frequently prescribed in puzzling.

A strong hint for an anti-cancer effect of dipyridamole came with the publication of the European Stroke Prevention Study in the Lancet 1987 (Dec 12;2(8572):1351-4).  Dipyridamole in addition to aspirin was administered to patients who had a stroke and observed for two years.  At the end of the study, the investigators observed that patients given dipyridamole in addition to aspirin has a 50% reduction in stroke mortality and a 38% reduction in fatal heart attacks.  Surprisingly, cancer mortality was also reduced by 30%.   At the time, it was hypothesized that dipyridamole inhibited cancer metastases by inhibiting tumor cell attachment to the vascular lining. That an antiplatelet or antithrombotic may have anticancer effects is not a new concept, and was proposed as early as 1958.  By 1964, it has been reported (Michaels, L. Lancet, Oct 17;2(7364):832-5) that coumadin, an anti-thrombotic, could reduce the mortality of lung cancer. And now we know that antithrombotics such as hydroxychloroquine (also an anti-malarial, and more on antimalarial’s off-label potential as anti-cancer in a later blog) and the non-steroidal anti-inflammatory drug aspirin as well as the blood thinner heparin may also reduce cancer risk or improve cancer survival, but these would be topic drugs for future posts in this blog. [ If interested in the possible inhibition of cancer metastases by anticoagulants, a thorough review by Hejna could be a starting point ( J Natl Cancer Inst 6:91, pp.22-36, 1999)]

Now where is the evidence?

a) In Vitro (cellular evidence):

Dipyridamole augments the cytotoxicity of chemotherapeutic agents Cisplatinum, Etoposide, Adriamycin, 5FU, FUDR, Methotrexate, Vinblastine, and the biological agent interferon, in part by inhibition of the efflux of the cytotoxic drugs.  It may therefore have application in helping circumvent multi-drug-resistant tumor cells.

Dipyridamole sensitizes cancer cells to TRAIL-induced apoptosis (Goda, AE et al. Oncogene 27, pp.3435-45, 2008)

Dipyridamole reduces invasiveness of various malignant cells in culture (Larabeke,N et al. Clin Expl Met 7:6, pp. 645-657, 1989)

In Vivo (animal evidence):

Dipyridamole prevents pancreas cancer metastasis in mice (Tzanakakis GN et al., Cancer 71:8, pp. 2466-71, 1993)

Combined treatment of adriamycin and dipyridamole inhibited lung metastasis of B16 melanoma cells in mice.

In an animal model of human bladder cancer, dipyridamole serves as a chemosensitizer of both CDDP and 5FU chemotherapy. (Urol. 1991 Nov;146(5):1418-24)

Clinical (human evidence):

Some of the earliest observations come from Dr. E.H. Rhodes of the St. Hiler and Kingman Hospital in England who reported in the Lancet (1985 Mar 23;1:693) on treating melanoma with dipyridamole. Thirty melanoma patients were maintained on dipyridamole over a period of 11 years. Of them, 26 with Clark’s level IV disease had a five-year survival of 74% compared with an expected (in the U.K.) 32%. Years into her retirement, Dr. Rhodes still felt that other solid tumors besides melanoma would be helped by dipyridamole as well (See Second Opinions).

More than  decade on, a Japanese team reported that treatment of advanced gastric cancer with chemotherapy modulated by dipyridamole ( 4mg/kg/d) appeared to be effective, safe and well tolerated. Int J Oncol. 1998 Dec;13(6):1203-6.

A phase I trial demonstrated that bioactive serum concentration of dipyridamole can be achieved in vivo, and that dipyridamole has significant effects on the pharmacokinetics of VP-16 chemotherapy.

Somewhat more recently, the team at UCLA examined dipyridamole with 5FU/LV and mitomycin chemotherapy for unresectable pancreas cancer and in 1998 reported a 39% response rate and 70% one-year survival rate in 38 patients.  Of the group, 27% of patients underwent curative resection after therapy and their one year survival rate was 83% with one patient still alive after 4 years at the time of the report (J Gastrointest Surg. 1998 Mar-Apr;2(2):159-66). A Japanese team modified the UCLA protocol and added heparin and gemcitabine to achieve an 83% response rate with 60% subsequently undergoing curative resection, albeit in a very small group of patients (Gan To Kagaku Ryoho. 2004 Sep;31(9):1365-70). A very recent continued phase II investigation of the original UCLA protocol by the same team reported  “potential improvement in survival and resectability of localized unresectable pancreatic without radiation” and recommended further studies (J Clin Oncol. 2007 May 1;25(13):1665-9)

Unfortunately though, a number of very small trials examining the potential usefulness of dipyridamole to enhance chemotherapeutic efficacy in sarcoma, colorectal, breast, renal cell, and prostate cancers failed to show meaningful improvement in response.

