Arsenic: from drug to poison to drug again

This post appeared originally on 23 May 2007 at the ScienceBlogs home of Terra Sigillata.

The 2 May issue of the Journal of the National Cancer Institute has an interesting news article on the advancing use of arsenic trioxide against a variety of human malignanices, mostly cancers of the blood.

The medical uses of arsenic reach back more than 2,000 years, but only recently has Western medicine embraced its surprising rise from folk cure-all to proven cancer treatment.

The January announcement of positive results in a 6-year NCI-sponsored phase III clinical trial to treat a rare form of leukemia is merely the latest in a series of kudos for arsenic’s medicinal prowess. The latest study affirms that arsenic can effectively maintain remissions in acute promyelocytic leukemia (APL). But some investigators hope that arsenic could go even farther and eventually replace chemotherapy as a front-line treatment for APL.

In 1908, Sahachiro Hata working in the laboratory of Nobel laureate Paul Ehrlich had identified an arsenic-containing compound they named Salvarsan (arsphenamine, compound 606) that was used to treat syphilis until the advent of penicillin. (The compound number came from it being 606th of those tested against Treponema pallidum in an animal model.). We consider arsenic a poison today, but Salvarsan was a great improvement over organic mercurial compounds of the day.

We still try to keep arsenic out of our water and seafood supply, but the old Paracelsan adage seems to hold that it is the dose that determine the difference between a remedy and a poison.

The JNCI article notes the recent successes in using arsenic trioxide (Trisenox) to treat leukemias and other cancers and its roots in traditional Chinese medicine:

[Mt Sinai School of Medicine Dr Samuel] Waxman was one of the first Western physicians to see promise in the a series of small studies in Chinese medical journals that reported intravenous doses of arsenic trioxide-induced long-term remission in APL [acute promyelocytic leukemia] patients. The medical uses of arsenic reach back at least 2,000 years, but it was political ideology that prompted its modern resurgence, Waxman explained.

Arsenic may never have entered the western pharmacopoeia were it not for the Chinese cultural revolution in the 1960s and 1970s, he said. During that time, Western medicine virtually disappeared in China, and physicians turned to traditional Chinese herbal cures that had sustained the culture for millennia. The Chinese physician Zhang Ting-Dong of Harbin Medical University made the initial breakthrough by formulating a stable, low-dose solution of 1% arsenic trioxide in injectable form. Zhang presented his work at a Chinese medical society meeting in the early 1980s and gained interest from colleagues in Shanghai.

Around this same time, a researcher in Waxman’s lab began an exchange with Zhu Chen, M.D., Ph.D., and others at Shanghai Second Medical University in China, and thus began a decades-long collaboration between the two groups. They, along with colleagues in Europe, established that arsenic is associated with degradation of the PML-RARα oncoprotein that, in part, defines APL. The group also reported that arsenic trioxide is associated with induced apoptosis of the abnormal promyelocytic white cells.

“These cells are particularly sensitive to arsenic-induced apoptosis,” Waxman said. “Secondly, they are undergoing differentiation, so you are getting a double hit from the same drug. Thirdly, it is very well tolerated in the doses given.”

In my last search of clinicaltrials.gov for arsenic, I find there are currently 26 clinical trials ongoing in the US to test arsenic trioxide or novel organic arsenic compounds for a variety of human malignancies.

Author: David Kroll

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