Clinical activity of arsenic trioxide for the treatment of multiple myeloma

Abstract

Arsenic has been used since ancient times as a therapeutic agent. However, until recently its use in modern medicine has been restricted to the treatment of a limited number of parasitic infections. In the early 1990s, reports from China described impressive results with arsenic trioxide in patients with de novo, relapsed, and refractory acute promyelocytic leukemia (APL). Other investigators subsequently confirmed these results leading to approval of its use for relapsed or refractory APL in the United States. Investigations of this agent have demonstrated that its efficacy in APL and preclinical tumor models is dependent upon a number of mechanisms, including induction of apoptosis, effects on cellular differentiation, cell cycling, and tumor angiogenesis. Subsequent preclinical studies showed significant activity of arsenic trioxide in multiple myeloma (MM). Based on this, in a phase II trial, we have evaluated the activity of arsenic trioxide in 14 patients with relapsed MM, refractory to conventional salvage therapy. With the dose and schedule used, treatment with arsenic trioxide produced responses in three patients and prolonged stable disease in a fourth patient, with the longest response lasting 6 weeks. Although treatment was reasonably well tolerated, in these patients with extensive prior therapy, 11 developed cytopenia, five associated with infectious complications and three developed deep vein thromboses. The results of this small trial support further investigation of this novel drug for the treatment of patients with relapsed or refractory MM.

Role of cysteine 288 in nucleophosmin cytoplasmic mutations: sensitization to toxicity induced by arsenic trioxide and bortezomib

“…In an early clinical trial study, Munshi et al 25 reported that ATO as a single agent was not effective in a phase II study of 11 relapsed/refractory or de novo AML and non-acute promyelocytic leukemia patients. However, only two of these patients had a normal karyotype, and the NPM1 status was not reported.…”

“…However, only two of these patients had a normal karyotype, and the NPM1 status was not reported. 25 In a recent clinical trial of ATO alone, one of the seven AML patients of unknown genetic phenotype who were resistant to therapy obtained a complete remission and one a partial remission. 56 In two other clinical studies, the addition of ATO to low-or high-dose cytarabine and idarubicin appeared to improve the complete remission rate, although again NPM1 mutational status was not determined.…”

“…9,23 Arsenic trioxide (ATO) has emerged as the most active single agent in the treatment of acute promyelocytic leukemia, 24 and ATO-based therapies are being investigated in other cancers including other hematopoietic malignancies. [25][26][27][28][29] Although the mechanisms underlying ATO-induced cytotoxicity are not completely understood, ATO-mediated induction of ROS has been shown to reduce the membrane potential of mitochondria, enhance the release of cytochrome c and induce both caspasedependent and caspase-independent apoptosis. [30][31][32] AML has a poor prognosis in older patients, and intensive induction carries high morbidity and significant mortality.…”

Antimony-trioxide- and arsenic-trioxide-induced apoptosis in myelogenic and lymphatic cell lines, recruitment of caspases, and loss of mitochondrial membrane potential are enhanced by modulators of the cellular glutathione redox system

“…We were interested in magnifying the efficacy of As 2 O 3 using substances that might be transferable to clinical application because the clinical applications of As 2 O 3 gain in importance not only for therapy of relapsed and refractory APL [29,30,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47], but also for treatment of multiple myeloma [48][49][50], myelodysplastic syndromes [51][52][53], and renal cancer [54]. Recently, two reports described apoptosis induction, caspase activation and ROS production by very high concentrations (up to 40 µM) of potassium antimonyl tartrate in lymphoid tumor cell lines [55] and growth inhibition and induction of apoptosis and reactive oxygen species [56].…”

Effect of arsenic trioxide on vascular endothelial cell proliferation and expression of vascular endothelial growth factor receptors Flt-1 and KDR in gastric cancer in nude mice

“…Arsenic trioxide (As 2 O 3 ) has shown substantial efficacy in treating both newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL) [15] . Recent studies have shown that a wide variety of malignancies, including both hematological cancer and solid tumors derived from several tissue types, may be susceptible to therapy with As 2 O 3 [16][17][18][19] . These successes have prompted investigations to elucidate the mechanisms of action underlying these clinical responses.…”