Chinje E C, Patterson A V, Saunders M P, Lockyer S D, Harris A L, Stratford I J
Experimental Oncology Group, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK.
Br J Cancer. 1999 Dec;81(7):1127-33. doi: 10.1038/sj.bjc.6690819.
The bioreductive drug tirapazamine (TPZ, SR 4233, WIN 59075) is a lead compound in a series of potent cytotoxins that selectively kill hypoxic rodent and human solid tumour cells in vitro and in vivo. Phases II and III trials have demonstrated its efficacy in combination with both fractionated radiotherapy and some chemotherapy. We have evaluated the generality of an enzyme-directed approach to TPZ toxicity by examining the importance of the one-electron reducing enzyme NADPH:cytochrome P450 reductase (P450R) in the metabolism and toxicity of this lead prodrug in a panel of seven human non-small-cell lung cancer cell lines. We relate our findings on TPZ sensitivity in these lung lines with our previously published results on TPZ sensitivity in six human breast cancer cell lines (Patterson et al (1995) Br J Cancer 72: 1144-1150) and with the sensitivity of all these cell types to eight unrelated cancer chemotherapeutic agents with diverse modes of action. Our results demonstrate that P450R plays a significant role in the activation of TPZ in this panel of lung lines, which is consistent with previous observations in a panel of breast cancer cell lines (Patterson et al (1995) Br J Cancer 72: 1144-1150; Patterson et al (1997) Br J Cancer 76: 1338-1347). However, in the lung lines it is likely that it is the inherent ability of these cells to respond to multiple forms of DNA damage, including that arising from P450R-dependent TPZ metabolism, that underlies the ultimate expression of toxicity.
生物还原药物替拉扎明（TPZ，SR 4233，WIN 59075）是一系列强效细胞毒素中的先导化合物，在体外和体内能选择性杀死缺氧的啮齿动物和人类实体瘤细胞。II期和III期试验已证明其与分次放疗和某些化疗联合使用时的疗效。我们通过检测单电子还原酶NADPH：细胞色素P450还原酶（P450R）在七种人非小细胞肺癌细胞系中该先导前体药物代谢和毒性中的重要性，评估了一种酶导向方法对TPZ毒性的普遍性。我们将这些肺癌细胞系中关于TPZ敏感性的研究结果与我们之前发表的六种人乳腺癌细胞系中TPZ敏感性的结果（Patterson等人，（1995年）《英国癌症杂志》72：1144 - 1150）以及所有这些细胞类型对八种作用方式不同的无关癌症化疗药物的敏感性进行了关联。我们的结果表明，P450R在这组肺癌细胞系中TPZ的激活中起重要作用，这与之前在一组乳腺癌细胞系中的观察结果一致（Patterson等人，（1995年）《英国癌症杂志》72：1144 - 1150；Patterson等人，（1997年）《英国癌症杂志》76：1338 - 1347）。然而，在肺癌细胞系中，可能是这些细胞对多种形式DNA损伤作出反应的固有能力，包括由P450R依赖性TPZ代谢产生的损伤，构成了毒性最终表达的基础。