My take

Given the safety and low cost of dipyridamole, I think that it can be considered as part of a cocktailed approach to cancers, especially melanoma and pancreas cancer.  For such cancers, I think it is reasonable to consider dipyridamole as a secondary preventative to minimize metastases and optimize survival as well.  More studies on various anti-thrombotics for cancer should be attempted.  And specifically for dipyridamole, hopefully larger and more rigorous trials could be done with newer dipyridamole derivatives with enhanced efficacy (and more incentive for drug companies to develop what would be considered a patentable and new agent).

Cimetidine for cancer

One of the commonest and cheapest of over-the-counter medicines, cimetidine (Tagamet®) is an anticancer?  This is one of the most surprising things to most of my patients, and I believe that many of my oncology colleagues don’t know this one either!

The following is the most comprehensive review of cimetidine use in cancer that one can currently find online.

Cimetidine, an H2-antagonist whose research and development as an stomach acid inhibitor for the treatment of peptic ulcers started its life in the early 60′s, and was approved and marketed from the 70′s as a treatment for heartburn and stomach ulcers. It went on to become the first drug to hit a billion US dollars per year sales and was a true block buster.  I still remember ordering it for patients with acute intestinal bleeding as an intravenous injection when I was training as a resident.

This is a particularly interesting drug from an off-label perspective, because it has been study for a large range of off-label uses, including for parathyroid storm, warts, herpes (shingles), weight loss, fibromyalgia, hives, HIV, conjunctival papillomatosis and irritable bowel syndrome.  There is also an accumulation of evidence suggesting that cimetidine enhances immune responsiveness (accounting at least in part for its potential use as an antiviral and for cancer).

Cimetidine for cancer?

Cimetidine’s possible anti-tumor action has been noticed as early as 1979 ( Also see below; Armitage JO and Sidney RD, Antitumor effect of cimetidine, Lancet 1(8121), pp. 882-3, 1979), the same year it was approved for use by the US FDA.  And reports of cimetidine’s immunomodulatory actions were soon after reported and it was about the same time that growth of colorectal cancer was reportedly retarded in vitro by cimetidine (JNCI, 67:6, pp. 1207-11, 1981). Since then, it has been demonstrated to possess anti-tumor activity against colon, gastric and kidney cancers, and melanomas. This activity involves a number of different mechanisms of action: a) it acts against metastases via inhibition of tumor cell adhesivenes; b) histamine acts as a growth factor in various tumor cell types via the activation of H2 receptors; and cimetidine antagonizes this effect as an anti-histamine; c) Cimetidine acts as an immunomodulator by enhancing the host’s immune response to tumor cells, via inhibition on T-cell suppressor activity; d) acts as an antiangiogenic.

a) In vitro (test tube) evidence:

Cimetidine and inhibit Caco-2 cancer cells in vitro, independently of the H2 receptor.

Cimetidine enhances the efficacy of 5 FU chemo on colon cancer SW620 cells.

Cimetidine was able to block the adhesion of gastric, esophageal and breast cancerto vascular endothelium via suppression of e-selectin (Gan To Kagaku Ryoho. 11, pp.1788-90, 2003. Japanese).

In vitro study on the effects of cimetidine on differentiation and antigen presenting capacity of monocyte-derived dendritic cells derived from advanced colorectal cancer patients suggest that cimetidine may enhance the host’s antitumour cell-mediated immunity by improving the suppressed dendritic cells function of advanced cancer patient (Br J Cancer 86:8, pp.1257-61, 2002).

b) In vitro (animal) evidence:

Suppresses VEGF and exerts antiangiogenic action on growth of colon cancer implants in mice (Tomita, K 2003; Natori T, 2005).

Tagamet added to chemo was superior in vivo when compared to chemo alone in extending survival of nude mice with human glioblastoma (Lefranc F et al. Int J Oncol 28:5, pp. 1021-1030, 2006)

Cimetidine diminished tumour proliferation in immunodeficient mice xenotransplanted with a human melanoma cell line.

