Rauth A M, Marshall R S, Kuehl B L
Division of Experimental Therapeutics, Ontario Cancer Institute, Toronto, Canada.
Cancer Metastasis Rev. 1993 Jun;12(2):153-64. doi: 10.1007/BF00689807.
Mitomycin C is being used as an adjunct to ionizing radiation in the treatment of some solid tumors. A rationale for this is that radioresistant hypoxic cells in solid tumors will have enhanced sensitivity to this bioreductively activated drug, compared to aerobic cells. The role of oxygen concentration and enzymatic drug reduction in bioreductive drug activation have been investigated. Techniques are reviewed for the in vitro determination of the oxygen concentration dependency of bioreductive drug activation. One of these techniques, an open cell suspension system using Chinese hamster ovary cells, is described. Results are shown that indicate that the oxygen concentration dependency of toxicity of mitomycin C and one of its analogues profiromycin, though qualitatively complementing the oxygen dependency of ionizing radiation toxicity, are not quantitatively optimal. Using a mitomycin C resistant human cell strain (3437T) from a cancer prone family, a possible role for DT-diaphorase, an oxygen insensitive 2-electron transfer enzyme, is suggested. A correlation between a low level of DT-diaphorase in 3437T cells and mitomycin C resistance under aerobic exposure conditions is seen. Under hypoxic exposure conditions this resistance is lost, suggesting 1-electron transfer enzymes control hypoxic cell bioreductive activation. An activation role for DT-diaphorase in mitomycin C toxicity in the treatment of solid tumors is contrasted to a potential detoxification role for the enzyme with other xenobiotics in the cancer prone family phenotype.
丝裂霉素C正被用作某些实体瘤放射治疗的辅助药物。其理论依据是，与需氧细胞相比，实体瘤中对辐射耐受的缺氧细胞对这种生物还原激活药物的敏感性会增强。已对氧浓度和酶促药物还原在生物还原药物激活中的作用进行了研究。本文综述了体外测定生物还原药物激活的氧浓度依赖性的技术。其中一种技术，即使用中国仓鼠卵巢细胞的开放细胞悬浮系统，也作了描述。结果表明，丝裂霉素C及其类似物丙亚胺的毒性对氧浓度的依赖性，虽然在性质上与电离辐射毒性的氧依赖性互补，但在数量上并非最佳。利用来自一个癌症易感家族的丝裂霉素C耐药人细胞系（3437T），提示了一种对氧不敏感的双电子传递酶——DT-黄递酶的可能作用。在有氧暴露条件下，观察到3437T细胞中DT-黄递酶水平低与丝裂霉素C耐药之间存在相关性。在缺氧暴露条件下，这种耐药性消失，提示单电子传递酶控制缺氧细胞的生物还原激活。在实体瘤治疗中，DT-黄递酶在丝裂霉素C毒性中的激活作用与该酶在癌症易感家族表型中对其他异生物素的潜在解毒作用形成对比。
