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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).

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