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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.

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.

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.