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-RAR{alpha} 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.
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Hey, MS-1 here. We're in our hematology unit right now, so I'm glad to hear about the latest (and perhaps oldest!) treatment for leukemia. :)
APL is very weird as a blood cancer though. All-trans retinoic acid is also used to treat it! Vitamin A. And now, arsenic.
I've got a question, though. You quote "The group also reported that arsenic trioxide is associated with induced apoptosis of the abnormal promyelocytic white cells."
APL has a lot Auer rods in them, which are strongly thrombogenic. How are these Auer rods dealt with during apoptosis? Isn't it dangerous to treat someone with APL with something that might induce disseminated intravascular coagulation (DIC)? DIC would make them clot all over the place and then bleed when they run out of coagulation factors... and it has a high mortality rate.
NMSO, you'd best ask your heme attending because the question is totally out of my league. Balancing hemostasis in leukemias before and after chemotherapy is a real challenge. The advantage of ATRA is that a large percentage of cell differentiate rather than undergo apoptosis. Your question is a good one - I've got some queries in to some colleagues but let me know when you have an answer.
As a newly minted pharmacist in the 1960s, I compounded a tonic prescribed by a local Italian-immigrant physician. Among many ingredients was one called Fowler's Solution.
Fowler's was potassium arsenite solution, and its main ingredient was arsenic trioxide. Needless to say, the patient received a very small dose of arsenic in his tonic !
My wife achieved a very good remission for relapsed APL with a 60 day cycle of arsenic (Trisenox). She received the Trisenox as a single agent for her relapse treatment.
The DIC that NMSO mentioned is more of a concern when someone has a high ratio of APL cells in their marrow. When my wife was initially diagnosed, and when she was treated for her relapse, she developed what her Dr referred to as "RAS" or Retinoic Acid Syndrome. Interestingly, the Dr's refer to the dangerous sequence of events that follow the destruction of APL cells as RAS (which often includes DIC), whether Retinoic acid (Trentinoin) http://en.wikipedia.org/wiki/Tretinoin is being used to destroy the cells or not.
My wife's Dr watched her very carefully when he was suspicious that she might be developing RAS. Suspicious is the right word too - because the first sign of RAS is usually an unexplained fever and there have been plenty of cases where docs chased a fever with antibiotics before assuming that RAS was the real cause, sometimes with very sad results. Unfortunately, delaying treatment for RAS is very dangerous.
Seems like Dexamethasone was very effective for knocking down the RAS whenever my wife developed it.
Chris
www.aplblog.com