Koch C J
Radiation Oncology, University of Pennsylvania, Philadelphia 19104-6072.
Cancer Res. 1993 Sep 1;53(17):3992-7.
Toxicity from drugs activated by bioreductive metabolism has been suggested as a means to eliminate the treatment resistance caused by hypoxic tumor cells. In general, drugs have been selected to maximize the hypoxic cytotoxicity ratio [exposure (drug concentration x time) in air:exposure in nitrogen] to cause equal toxicity. On this basis, two recently developed drugs have very similar characteristics; an aziridine derivative of misonidazole (RSU1069) and a benzotriazine di-N-oxide (SR4233). The oxygen dependence of the toxic response has not previously been characterized. This report shows that the toxicity from SR4233 extends over a much greater range of oxygen concentrations than does that of RSU1069. Furthermore, unlike all previous drugs studied, the toxicity of SR4233 does not level off at high oxygen concentrations, but continues to decrease as the oxygen concentration increases. For 1 mM oxygen (the solubility of oxygen in medium at 37 degrees C equilibrated with 100% oxygen and water vapor) the toxicity from SR4233 is at least 2000-fold less than that for hypoxia. Modeling the effect of oxygen on combined radiation and toxicity shows that radiation plus SR4233 should be much more effective in eliminating hypoxic cells than radiation plus RSU1069. The unusual oxygen dependence of toxicity by SR4233 may indicate a unique biochemical activation process.
生物还原代谢激活的药物毒性已被视为消除缺氧肿瘤细胞引起的治疗抗性的一种手段。一般来说,已选择药物以最大化缺氧细胞毒性比率[在空气中的暴露量(药物浓度×时间):在氮气中的暴露量]以产生同等毒性。在此基础上,最近开发的两种药物具有非常相似的特性;米索硝唑的氮丙啶衍生物(RSU1069)和苯并三嗪二-N-氧化物(SR4233)。此前尚未对毒性反应的氧依赖性进行表征。本报告表明,与RSU1069相比,SR4233的毒性在更大的氧浓度范围内存在。此外,与之前研究的所有药物不同,SR4233的毒性在高氧浓度下不会趋于平稳,而是随着氧浓度的增加持续降低。对于1 mM氧气(37℃下与100%氧气和水蒸气平衡的培养基中氧气的溶解度),SR4233的毒性比缺氧时至少低2000倍。对氧气对联合放疗和毒性的影响进行建模表明,放疗加SR4233在消除缺氧细胞方面应比放疗加RSU1069有效得多。SR4233毒性异常的氧依赖性可能表明其独特的生化激活过程。