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- Fig. 1.
Targeting MM with the hypoxia-activated prodrug TH-302. TH-302 is a potent and highly selective hypoxia-activated prodrug developed by Threshold Pharmaceuticals. It is a 2-nitroimidazole prodrug of the cytotoxin bromo-isophosphoramide mustard that exhibits hypoxia-selective cytotoxicity across a broad spectrum of human cancer cell lines in vitro, and shows in vivo efficacy in a large panel of human tumor xenografts. During normal disease progression, MM cells exist in an increasingly hypoxic niche (purple cells), which enhances angiogenesis and promotes disease progression. The uptake and reduction of TH-302 by hypoxic MM cells triggers apoptosis and G0-G1 phase cell cycle arrest in a dose-dependent manner (Hu et al., 2010). TH-302 is also being evaluated in Phase 1/2 clinical trials for the treatment of solid tumors as a monotherapy and in combination with other chemotherapeutic agents.
- Fig. 2.
5TMM series: the natural model of MM. MM spontaneously develops in elderly mice of the C57BL/KaLwRij strain. BM cells are isolated from diseased mice by flushing out the content of the long bones, purified by Lympholyte M gradient centrifugation and injected into the lateral tail vein of young syngeneic recipients to create 5TMM mouse models of MM. Tumor progression is monitored by serum paraprotein quantification using electrophoresis (Asosingh et al., 2000; Vanderkerken et al., 2003).
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