Coggins C A, Elion G B, Houghton P J, Hare C B, Keir S, Colvin O M, Bigner D D, Friedman H S
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Cancer Chemother Pharmacol. 1998;41(6):485-90. doi: 10.1007/s002800050771.
Two major obstacles in the treatment of patients with central nervous system malignancies are drug resistance and host toxicity. The goal of combination chemotherapy is to achieve therapeutic effects that are more favorable than using a single drug alone, but without an increase in normal organ toxicity. The study reported here examined the combination of a topoisomerase I inhibitor, irinotecan (CPT-11), with three different alkylating agents: 1,3-bis(2-chloroethyl)-1-nitrosourea, busulfan, and cyclophosphamide. We evaluated the antitumor effects of these three combinations against a panel of human tumor xenografts derived from central nervous system malignancies, including adult high-grade gliomas (D-54 MG, D-245 MG) and a childhood ependymoma (D-612 EP). In replicate experiments, the alkylating agents were given on day 1 in doses varying from 10% to 75% of the dose lethal to 10% of the animals, and CPT-11 was given on days 1-5 and 8-12 in doses varying from 10% to 100% of the dose lethal to 10% of the animals. The antitumor effects of the various combinations ranged from less than additive (7.61 days below additive with 0.5 CPT-11 + 0.75 cyclophosphamide in D-54 MG) to statistically significant (P < 0.001) supraadditive effects (18.80 days above additive with 0.5 CPT-11 + 0.5 1,3-bis(2-chloroethyl)-1-nitrosourea in D-54 MG). These studies show that the combination of the topoisomerase inhibitor CPT-11 and alkylating agents may increase the antitumor effect in some cases well above additive with no increase in host toxicity (0/10 deaths in both experiments cited above) and should be considered for combination chemotherapy of central nervous system malignancies.
治疗中枢神经系统恶性肿瘤患者面临的两大主要障碍是耐药性和宿主毒性。联合化疗的目标是获得比单独使用单一药物更有利的治疗效果，同时不增加正常器官的毒性。本文报道的研究考察了拓扑异构酶I抑制剂伊立替康（CPT-11）与三种不同烷化剂的联合使用情况，这三种烷化剂分别是1,3-双（2-氯乙基）-1-亚硝基脲、白消安和环磷酰胺。我们评估了这三种联合用药方案对一组源自中枢神经系统恶性肿瘤的人肿瘤异种移植模型的抗肿瘤效果，这些模型包括成人高级别胶质瘤（D-54 MG、D-245 MG）和儿童室管膜瘤（D-612 EP）。在重复实验中，烷化剂于第1天给药,剂量为对10%的动物致死剂量的10%至75%，CPT-11于第1 - 5天和第8 - 12天给药，剂量为对10%的动物致死剂量的10%至100%。各种联合用药方案的抗肿瘤效果从低于相加效应（在D-54 MG模型中，0.5 CPT-11 + 0.75环磷酰胺低于相加效应7.61天）到具有统计学意义（P < 0.001）的超相加效应（在D-54 MG模型中，0.5 CPT-11 + 0.5 1,3-双（2-氯乙基）-1-亚硝基脲高于相加效应18.80天）不等。这些研究表明，拓扑异构酶抑制剂CPT-11与烷化剂联合使用在某些情况下可能会使抗肿瘤效果大幅高于相加效应，且不增加宿主毒性（上述两个实验中均无死亡，死亡率为0/10），应考虑将其用于中枢神经系统恶性肿瘤的联合化疗。
