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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.


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.

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.