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Sylvester Comprehensive Cancer Center [N. J. B., J. M-G., I. J-M., I. R., M. K-D., M. G., H. F. F., L. H. B., K. P. L.], Division of Hematology and Oncology, Department of Medicine [N. J. B., M. K-D., M. G., H. F. F., K. P. L.], and Department of Microbiology and Immunology [J. M-G., L. H. B., K. P. L.], University of Miami, Florida, and Division of Hematology and Oncology, Department of Medicine, Grady Memorial Hospital, Emory University, Atlanta, Georgia [J. N., J. E.]
Patients with multiple myeloma (MM) invariably relapse with chemotherapy-resistant disease, underscoring the need for new agents that bypass these resistance mechanisms. We have reported that ascorbic acid (AA) enhances the activity of arsenic trioxide (As203) against drug-resistant MM in vitro by depleting intracellular glutathione (GSH). These data led us to open a National Cancer Institute/Cancer Therapy Evaluation Program-sponsored Phase I/II trial of As203 + AA for relapsed/refractory MM. We now present the completed Phase I component of this trial. The primary objective of the trial’s Phase I component was to assess whether the addition of AA affected the well-described toxicity profile of As203 alone. Correlative studies were undertaken of As203 and AA pharmacokinetics, the ability of AA to deplete intracellular GSH in vivo, and the development of arsenic resistance. Six patients with stage IIIA relapsed/refractory myeloma were studied. We found that 0.25 mg/kg/day As2O3 + 1000 mg/day AA could be given for 25 days (over a 35-day period) without dose-limiting toxicity. One episode of grade 3 hematological toxicity (leukopenia) and no grade 3 nonhematological toxicities (in particular, cardiac) were observed. The coadministration of AA did not alter the pharmacokinetics of As203, and elevated AA levels were associated with decreased intracellular GSH. Serial in vitro studies demonstrated continued sensitivity of patient myeloma cells to As203 + AA. Two patients (both with thalidomide-refractory disease) had partial responses; four patients had stable disease. In conclusion, we have found that As203 + AA has acceptable toxicity and that there is promising evidence of activity in refractory/relapsed myeloma.
Commentary
Clin. Cancer Res. 2002 8: 3643-3645.
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