© 1998 by Oxford University Press
The sixteenth meeting of the Chemotherapy Foundation managed to barrel through 73 diverse discussions of chemotherapy treatments and methods in a 76-hour period and still leave a few oncologists anxious for more. Bernard Fisher, M.D., garnered the most applause for his humor-laced presentation of the National Surgical Adjuvant Breast and Bowel Project's tamoxifen findings, comparing his quest for the worth and actions of tamoxifen to the task of decoding the Rosetta stone and the resulting discovery equivalent to obtaining the Hope diamond, which has cursed many who have owned it.
But some of the other interesting presentations focused on chemotherapies as ancient as the Rosetta stone, namely arsenic-derivatives. Raymond Warrell, Jr., M.D., of Memorial Sloan-Kettering Cancer Center, New York, noted that, historically, arsenic has been topically effective for superficial tumors, but since the 1960s has not been used much in the United States. "Eastern medicine has continued to use arsenic, however," Warrell said, "and recently Chinese researchers have reported that arsenic trioxide could induce remission of acute promyleocytic leukemia."
Warrell's lab has undertaken an active investigation into the effectiveness of arsenic trioxide for APL and other cancers. "We've looked at patients who have had relapses with other therapies and found that in 11 of 12 APL patients who were given arsenic trioxide, complete remission occurred. Our longest survivor has been on the therapy for 12 months so far."
Warrell also noted that there were surprisingly few side effects with this treatment. Four patients received four cycles of treatment without evidence of adverse cumulative effects. The arsenic therapy appears to be much better than the currently used all-trans-retinoic acid therapy, which is the gold standard for APL. Based on Warrell's success, a multicenter trial at over a dozen sites has been initiated to try and confirm these early findings.
Arsenic trioxide apparently concentrates primarily in the red blood cells. It's initial action seems to be an induction of partial differentiation, followed by programmed cell death. Resistance has been shown to develop rapidly and since the drug doesn't specifically target APL cells, it may have utility against other cancers, Warrell said.
Samuel Waxman, M.D., of Mount Sinai Medical Center, said that arsenic trioxide, based on both in vitro and in vivo experiments, appears to be selectively apoptotic in that it affects certain cell lines, but not others (bone marrow progenitor cells, for example).
Waxman found that 33 of 34 of his patients who were refractory to conventional APL therapy showed complete remission with arsenic trioxide for a median period of 14 months. Waxman also found that "administration of arsenic trioxide prior to all-trans-retinoic acid therapy was much more beneficial than a reverse administration of the drugs." Waxman's next effort will be an attempt to understand how to make arsenic trioxide insensitive cells responsive to low levels of the drug.
Elevated liver enzymes associated with the arsenical indicate that close patient monitoring is essential. As an interesting footnote to the toxicity problem, Warrell mentioned the visibility that arsenic was gaining, due, in part, to "an above-the-fold, front-page article in The New York Times about a plague of arsenic poisoning that is occurring in Bangladesh due to attempts to bring clean water to the impoverished nation." Bangladesh is undergoing one of the biggest mass poisonings in history, with tens of thousands and perhaps millions of people affected due to leaching of arsenic from the ground water through supposedly safe tube wells that were devised as part of a safe water program.
Warrell said that "the symptoms of arsenic poisoning in Bangladesh are similar to the symptoms of arsenic toxicity we see in some patients given arsenic trioxide for APL, with skin that becomes spotted and warts and sores that begin to cover their hands, feet, and bellies." In contrast to the new found beneficial effects of arsenicals in this country, Allan Smith, Ph.D., of the University of California at Berkeley, states that "arsenic in the drinking water in Bangladesh poses the highest cancer risk we have ever found."
-- Mike Miller
Scientists Explore Use of Arsenic in Therapy
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