Arvelo F, Poupon M F, Goguel A F, Lizard G, Bourgeois Y, Arriagada R, Le Chevalier T
Institute Curie, URA CNRS 620, Paris, France.
J Cancer Res Clin Oncol. 1993;120(1-2):17-23. doi: 10.1007/BF01200719.
Small-cell lung carcinomas (SCLC) are highly responsive to various chemotherapies. However only a minority of patients benefit from long survival. SCLC patients treated at the Institut Gustave Roussy received a combined chemotherapy (CCAV) including cisplatin, cyclophosphamide (Cpa), Adriamycin (doxorubicin; Adm) and vepeside (VP16). We report here the intrinsic sensitivity of a small-cell lung carcinoma, designated SCLC-6, grafted in nude mice. This xenografted tumour was derived from an untreated patient. The CCAV regimen given to the patient donor of the tumour sample resulted in a complete response followed by recurrence and death, 8 months after the initial cure. The expression of P-glycoprotein encoded by the MDR1 gene was detected with the C219 antibody on the membrane of SCLC-6 tumour cells. When given to SCLC-6-tumour-bearing nude mice, CCAV induced a strong inhibition of tumour growth (84% of growth inhibition, 20 days after start of the treatment), but no cure. Intensification of CCAV doses did not improve the response. The efficacy of individual agents of the CCAV, given at maximal tolerated doses was analysed. Only cisplatin (10 mg/kg) and Cpa (3 x 50 mg/kg) inhibited SCLC-6 growth (79% and 100% inhibition respectively), VP16 (3 x 24 mg/kg) was poorly efficient (42%) and Adm (10 mg/kg) not at all. Two-drug combinations such as cisplatin plus VP16 or cisplatin plus Cpa inhibited tumour growth (81% and 70%, respectively). Curiously, the efficacy of Cpa, given in combination with cisplatin was less than that of Cpa alone. Repeated treatments with CCAV administered to mice at each in vivo passage of the tumour induced a loss of chemosensitivity, which was observed until the ninth passage. An improvement of the therapeutic response was obtained by adding a headline reverser of multi-drug resistance, verapamil (25 mg/kg), to CCAV (81% versus 63% inhibition). MDR1-related resistance appeared to play a role in the failure of SCLC-6 chemotherapy; frequent recurrences after treatment with cisplatin and Cpa, two drugs that are not recognized by the P-glycoprotein, indicated that other modes of resistance were simultaneously active.
小细胞肺癌（SCLC）对各种化疗高度敏感。然而，只有少数患者能从长期生存中获益。在古斯塔夫·鲁西研究所接受治疗的SCLC患者接受了包括顺铂、环磷酰胺（Cpa）、阿霉素（多柔比星；Adm）和依托泊苷（VP16）的联合化疗（CCAV）。我们在此报告移植到裸鼠体内的一株小细胞肺癌，命名为SCLC-6的内在敏感性。这种异种移植肿瘤来源于一名未经治疗的患者。给予肿瘤样本供体患者的CCAV方案导致完全缓解，但在初始治愈8个月后复发并死亡。用C219抗体在SCLC-6肿瘤细胞膜上检测到了由MDR1基因编码的P-糖蛋白的表达。当给予携带SCLC-6肿瘤的裸鼠时，CCAV诱导肿瘤生长受到强烈抑制（治疗开始20天后生长抑制率为84%），但未治愈。增加CCAV剂量并未改善反应。分析了以最大耐受剂量给予的CCAV中各药物的疗效。只有顺铂（10mg/kg）和Cpa（3×50mg/kg）抑制了SCLC-6的生长（分别为79%和100%抑制），VP16（3×24mg/kg）效果不佳（42%），Adm（10mg/kg）则完全无效。两种药物联合使用，如顺铂加VP16或顺铂加Cpa，抑制了肿瘤生长（分别为81%和70%）。奇怪的是，Cpa与顺铂联合使用时的疗效低于单独使用Cpa时。在肿瘤的每次体内传代时，对小鼠重复给予CCAV治疗会导致化学敏感性丧失，这种情况一直持续到第九代。通过在CCAV中添加一种多药耐药的一线逆转剂维拉帕米（25mg/kg），治疗反应得到了改善（抑制率从63%提高到81%）。MDR1相关耐药似乎在SCLC-6化疗失败中起作用；用顺铂和Cpa治疗后频繁复发，这两种药物不被P-糖蛋白识别，表明其他耐药模式同时起作用。