Cimetidine antagonised the trophic effect of histamine on colorectal cancer cell lines in vivo and in vitro, possibly mediated via tumour histamine type 2 receptors

Cimetidine synergistically enhanced IL-2-induced NK and LAK cell activities in tumor-bearing rodents, and significantly prolonged their survival.

c) Clinical (human) evidence:

Armitage and Sidney first reported on possible anticancer effect of cimetidine in humans (Lancet, 1979) but they didn’t know why it would work.  They had two cases of cancer. One was a man with a head and neck cancer with presumed lung metastases but refused chemotherapy.  On cimetidine alone for tummy upsets, his metastases disappeared after two years.  The second case was a woman with metastatic lung cancer to the brain who was placed on cimetidine for heartburn and whose cancer grew smaller.

In 1982, four cases of metastatic melanoma responding to cimetidine alone was reported, and this was followed by a report from Sweden than cimetidine administered to six metastatic melanoma patients who were not responding to interferon alone resulted in complete remission in 2 and response/stability in another 2.  Subsequent reports on cancers of the oesophagus, stomach, liver, ovary, kidney and gallbladder treated with cimetidine noted improvement in 5 out of 7 cases.

Many investigative uses of cimetidine for cancer revolved around colorectal patients. Svendsen LB and colleagues from Denmark were one of the first to report on cimetidine as an adjuvant treatment in colon cancer where there seemed to be a survival benefit for those patients with Duke’s C disease but not for those who had disseminated disease (Dis Colon Rectum 38:5, pp. 514-8, 1995). An Australian team published in the same year a small trial of chemo plus cimetidine vs. chemo alone in metasatatic colon cancer and found a 36% CEA response in the cimetidine arm vs. 0% in the control (Eur J Clin Onc 21:5, pp/ 523-525, 1995). Four years later, the same team did a remarkable randomized controlled study showing that 800mg of cimetidine twice daily for only 5 days preoperatively appeared to have had a positive effect on colorectal cancer patient’s survival (Kelly MD et al. Cancer 85:8, pp.1658-1663, 1995). The best supportive evidence comes from Sumio Matsumoto of Japan. He conducted a clinical trial using 800mg / day of cimetidine for one year in patients with colorectal cases receiving 5-FU chemo after surgery (See Lancet 346, p.115, 1995, also Br J Cancer 86:1,  pp.162-167,2002).  His results were more positive than that reported by the Danish (see above) where at four and ten years, survival in the cimetidine treated patients was 96.3% and 84.6%, compared to 68.8% and 49.8% (p<0.0001) respectively. In patients with cancer of the rectum the results were even better: all of the cimetidine-treated patients were still alive at four years compared to only just over half of the controls.  The Japanese found that survival benefit was seen mainly with tumors expressing sialyl Lewis antigens X and A suggesting an immunomodulatory or cellular adhesion effect of cimetidine (Gan To Kagaku Ryoho. 11, pp.1788-90, 2003).  Another Japanese group recently examined the effect of cimetidine for recurrent colorectal cancer but found found no effect on survival, unless the recurrences was resected (Gan To Kagaku Ryoho 33:12, pp.1730-2, 2006).

Mixed results of efficacy were reported against renal cell cancer: Both American and Japanese reports mentioned complete response to cimetidine treatment alone (Am J Clin Oncol 15:2,pp.157-9, 1992; Nippon Hinyokika Gakkai Zasshi. 87:10, pp.201-4, 1996), and a Japanese study of combined interferon and cimetidine yielded a “definitively good” 40% response (J Urol 157:5,pp.1604-7, 1997), yet more recent trials yielded minimal responses (Am J Clin Oncol 21:5, pp.475-8, 1998).  Studies found no effect of cimetidine on gastric (Br J Cancer 81:9, pp.1356-62, 1999) or hormone refractory prostate cancers (Prostate 17:2, pp.95-9, 1990).

My take

Given its low toxicity and low cost, cimetidine can probably be administered to patients with colorectal cancer and possibly other adenocarcinomas that express the Sialyl Lewis antigens to minimize metastases and recurrence and enhance survival.  Enough supportive data also exist for routinely adding cimetidine in a cocktailed approach to melanoma and renal cell cancers patients. In more recent work, the demonstration that cimetidine may enhance dendritic cell function (See above) suggest that cimetidine should be routinely included in patients undergoing dendritic cell therapy.

Any downsides or concerns?

Generally not, but cimetidine does have occassional side-effects and the drug has a long list of potential interactions that one has to be careful about, and its use in cancer should be under the guidance of a professional.  I do have a concern for use of cimetidine in breast cancer because of its effect to increase serum prolactin which could stimulate breast cancer, although multiple epidemiologic studies have not demonstrated any higher incidence of breast (or other) cancers in cimetidine users (Cancer Epidemiol Biomarkers Prev 17:1, pp.67-72, 2008).

