Arvelo F, Poupon M F, Bichat F, Grossin F, Bourgeois Y, Jacrot M, Bastian G, Le Chevalier T
Centro de Biologia Celular, Facultad de Ciencias, Universidad Central de Venezuela, Caracas, Venezuela.
Eur J Cancer. 1995 Oct;31A(11):1862-8. doi: 10.1016/0959-8049(95)00386-w.
Small cell lung carcinomas (SCLC) are characterised by chemosensitivity to diverse antitumoral compounds. However, responses are transitory and relapses are commonly observed. We examined the ability of verapamil, a reverser of P-glycoprotein (Pgp)-related resistance, to improve the efficacy of CyCAV combined chemotherapy (Cy, cyclophosphamide (CPA); C, cisplatin (CDDP); A, doxorubicin (ADM);V, etoposide (VP16)), as currently administered to SCLC patients at Institut Gustave-Roussy, France, and adapted to the treatment of nude mice implanted with these tumours. Although Pgp encoded by the MDR1 (multidrug resistance) gene is not the only mechanism for multidrug resistance (MDR), and not all drugs included in this regimen are recognised by Pgp, we anticipated a therapeutic benefit. Four different SCLC lines, expressing the MDR1 gene and recently grafted into nude mice, were used. SCLC-75, SCLC-6 and SCLC-41 originated from untreated patients, and SCLC-74T was derived from a patient treated with a combination of ADM, CPA and VP16. SCLC-41% and SCLC-6T tumours were used after having undergone, respectively, five and nine cycles of in vivo passage and CyCAV treatment of the tumour-bearing nude mice, to reinforce their chemoresistance. The efficacy of the CyCAV regimen, associated with or without verapamil (given 24 h before CyCAV on days 1-5), was tested on the growth of these SCLC. Verapamil (25 mg/kg) improved the antitumour effect of CyCAV in mice bearing SCLC-6T, SCLC-41T and SCLC-75 tumours, although toxicity was observed. Verapamil modestly delayed the plasma clearance of ADM. Two daily injections of 10 mg/kg of verapamil, administered at a 3 h interval, proved to be effective, whereas the same total dose administered as a bolus was not. These results indicate that the association of some reversers of MDR, including drugs possibly interacting with Pgp, might potentiate SCLC combined chemotherapy.
小细胞肺癌（SCLC）的特点是对多种抗肿瘤化合物具有化学敏感性。然而，反应是短暂的，复发很常见。我们研究了维拉帕米（一种P-糖蛋白（Pgp）相关耐药逆转剂）提高CyCAV联合化疗（Cy，环磷酰胺（CPA）；C，顺铂（CDDP）；A，阿霉素（ADM）；V，依托泊苷（VP16））疗效的能力，目前法国古斯塔夫-鲁西研究所将该联合化疗方案用于SCLC患者，并将其应用于接种这些肿瘤的裸鼠治疗。尽管由多药耐药（MDR）基因MDR1编码的Pgp不是多药耐药的唯一机制，且该方案中并非所有药物都被Pgp识别，但我们预期会有治疗益处。使用了四个表达MDR1基因且最近接种到裸鼠体内的不同SCLC细胞系。SCLC-75、SCLC-6和SCLC-41来源于未经治疗的患者，SCLC-74T来源于一名接受ADM、CPA和VP16联合治疗的患者。SCLC-41%和SCLC-6T肿瘤在分别经过五个和九个周期的体内传代以及对荷瘤裸鼠进行CyCAV治疗后使用，以增强其化疗耐药性。在这些SCLC的生长上测试了CyCAV方案联合或不联合维拉帕米（在第1 - 5天CyCAV前24小时给予）的疗效。维拉帕米（25 mg/kg）提高了CyCAV对荷SCLC-6T、SCLC-41T和SCLC-75肿瘤小鼠的抗肿瘤作用，尽管观察到了毒性。维拉帕米适度延迟了ADM的血浆清除。每3小时间隔注射两次10 mg/kg的维拉帕米被证明是有效的，而以推注方式给予相同总剂量则无效。这些结果表明，一些MDR逆转剂（包括可能与Pgp相互作用的药物）的联合使用可能增强SCLC联合化疗的效果。
