Tirapazamine

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.

IC50: N/A

替拉帕替汀（SR259075；Win59075；SR4233）是一种实验性抗癌药物，只在极低氧气水平下活化为有毒自由基，这种现象被称为肿瘤低氧。

体外研究：替拉帕替汀可通过减少HIF-1α蛋白质合成来下调HIF-1α表达。与SN-38（伊立替康的活性代谢物）联合应用的替拉帕替汀可增强细胞凋亡，同时还会导致线粒体去极化和caspase途径激活[1]。

体内研究：替拉帕替汀与SN-38联合治疗显著阻止了HIF-1α蛋白的积累，降低了HIF-1α转录激活，并减弱了同源重组修复途径中蛋白质的磷酸化，最终导致这两种药物的协同作用。此外，替拉帕替汀与伊立替康联合治疗还对人肝癌Bel-7402移植瘤小鼠模型的抗癌效果增强[1]。大鼠经腹腔注射替拉帕替汀（5TP和10TP两种剂量）六次，每周一次，同时给予多柔比星（DOX）1.8mg。接下来两组同时给予这两种药物（5TP+DOX和10TP+DOX）。替拉帕替汀降低了心脏的脂质过氧化，DOX引起的RyR2蛋白质也恢复到正常水平[2]。

临床试验：已进行了临床研究。

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.