Why not more research?

The simple reason has to do with money and incentive in this capitalism-dominant world we live in.  The patent for cimetidine has long expired and it is a lowly over-the-counter drug these days and drug research (especially trials) is prohibitively expensive.  No drug company in its right mind would spare funds to study a drug they do not own just for the sake of benefitting mankind. It would be up to universities, government research centers, and other non-profits to pursue which is why the more recent studies are mostly from coutries (eg Japan, Scandanavia, China) with socialized healthcare systems and/or low cost to do trials and whose governments may be more interested in saving money ( read: looking for cheaper alternatives) to study this kind of “lowly” drug.  It is unfortunate but a reality in the world we live in.

Gossypol (棉酚) for cancer

This is an unusual one because Gossypol it is not yet approved for us in the US or Europe.  However, notwithstanding approvals or not, it is developed mainly as a male contraceptive.  As such its potential application as a cancer therapy is vastly interesting and can loosely be classified as “off-label”.

What is Gossypol?

Gossypol is a polyphenolic compound isolated from the seeds, stems, and roots of the cotton plant (genus Gossypium, family Malvaceae; pls feel free to search under these in our Asian Anti-cancer Herbs database for more research data). It was discovered during the late 1960s, when people in rural China complained of fatigue attributable to exposure to cotton seed oil.  Years later, many couples had fertility problems despite reduced exposure to the oil. The finding that exposure to cotton seed oil was related to lowered sperm counts in men exposed led to the hypothesis its active ingredient Gossypol could be used as a male fertility-control agent, which is gossypol’s main pharmacologic application now.   Of course, a natural line of thinking with an agent that may inhibit dividing or growing cells such as sperm would lead one to query if it may have chemotherapeutic properties that may be applicable in cancer, so this is where the idea of Gossypol for cancer arises.

And where is the evidence?

a) In Vitro (cellular evidence):

Russian scientist Vermel EM et al. reported on the anti-cancer activity of gossypol in animals as early as 1963 and Jolad SD et al reported in 1975 (J Pharm Sci 64:11, pp.1889-1890, 1975) that Gossypol extracted from Montezuma speciosissima Sesse and Moc. demonstrated tumor-inhibiting properties in the P-338 lympocytic leukemia test system (3PS).

Gossypol promotes apoptosis of breast, bladder, lymphoma, leukemia (CML and CLL), myeloma, prostate, colorectal, alveolar cell lung, glioma, pancreas, melanoma, nasopharyngeal, and head and neck squamous cell cancers.  A preponderance of the research reported on efficacy against hematologic cancers and prostate cancer.

Gossypol was known in the 1990s as a compound which depleted cellular energy by inhibition of intracellular dehydrogenases. More recently, (-)-Gossypol, now understood to be a natural BH3 mimetic, is found to be a small-molecule inhibitor of Bcl-2/Bcl-xL/Mcl-1, possibly exerts its antitumor activity through inhibition of the antiapoptotic protein Bcl-xL accompanied by an increase of proapoptotic Noxa and Puma (Meng Y, et al. Mol Cancer Ther, 7:7, pp. 2192-2202, 2008). A separate line of evidence suggests that Gossypol may exert its apoptotic effects via downregulated expression of NF-kappaB-regulated gene products, including inhibitor of apoptosis protein IAP-1, IAP-2, and X-linked IAP (Moon DO, et al. Cancer Lett 264:2, pp.192-200, 2008).

It is also known as a protein kinase C inhibitor.

Besides direct anticancer action, it enhances anti-tumor activity of chemotherapy against lymphoma, modulates multi-drug resistance gene expression in human breast cancer cells, and enhanced breast cancer sensitivity to Tamoxifen as well as Adriamycin.

In Vivo (animal evidence):

Testing of gossypol on tumor growth and the survival of 10- to 12-week-old BDF1 mice bearing injected mammary adenocarcinoma 755 (Ca 755) or P388 or L1210 leukemias was investigated and reported as early as 1985.

Gossypol enhances prostate cancer response to radiation therapy (mice), enhances chemotherapy against diffuse large cell lymphoma in WSU-DLCL2-SCID mouse model pre-clinical testing.

Many other reports of in vivo activity of Gossypol against transplanted tumors in rodents exists.

