Tannock I F
Br J Cancer. 1980 Dec;42(6):871-80. doi: 10.1038/bjc.1980.335.
The addition of misonidazole (MISO) or metronidazole (METRO) to treatment with cyclophosphamide (CY) increased delay to regrowth of 2 experimental tumours. The effect was observed for large an small tumours, was present for doses of MISO that are ineffective for killing hypoxic cells, and required that it be given with, or shortly before CY. Mice receiving combined treatment had more weight loss and myelosuppression than those receiving CY alone, and the Therapeutic Index was lower. MISO caused a marked increase in growth delay when combined with BCNU to treat the KHT sarcoma. This effect was observed for small and large tumours, required simultaneous administration of drugs, and also led to increased host toxicity. There was no therapeutic advantage from combined treatment. Survival of aerobic or anoxic Chinese hamster ovary (CHO) cells was assessed after exposure in vitro to serum from mice that had received CY or BCNU alone. MISO alone, or combined treatment. Results of these experiments suggest that (1) MISO delays the excretion or breakdown of active metabolites of CY, and (2) at a dose that does not kill hypoxic cells, it may selectively "sensitize" hypoxic cells (but not aerobic cells) to the action of BCNU. The presence of other undetermined interactions of BCNU and MISO is inferred from the increased toxicity to (aerobic) normal tissue. Misonidazole or metronidazole should be used with caution in patients who are receiving BCNU or cyclophosphamide.
在环磷酰胺（CY）治疗中加入米索硝唑（MISO）或甲硝唑（METRO）可延长两种实验性肿瘤的再生长延迟时间。对大小肿瘤均观察到了这种效果，对于对杀死缺氧细胞无效的米索硝唑剂量也存在这种效果，并且需要在使用CY时或使用CY前不久给予。接受联合治疗的小鼠比单独接受CY治疗的小鼠体重减轻更多且骨髓抑制更严重，治疗指数更低。米索硝唑与卡莫司汀（BCNU）联合治疗KHT肉瘤时可显著增加生长延迟。对大小肿瘤均观察到了这种效果，需要同时给药，并且也会导致宿主毒性增加。联合治疗没有治疗优势。在体外将中国仓鼠卵巢（CHO）需氧或厌氧细胞暴露于单独接受CY或BCNU、米索硝唑单独使用或联合治疗的小鼠血清后，评估细胞存活率。这些实验结果表明：（1）米索硝唑延迟CY活性代谢产物的排泄或分解；（2）在不杀死缺氧细胞的剂量下，它可能选择性地使缺氧细胞（而非需氧细胞）对卡莫司汀的作用“敏感化”。从对（需氧）正常组织毒性增加可推断出卡莫司汀和米索硝唑存在其他未确定的相互作用。在接受卡莫司汀或环磷酰胺治疗的患者中，应谨慎使用米索硝唑或甲硝唑。
