Nemati F, Livartowski A, De Cremoux P, Bourgeois Y, Arvelo F, Pouillart P, Poupon M F
UMR 147, Centre National de la Recherche Scientifique, Institut Curie, Paris, France.
Clin Cancer Res. 2000 May;6(5):2075-86.
Combined modalities are currently used for cancer therapy, although their mechanisms of activity remain incompletely deciphered. The design of new drug combinations suffers from our inability to anticipate accurately their efficacy or toxicity. They can be evaluated in vivo, using human tumors grafted into immunodeficient mice, as we did here with combined protocols used in the clinical setting. Xenografts of small cell lung carcinoma (SCLC) from eight patients were used to test the tumor sensitivity to etoposide (VP16; 12-16 mg/kg/days, days 1, 2, and 3), cisplatin (CDDP; 6-9 mg/kg/day, day 1) and ifosfamide (IFO; 90-210 mg/kg/day, days 1, 2, and 3) as single agents and to evaluate the efficacy of the two-drug or three-drug combinations. Five xenografts came from untreated patients (SCLC-61, SCLC-6, SCLC-10, SCLC-41, and SCLC-96) and three after treatment (SCLC-74, SCLC-101, and SCLC-108). p53 was inactivated in all of them. Tumor growth inhibition, growth delay, and the survival rate of tumor-bearing mice reflected individual SCLC chemosensitivity. As single agents, IFO inhibited tumor growth in a dose-dependent manner, whereas CDDP and VP16 had little or no effect. Both CDDP and IFO potentiated VP16, inducing complete regressions in the most sensitive SCLCs; VP16-IFO was more effective than VP16-CDDP, with complete regressions in six versus three of the eight tumors tested, respectively. CDDP-IFO was less effective than VP16-IFO, with three of eight SCLCs giving complete regressions. The three-drug combination led to modest improvement over the best two-drug combination but only for sensitive SCLCs. Because drug-responses distinguished two classes of SCLCs, as sensitive or refractory, MDR1, glutathione S-transferase pi, lung-related multidrug resistance protein, multidrug resistance protein, and topoisomerase IIalpha mRNA expression was studied by semiquantitative reverse transcription. There was no correlation with SCLC sensitivity; topoisomerase IIalpha and multidrug resistance protein was expressed in all cases, lung-related multidrug resistance protein and glutathione S-transferase pie in seven of eight, and MDR1 gene in four of eight. In conclusion, these SCLC xenografts displayed a pattern of chemotherapy response close to that observed in patients. This model confirmed that in two-drug combinations, each component potentiated the effects of the other, with VP16-IFO tending to be the best two-drug combination, both of which were more effective than VP16-CDDP and better tolerated than CDDP-IFO. The addition of a third agent gave a modest, if any, therapeutic benefit in the responders but none in refractory SCLCs. There was no correlation between the extent of response and resistance markers.
目前联合治疗方式被用于癌症治疗，尽管其作用机制仍未完全阐明。新的药物组合设计因我们无法准确预测其疗效或毒性而受到影响。它们可以在体内进行评估，利用接种到免疫缺陷小鼠体内的人肿瘤，就像我们在这里使用临床环境中使用的联合方案所做的那样。来自8名患者的小细胞肺癌（SCLC）异种移植物被用于测试肿瘤对依托泊苷（VP16；12 - 16毫克/千克/天，第1、2和3天）、顺铂（CDDP；6 - 9毫克/千克/天，第1天）和异环磷酰胺（IFO；90 - 210毫克/千克/天，第1、2和3天）作为单一药物的敏感性，并评估两药或三药组合的疗效。5个异种移植物来自未经治疗的患者（SCLC - 61、SCLC - 6、SCLC - 10、SCLC - 41和SCLC - 96），3个来自治疗后的患者（SCLC - 74、SCLC - 101和SCLC - 108）。所有异种移植物中的p53均失活。荷瘤小鼠的肿瘤生长抑制、生长延迟和存活率反映了个体SCLC的化疗敏感性。作为单一药物，IFO以剂量依赖的方式抑制肿瘤生长，而CDDP和VP16几乎没有作用或没有作用。CDDP和IFO均增强了VP16的作用，在最敏感的SCLC中诱导完全消退；VP16 - IFO比VP16 - CDDP更有效，在分别测试的8个肿瘤中，有6个和3个完全消退。CDDP - IFO比VP16 - IFO效果差，8个SCLC中有3个完全消退。三药组合比最佳两药组合有适度改善，但仅对敏感的SCLC有效。由于药物反应区分了两类SCLC，即敏感或难治，通过半定量逆转录研究了MDR1、谷胱甘肽S - 转移酶pi、肺相关多药耐药蛋白、多药耐药蛋白和拓扑异构酶IIα mRNA表达。与SCLC敏感性无相关性；拓扑异构酶IIα和多药耐药蛋白在所有病例中均有表达，肺相关多药耐药蛋白和谷胱甘肽S - 转移酶pi在8个中有7个表达，MDR1基因在8个中有4个表达。总之，这些SCLC异种移植物显示出的化疗反应模式与在患者中观察到的相近。该模型证实，在两药组合中，每种成分增强了另一种成分的作用，VP16 - IFO倾向于成为最佳两药组合，两者均比VP16 - CDDP更有效且比CDDP - IFO耐受性更好。添加第三种药物对反应者有适度的治疗益处（如果有的话），但对难治性SCLC没有益处。反应程度与耐药标志物之间没有相关性。
