Arsenic Trioxide

Arsenic compounds are some of the oldest treatments for leukemia. Potassium arsenite, Fowler's solution, was used to treat leukemia patients in the 19th and early 20th centuries and some impressive clinical responses were achieved (53). Arsenic trioxide (As2O3, Trisenox®; Cell Therapeutics, Inc., Seattle, Washington, U.S.A.) has been demonstrated to induce apoptosis in Bcr-Abl-positive but not negative lymphoid cell lines and to reduce the proliferation of CML blasts but not of peripheral CD34+ progenitors (53). Apoptosis induced in CML cell lines was found to be associated with the cytosolic accumulation of cytochrome c and pre-apoptotic mitochondrial events, such as the loss of inner membrane potential and an increase in ROS (54). Recently it has been shown that As2O3 induced apop-tosis occurs via the endoplasmic reticulum stress mediated pathway of cell apoptosis (55). It has also been reported that As2O3 treatment of CMl cell lines inhibits the translation of BCR-ABL mRNA leading to attenuation of cellular levels of the oncoprotein (56). In the in vitro studies, the combination of AS2O3 with imatinib was found to induce additive to synergistic inhibition of the growth of Bcr-Abl-expres-sing cell lines (57), and to induce cell death in imatinib-resistant cell lines, which overexpressed Bcr-Abl or had the M351T or Y253F, but not the T315I, Abl-kinase domain mutations (40). This latter finding suggests that the combination of imatinib with As2O3 may only be of clinical benefit if the mechanism of imatinib-resistance is still susceptible to dose escalation of imatinib-monotherapy (40). Hence, there is renewed interest in the potential of arsenic compounds for the treatment of CML but in a novel context of agents that can be combined with other drugs to yield synergistic effects.

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