Clinical (human evidence):

Much clinical experience of Gossypol’s anticancer use and demonstration of its efficacy has been accumulating in the past 20 years.

One of the earliest trials was reported from the U.K. (Stein RC, et al. Cancer Chemother Pharmacol 30:6, pp. 480-2, 1992) where advanced cancer patients were given Gossypol, but benefit was not seen.

In 1993, the NIH published a trial of oral Gossypol using doses of 30-70 mg a day in metastatic adrenal cancer patients where 30% of eligible patients had some reponse to therapy (Flack MR et al., J Clin Endocrinol Metab 76:4, pp. 1019-24, 1993). A study was also carried out using low dose Gossypol of 10mg twice a day on adults with heavily pre-treated, poor prognosis recurrent malignant gliomas and found approximately 25% with some response including one patient who remained stable with improved quality of life for one and a half years. More importantly, toxicity was found to be mild.

Around the same time, a Phase I/II clinical trial of Gossypol against refractory metastatic breast cancer was carried out at Memorial Sloan-Kettering in New York  ( Van Poznak C, et al. Breast Cancer Res Treat, 66:3, pp. 239-248). Doses were in the 30-50mg per day range with 30% of patients experiencing fatigue, 15%, nausea/vomitting, and diarrhea in 10%.  Antitumor activity was seen with a 15% response/stability rate.

Significantly, long-term clinical remission of a patient with chronic lymphocytic leukemia using gossypol was reported. (Politzer, Phytomedicine 15:8, pp. 563-5, 2008)

So What’s new?

Gossypol is currently the only orally bioavailable pan-Bcl-2 inhibitor under clinical investigation.

In the US, phase I/II clinical trials are currently ongoing or planned with gossypol under the product code “AT-101″ by Ascenta Therapeutics as an adjuvant therapy for human prostate cancer.  A small trial of the product in 23 men with prostate cancer who were chemo-naive but had rising PSA and who took 30mg of product for 21 out of 28 days over 20 to 24 weeks noted decreases in PSA parameters in some.  5 out of the 23 patients had to discontinue the drug because of gastrointestinal side-effects (ileus).  Last summer, Ascenta also presented preliminary data indicating that AT-101 has activity in combination with taxol and prednisone in advanced prostate cancer.

The biotech firm Bioenvision (now owned by Genzyme) was in collaboration with Bowman Research to develop a process to separate and purify more efficacious but less toxic iso-forms of gossypol, but the isoforms are not currently in the company’s development pipeline.

My Take

This is a fairly low toxicity and inexpensive natural derivative that can be used in combination with chemotherapy or other anti-apoptotic agents for a wide-range of cancers but appear especially promising for prostate, breast and B-cell hematologic malignancies.   The main concern here is side-effects which include fatigue, nausea/vomitting, diarrhea, and ileus.  Side-effects can be managed by individualized dosing and schedule adjustments. The long-term concern of infertility in males should be considered in young male patients.  The lack of bone marrow suppression makes it a good agent to combine with with chemotherapies.  The potential usefulness of an agent like this points the way to screen other anti-fertility herbs in traditional pharmacopoeias for other potentially useful anti-cancers.  Additionally, this interesting natural derivative has been demonstrating promise as an anti-HIV, as well as anti-malarial .  (More on the very interesting off-label potential of a whole range of anti-malarials against cancer in this blog in the near future, when I get to it) .  Your comments please !

Metformin for Cancer

My interest for Metformin started with its use to enhance fertility (one of my practice interests) and led more recently to its potential use in cancer (my other practice interest).

Metformin is a diabetes medicine which originates interestingly from the French Lilac (Galega officinalis) plant (herbal medicine is my other interest!).  First described in 1957, it is one of the safest and most commonly prescribed drug for diabetes treatment in the world.

Metformin’s many physiologic actions include suppressing liver’s own sugar production (”hepatic gluconeogenesis”), increasing insulin sensitivity, enhancing body sugar utilization and decreasing absorption of sugar from the intestines. Overall, we can summarily say that Metformin improves overall sugar metabolism (I have long supported reducing carbohydrate consumption as an adjunct in controlling cancer, perhaps to my colleagues’ consternation if not ridicule. Sugar and cancer is a very important theme, though usually under appreciated by conventional oncologists despite the strength of corollary data. But alas, the topic would be a whole separate blog)

Given so many modern illnesses (eg hyperlipidemia, obesity, diabetes etc) resulting from deranged carbohydrate metabolism, it is not hard to imagine that Metformin may have a role to play in the treatment of conditions resulting from defective insulin signalling (incl. polycystic ovary syndrome [PCOS], infertility, non-alcoholic fatty liver disease (NAFLD) or steato hepatitis, metabolic syndrome X, etc), and these could all be considered “off-label” uses for Metformin as a drug .

