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Development of an organic arsenic derivative as a therapy for leukaemia

Arsenic trioxide (ATO) is an inorganic arsenic derivative that is effective in patients with relapsed acute promyelocytic leukemia (APL) and is being evaluated as therapy for other leukemias and solid tumors. However, its use is limited by toxicity. In contrast, organic arsenic derivatives (OAD) are much less toxic ; hepatic methylation of inorganic arsenic compounds (like ATO) to yield OAD is a mechanism of detoxification. We hypothesized that, compared to ATO, selected OAD have similar clinical benefit with significantly lower toxicity. We have synthesized over 100 OADs and found some to have potent anti-cancer activity in the NIH 60 cell line screen. Based on its activity, we selected S-dimethylarsino-glutathione (SGLU1) for further study in our laboratory and have confirmed its potent activity against human leukemia, lymphoma, and multiple myeloma cell lines. In vivo anti-cancer activity of SGLU1 was evaluated by NIH in the P388 mouse lymphocytic leukemia model. SGLU1 administered IP at 100 mg/kg (highest dose tested) for 9 days resulted in a 64% increase in survival ; in contrast, others have shown in a murine model of APL, the disease most sensitive to ATO, that IP administration of ATO for 28 days at the maximum tolerated dose of 5 mg/kg was required for a 100% increase in survival. SGLU1 also exerts cytotoxic effects on leukemic cells from patients with leukemia. In vitro anti-leukemic activity of SGLU1 is comparable to that of ATO, but its toxicity against healthy donor cells is significantly less than that of ATO. Studies to determine the toxicity of a single dose injection of SGLU1 showed the concentration of SGLU1 that kills 50% of mice (LD50) to be 350 mg/kg, and for ATO to be 10 mg/kg. When administered IV daily for 5 days, LD50 for SGLU1 is 250 mg/kg/d (1250 mg/kg total dose), and 5 mg/kg/d for ATO (25 mg/kg total dose). For toxicology evaluation, 5 mice per sex received 5 daily IV injections ; doses escalated from a starting dose of 50 mg/kg/day. All surviving mice were sacrificed after 28 days. Microscopic observations included drug-related lesions in lung, liver, thymus and testes, but only at very high doses. The no-observed effect level (NOEL) for female mice was 150 mg/kg/day based on a single observation of centrilobular hypertrophy of hepatocytes in 1 of 5 female mice treated at a dose of 200 mg/kg/day. This event was not unexpected since SGLU1 is likely metabolized in the liver. The NOEL for male mice was 100 mg/kg/day based on testicular seminiferous tubular degeneration observed in 1 of 5 male mice treated at 150 mg/kg/day. Pharmaceutical evaluation of SGLU1 revealed its synthesis to be straightforward, yielding highly pure material, and sufficient solubility and stability for administration in a clinical setting. Ex vivo cardiotoxicity testing to determine the potential effects of escalating doses of SGLU1 on cardiovascular function in guinea pig hearts (the Langendorff preparation test) yielded no adverse effects in clinically relevant doses (up to 100 microM). A 28-day toxicity study with pharmacokinetics in Beagle dogs is underway. Studies designed to understand the mechanism of action of SGLU1 show that it has different mode of action than ATO (reported separately ASH 2003 abstract). Results of our work reflect a high potential for identification of a new therapeutic approach for patients with leukemia.

Arsenic; Leukemia; Experimental Therapeutics

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