Weitman S, Mangold G, Marty J, Dexter D, Hilsenbeck S, Rake J, Juniewicz P, Von Hoff D
Institute for Drug Development, San Antonio, TX 78245-3217, USA.
Cancer Chemother Pharmacol. 1999;43(5):402-8. doi: 10.1007/s002800050914.
Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide; SR 4233) is a bioreductive agent that exhibits relatively selective cytotoxicity towards cells under hypoxic conditions and can enhance the antitumor activity of many standard oncolytics. In the present study we examined the interaction between tirapazamine in vivo with paclitaxel and paraplatin in two- and three-way combination studies using the MV-522 human lung carcinoma xenograft model.
Agents were administered as a single i.p. bolus, with tirapazamine being given 3 h prior to paclitaxel, paraplatin, or their combination. Tumor growth inhibition (TGI), final tumor weights, partial and complete responses, and time to tumor doubling were determined after drug administration.
Tirapazamine as a single agent was ineffective against this human lung tumor model. A substantial increase in TGI was seen in animals treated with the triple-agent regimen (tirapazamine-paclitaxel-paraplatin) compared to animals treated with double-agent regimens that did not include tirapazamine. The addition of tirapazamine to paclitaxel-paraplatin therapy resulted in a 50% complete response rate; there were no complete responses seen when only the paclitaxel-paraplatin combination was administered. Time to tumor doubling was also significantly improved with the addition of tirapazamine to the paclitaxel and paraplatin combinations. Tirapazamine did not increase the toxicity of paclitaxel, paraplatin, or their combinations as judged by its minimal impact on body weight and the fact that no toxic deaths were observed with tirapazamine-containing regimens.
These results are important since recent studies have suggested that the combination of paclitaxel and paraplatin may be particularly active in patients with advanced stage non-small-cell lung cancer. Since tirapazamine can significantly improve efficacy, but does not appear to enhance the toxicity of paclitaxel and paraplatin, its evaluation in future clinical trials in combination with paclitaxel-paraplatin-based therapy appears warranted.
替拉扎明（3-氨基-1,2,4-苯并三嗪1,4-二氧化物；SR 4233）是一种生物还原剂，对缺氧条件下的细胞表现出相对选择性的细胞毒性，并且可以增强许多标准溶瘤剂的抗肿瘤活性。在本研究中，我们使用MV-522人肺癌异种移植模型，在二联和三联组合研究中检测了替拉扎明在体内与紫杉醇和顺铂的相互作用。
药物通过腹腔内单次推注给药，替拉扎明在紫杉醇、顺铂或它们的组合给药前3小时给予。给药后测定肿瘤生长抑制（TGI）、最终肿瘤重量、部分缓解和完全缓解以及肿瘤倍增时间。
替拉扎明作为单一药物对该人肺癌肿瘤模型无效。与未使用替拉扎明的二联治疗方案的动物相比，三联治疗方案（替拉扎明-紫杉醇-顺铂）治疗的动物的TGI有显著增加。在紫杉醇-顺铂治疗中添加替拉扎明导致50%的完全缓解率；仅给予紫杉醇-顺铂组合时未观察到完全缓解。在紫杉醇和顺铂组合中添加替拉扎明也显著改善了肿瘤倍增时间。根据替拉扎明对体重的最小影响以及含替拉扎明方案未观察到毒性死亡这一事实判断，替拉扎明未增加紫杉醇、顺铂或它们组合的毒性。
这些结果很重要，因为最近的研究表明，紫杉醇和顺铂的组合可能对晚期非小细胞肺癌患者特别有效。由于替拉扎明可以显著提高疗效，但似乎不会增强紫杉醇和顺铂的毒性，因此在未来与基于紫杉醇-顺铂的治疗联合的临床试验中对其进行评估似乎是有必要的。
