Drug Repositioning – Disulfuram

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Drug Repositioning Disulfuram

Drug Repositioning ( also-known-as therapeutic switching and drug repurposing). It is an area of translational biology that identifies new or different therapeutically-useful indications for marketed drugs by targeting alternative diseases.

Molecules that have passed safety evaluation in Phase I clinical trials but proved ineffective for efficacy reasons in Phase II or Phase III trials against other diseases can also be repurposed. Successful examples of such repositioning abound: some are high profile, household names – Thalidomide, thalidomide in severe erythema nodosumleprosum; Zyban, an antidepressant, is now successful in smoking cessation; even Viagra began as a heart medicine -while others are not so well known.

Disulfuram (Antabuse)

This drug has been in clinical use since 1940 mainly to discourage alcohol abuse. It is currently in two clinical trails for glioma theraphy due to a multitude of anticancer and anti-glioma actions, including aldehyde dehydrogenase inhibition, proteasome inhibition, MGMT and P-glycoprotein inhibition, and inhibition of the two matrix metalloproteinases MMP-2 and MMP-9, which are critical for cell invasion. It must be noted however, that most of the favorable evidence in terms of glioma theraphy thus far come from invitro laboratory studies.

In vitro, disulfuram is one of the most effective agents for targeting glioma cells, In a high throughput of 2000 compounds being tested against glioblastomastem cells, disulfuram emerged as the most promising candidate for the further testing. In this study, its effects were attributed to its inhibition of the ubiquitin-proteasome pathways, as mentioned above.

Disulfuram has so many various potential modes of action that it still unclear which is the most important. A phase II trial for newly diagnosed glioblastoma has started in September 2015 in Greece, and a phase I trial currently underway at the Washington university school of Medicine  (St.Louis, Missouri) will shed more light on its efficacy in brain tumors.     

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