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).

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!