Arsenic Trioxide

Arsenic trioxide is an antitumor agent with a multifac-eted mechanism of action that induces apoptosis in vitro in MM cell lines and freshly isolated cells from MM patients. In preliminary studies, it has demonstrated good clinical activity in patients with late-stage MM. Arsenic trioxide affects myeloma cell survival, possibly through the inhibition of glutathione peroxi-dase, inducing apoptosis and inhibiting the proliferation of MM cell lines and primary MM cells in a dose-dependent manner.62 63 Unlike the antitumor activity of dexamethasone, which is inhibited by IL-6, arsenic-trioxide-induced apoptosis is not prevented by IL-6.63 Arsenic trioxide induces apoptosis through activation of caspases 8 and 10 in mutated p53 myeloma cells, while it does so by activation of caspase 9 in the mito-chondrial apoptotic pathway in myeloma cells with functional p53.64 In addition, it inhibits TNFa-induced cell adhesion, inhibits secretion of IL-6 and VEGF, and increases dexamethasone-induced apoptosis.65 66 The cytotoxic action of arsenic trioxide is increased when administered with ascorbic acid in vitro.67

Cross-resistance to other chemotherapeutic agents is less likely with arsenic trioxide because it can induce dose-dependent apoptosis in drug-resistant MM cell lines.68 Antiangiogenic properties, such as inhibition of VEGF production and capillary formation, also promote the antitumor efficacy of arsenic trioxide.68 In addition, treatment with arsenic trioxide increases lymphokine-activated killer cell activity and upregu-lates CD38 ligand and CD38 on immune effector cells and myeloma cells, indicating that immunomodulation may contribute to its antitumor activity.69 A recent phase II, multicenter, open-label study of arsenic triox-ide (ATO) was conducted in 24 MM patients (eight with relapsed disease and 16 refractory to prior therapy).68

Patients received ATO 0.25 mg/kg/day for 5 days/week during the first 2 weeks of each 4-week cycle. Sixteen patients had grade III or IV neutropenia and one required antibiotics. Eight of 24 (33%) patients had reductions in serum M-protein levels in excess of 25%, while an additional 6 (25%) patients had stable disease.68 The median time to response was 67.5 days, with a median duration of response of 130 days.68 Arsenic trioxide therapy lowered serum creatinine levels in two patients with high baseline values. These data show that ATO is active and reasonably well tolerated as a single-agent salvage therapy, even in patients with late-stage, relapsed and refractory MM.

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