A higher incidence of cancer in patients with diabetes has been observed for a century, so much so that Dr Anna Barker, deputy director at the National Cancer Institute estimated that the obesity and diabetes pandemic will cause an additional 30-40% increase in incidence of total solid tumour cancers over the next 10 years – notably in breast, prostate, and colorectal cancer (Financial Times, Oct 1st, 2008). So it makes common sense that an anti-diabetic medicine may somehow inhibit cancer.  More recently, despite many mainstream oncologists curiously still denying a role of sugar and diet for cancer control, science has reviewed an emerging key role for insulin and sugar metabolism or insulin signalling in determining cancer risk, tumor growth or cancer progression (See recent review “Insulin, Insulin-like growth factors, Insulin resistance and neoplasia” by Pollack MN of McGill University in Am J Clin Nutri 2007 Sep;86(3):s820-2 for an overview), then it is no surprise that Metformin has off-label application potential in cancer treatment, as do drugs from another class of anti-diabetic agents, the PPAR agonists [discussion to be posted in this blog soon].

And there is a bit of evidence for this:-

a) In Vitro (cellular evidence):

Active against breast cancer (Zakikhani M, Cancer Res. 2006 Nov 1;66(21):10269-73), ovarian cancer (Gotlieb WH et al. Gynecol Oncol. 2008 Aug;110(2):246-50), prostate cancer (Ben Sahra I, et al. Oncogene. 2008 Jun 5;27(25):3576-86), glioma brain cancer (Isakovic A, Cell Mol Life Sci. 2007 May;64(10):1290-302).

Observed mechanisms of action of Metformin against various cancers seems mainly to be related to apoptosis and includes decrease in cyclin D1, AMPK activation leading to inhibition of mTOR and a reduction in translation initiation, selective toxicity to p53-deficient cells, and induction of caspase-dependent apoptosis associated with c-Jun N-terminal kinase (JNK) activation.

b) In Vivo (animal evidence):

Prevention of pancreas cancer in hamsters (Schneider MB, Gastroenterology. 2001 Apr;120(5):1263-70)

Metformin inhibits development of breast cancer in mice (Anisimov VN, : Bull Exp Biol Med. 2005 Jun;139(6):721-3)

Metformin suppresses intestinal polyp growth in mice (Tomimoto et al. 2008)

Metformin attenuates growth of lung cancer in mice (Algire C. et al, Endocr Relat Cancer. 2008 Sep;15(3):833-9)

Metformin inhibits prostate cancer (Ben Sahra I, et al. Oncogene. 2008 Jun 5;27(25):3576-86)

c) Clinical (human evidence):

Dr. Dario Alessi’s research (U. of Dundee) involving data from patient records over ten years, have shown that patients on metformin showed anywhere between a 30-40% protection against all forms of cancer. While this and lowered instance of breast cancer in women with diabetes treated with Metformin has been known for a while, but recent work presented this year demonstrating Metformin’s role in increasing the response rates of breast cancer patients with diabetes is very exciting:

“Using the M. D. Anderson Breast Medical Oncology database, Drs. Gonzalez-Angulo, Jiralerspong and their team at MD Anderson identified 2,529 women with early-stage breast cancer who received chemotherapy. Of the patients, 68 were diabetic but not taking metaformin and 87 were diabetic and taking the drug. The researchers found that the pathologic complete response rates in the breast cancer patients taking Metformin was 24 percent, three times higher than the rates in patients not taking the drug”

When interviewed, Dr. Gonzalez-Angulo thinks that the result maybe from decreased insulin levels as insulin is a known potent growth factor for cancer.  The MD Anderson doctors are planning a trial of Metformin in metastatic breast cancer patients who are obese (and who may thus have insulin resistance and high circulating insulin levels).

My take

Such a benign drug as Metformin can be safely given as an off-label adjunctive treatment in cancer patients, especially breast, ovarian, colorectal, prostate, pancreas and perhaps in glioma patients who have Type 2 diabetes, exhibit metabolic syndrome X, who have elevated circulating insulin levels, or are obese, or even simply those who cannot or do not adhere to a low carb low fat diet.

Intriguingly, Metformin may also promote longevity (independent of cancer risks), but that will be the the topic of another blog!