Siemann D W
Cancer Treat Rep. 1983 Mar;67(3):259-65.
Previous investigations have shown that the combination of the conventional chemotherapeutic agent lomustine (CCNU) and the nitroimidazole radiation sensitizer misonidazole can lead to an improved therapeutic result. To study whether altered CCNU metabolism plays a role in this chemopotentiation, mice were treated with known modifiers of hepatic microsomal enzymes prior to CCNU exposure, and tumor response and systemic toxicity were assessed. KHT sarcoma-bearing C3H/HeJ mice were pretreated with either (a) five daily doses of phenobarbital (80 mg/kg) to induce the microsomal enzymes and then CCNU 48 hours later or (b) a 50-mg/kg dose of the microsomal enzyme inhibitor SKF 525A 1 hour before CCNU. Tumor response and normal tissue toxicity following treatment were measured using a regrowth delay and 30-day lethality assay, respectively. Phenobarbital pretreatment reduced both the antitumor efficacy and toxicity of CCNU (factor of approximately 0.8), while SKF 525A increased the effect of CCNU in both cases (factor of approximately 1.6). Thus, unlike pretreatments with the sensitizer misonidazole, pretreatments with phenobarbital or SKF 525A did not result in a therapeutic advantage for CCNU.
先前的研究表明，传统化疗药物洛莫司汀（CCNU）与硝基咪唑类辐射增敏剂米索硝唑联合使用可提高治疗效果。为了研究CCNU代谢改变是否在这种化疗增敏中起作用，在给予CCNU之前，先用已知的肝微粒体酶调节剂处理小鼠，然后评估肿瘤反应和全身毒性。将携带KHT肉瘤的C3H/HeJ小鼠预先用以下方法处理：（a）每天给予五剂苯巴比妥（80mg/kg）以诱导微粒体酶，48小时后给予CCNU；或（b）在给予CCNU前1小时给予50mg/kg剂量的微粒体酶抑制剂SKF 525A。分别使用再生长延迟和30天致死率测定法测量治疗后的肿瘤反应和正常组织毒性。苯巴比妥预处理降低了CCNU的抗肿瘤疗效和毒性（约为0.8倍），而SKF 525A在两种情况下均增加了CCNU的作用（约为1.6倍）。因此，与用增敏剂米索硝唑预处理不同，用苯巴比妥或SKF 525A预处理并未给CCNU带来治疗优势。
