IC50: N/A

Tirapazamine (SR259075; Win59075; SR4233) is an experimental anticancer drug that is activated to a toxic radical only at very low levels of oxygen; a phenomenon known as tumor hypoxia.

In vitro: Tirapazamine could downregulate HIF-1α expression by reducing HIF-1α protein synthesis. The enhanced apoptosis induced by tirapazamine plus SN-38 (the active metabolite of irinotecan) was followed by increased mitochondrial depolarization and caspase pathway activation [1].

In vivo: Tirapazamine plus SN-38 treatment dramatically blocked the accumulation of HIF-1α protein, reduced the HIF-1α transcriptional activation, and weakened the phosphorylation of proteins in the homologous recombination repair pathway, ultimately resulting in the synergism of these two drugs. Moreover, the increased anticancer efficacy of tirapazamine combined with irinotecan played a further role on a human liver cancer Bel-7402 xenograft mouse model [1]. Rats were intraperitoneally injected six times once a week with tirapazamine in two doses [5 (5TP) and 10 mg (10TP)], while doxorubicin was administered in dose 1.8 mg (DOX). Subsequent two groups received both drugs at the same time (5TP+DOX and 10TP+DOX). Tirapazamine decreased heart lipid peroxidation and RyR2 protein was up to normal level altered by doxorubicin [2].

Clinical trial: Clinical study has been conducted.

References:
[1].? Cai TY1, Liu XW, Zhu H, Cao J, Zhang J, Ding L, Lou JS, He QJ, Yang B. Tirapazamine sensitizes hepatocellular carcinoma cells to topoisomerase I inhibitors via cooperative modulation of hypoxia-inducible factor-1α. Mol Cancer Ther. 2014 Mar;13(3):630-42.
[2].? Sliwinska J1, Dudka J, Korga A, Burdan F, Matysiak W, Jodlowska-Jedrych B, Mandziuk S, Dawidek-Pietryka K.Tirapazamine-doxorubicin interaction referring to heart oxidative stress and Ca balance protein levels. Oxid Med Cell Longev. 2012;2012:890826.