Archive for the ‘chemo-sensitizer’ Category

Disulfiram (Antabuse) for cancer

November 24, 2008 1 comment

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

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

Now where is the evidence?

a) In Vitro (cellular evidence):

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

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

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

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

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

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

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

b) In Vivo (animal evidence)

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

Disulfiram reduced ifosfamide-induced nephrotoxicity in rodents.

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

c) Clinical (human experiences)

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

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

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

My take

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

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

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

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

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

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

Dipyridamole for cancer

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

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

Now where is the evidence?

a) In Vitro (cellular evidence):

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

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

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

In Vivo (animal evidence):

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

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

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

Clinical (human evidence):

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

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

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

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

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

My take

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

Gossypol (棉酚) for cancer

November 7, 2008 1 comment

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

What is Gossypol?gossypol

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

And where is the evidence?

a) In Vitro (cellular evidence):

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

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

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

It is also known as a protein kinase C inhibitor.

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

In Vivo (animal evidence):

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

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

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

Clinical (human evidence):

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

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

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

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

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

So What’s new?

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

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

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

My Take

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