ARSENIC TRIOXIDE TREATMENT OF LYMPHOPROLIFERATIVE DISORD

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As2O3, given by an intravenous infusion empirically designed in China, has become a new therapeutic agent of choice in the treatment of refractory acute promyelocytic leukemia (APL). It is an unusual agent since it is effective in APL patients that are chemotherapy-resistant and at the apparent therapeutic concentration of 1-2 M induces clinical remission with minimal myelotoxicity. Similar to all trans retinoic acid, As203 may be uniquely effective in treating APL since it can induce both differentiation and apoptosis in APL cells in vitro and in vivo. Whether As203 can be extended as a cancer treatment remains to be determined. We elected to extend the use of As203 to lymphoproliferative disorders (LPD). Anecdotal, unpublished reports from China and more recent case reports in the United States suggest that As203 may be an effective treatment of LPD. Consistent with this is our observation that As203 (1-2 M) treatment of cell lines and primary cultures of LPD (B-cell lymphoma, CLL, ALL, multiple myeloma but not T-cell lymphoma) causes significant growth inhibition and, in some cells, measurable apoptosis similar to NB4 cells (t(15:17) APL cell line). As303 is also appealing since it effectively inhibits growth and induces apoptosis in malignant cells with mutant p53, in lymphoma cells with t(14:18) that overexpress Bcl-2 and does not demonstrate cross resistance to taxol and doxorubicin in P388 lymphoma cells expressing MDR-1. As203 probably has multiple effects that contribute to the induction of cell death dependent on dose, cell type or cellular environment. In vitro, As203 in some cells increases H202 accumulation which acts on the mitochrondria to induce caspase dependent apoptosis. However, these observations made in vitro should be interpreted with caution since cellular levels of glutathione and H202 may be artifactually altered in tissue culture media and are likely to differ from that of cells in vivo. Little is known about the consequence of in vivo exposure of 1-2 M As203 and its effect on human malignant cells. We will compare and contrast in vitro and in vivo effects of As203 treatment of LPD cell lines and primary cultures of LPD cells obtained from animals and patients. These materials will be used: 1) to evaluate the importance of the intracellular redox profile and accumulation of H202 and arsenic to As203-induced growth inhibition and apoptosis; 2) to characterize the cellular responses to As203 at mRNA level using cDNA microarray in LPD cells obtained from patients treated with As203; 3) to design combination therapies in vitro and in vivo to improve the sensitivity of LPD cells to As203; 4) we have designed a phase II pilot study to evaluate 0.25 mg/kg/day As203 (2-1/2 higher concentration than used in APL) in the treatment of patients with relapsed and refractory indolent LPD. The study is designed to identify potential surrogate markers of As203 activity. Should our laboratory study identify agents or schedules that enhance the response to As203, we will use them to appropriately modify the initial phase II pilot study.