Lartigau E, Guichard M
Laboratoire de Radiobiologie, Institut Gustave Roussy, Villejuif, France.
Br J Cancer. 1996 Jun;73(12):1480-5. doi: 10.1038/bjc.1996.280.
Recent data have shown that the in vitro and in vivo cytotoxicity of bioreductive drugs could be significantly increased when combined with chemotherapy drugs such as cisplatinum, depending on the timing of administration. The aim of this study was to define the toxicity (animal lethality) and the activity (growth delay assay, excision assay) of a bioreductive drug, tirapazamine, alone and combined with chemotherapy agents (5-FU, VP16, bleo, DTIC and c-DDP) on nude mice bearing xenografted human tumours: a rectal carcinoma (HRT18) and a melanoma (Na11+). Animal lethality was markedly increased when tirapazamine at the lethal dose 10% was combined with the other drugs. For the HRT18 tumour the combination of tirapazamine and bleomycin significantly increased the delay of regrowth compared with bleomycin alone (P = 0.04) and was more cytotoxic than tirapazamine alone (P = 0.04). For the Na11+ tumours the combination of tirapazamine with VP16 significantly increased tumour doubling time compared with the controls (P = 0.001) or VP16 alone. The combination of tirapazamine and VP16 was more cytotoxic than VP16 alone (P = 0.0001). When compared with c-DDP or tirapazamine alone, there was a significant decrease in plating efficiency when tirapazamine and c-DDP were given at the same time (P = 0.04), but not when tirapazamine was given 3 h before c-DDP. In conclusion, tirapazamine was shown to be cytotoxic against clonogenic human tumour cells. Its efficacy in vivo may depend on its combination with already active chemotherapy drugs on the tumour model used. The timing of administration may be less important than previously thought.
近期数据表明，根据给药时间，生物还原药物与顺铂等化疗药物联合使用时，其体外和体内细胞毒性可能会显著增加。本研究的目的是确定生物还原药物替拉扎明单独使用以及与化疗药物（5-氟尿嘧啶、依托泊苷、博来霉素、达卡巴嗪和顺铂）联合使用对携带人异种移植肿瘤的裸鼠（直肠癌HRT18和黑色素瘤Na11+）的毒性（动物致死率）和活性（生长延迟试验、切除试验）。当10%致死剂量的替拉扎明与其他药物联合使用时，动物致死率显著增加。对于HRT18肿瘤，替拉扎明与博来霉素联合使用相比单独使用博来霉素显著增加了再生长延迟（P = 0.04），且比单独使用替拉扎明更具细胞毒性（P = 0.04）。对于Na11+肿瘤，替拉扎明与依托泊苷联合使用相比对照组（P = 0.001）或单独使用依托泊苷显著增加了肿瘤倍增时间。替拉扎明与依托泊苷联合使用比单独使用依托泊苷更具细胞毒性（P = 0.0001）。与单独使用顺铂或替拉扎明相比，替拉扎明和顺铂同时给药时接种效率显著降低（P = 0.04），但替拉扎明在顺铂前3小时给药时则不然。总之，替拉扎明对人肿瘤克隆细胞具有细胞毒性。其体内疗效可能取决于与所使用肿瘤模型上已有的活性化疗药物联合使用。给药时间可能没有之前认为的那么重要。
