Toxicity and Efficacy of Benzamide Riboside in Cancer Chemotherapy Models

Hiremagalur   N.   Jayaram; Joel   A.   Yalowitz; Francisco      Arguello; John   F.   Greene,Jr

Abstract

Benzamide riboside (BR), a synthetic C-nucleoside, acts as a strong growth inhibitor of cancer cells in vitro and in vivo. BR, like TR and related nucleoside prodrugs, act by anabolism to NAD analogs. These analogs selectively inhibit IMPDH, leading to depletion of cellular GTP, growth cessation, and cell differentiation. To date only preclinical studies have been carried out. However, in tiazofurin (TR), a related drug, phase I / II clinical trials have been conducted in patients with acute leukemia and shown to be a very promising agent with a response rate of 85percent in 26 patients in one of the trials. Tiazofurin is now undergoing phase III clinical trials as a result. Dose limiting toxicity of tiazofurin was headache, somnolence and nausea with no myelosuppression noted. By contrast, BR showed skeletal muscle toxicity, hepatotoxicity and myelosuppression in preclinical data. Skeletal muscle toxicity was noted in the paraspinal muscles and may represent dose-limiting toxicity. Since BR does exhibit myelosuppression, the most common chemotherapy-related side effect in humans, careful judgment is warranted should BR be included in multidrug regimens, although BRs potent cytotoxicity to tumor cells in preclinical models still makes it a promising drug.

Keywords: c-nucleoside, benzamide riboside, cancer chemotherapy, toxicity, apoptosis

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