ADDING A REVERSER (VERAPAMIL) TO COMBINED CHEMOTHERAPY OVERRIDES RESISTANCE IN SMALL-CELL LUNG-CANCER XENOGRAFTS

Small cell lung carcinomas (SCLC) are characterised by chemosensitivit y to diverse antitumoral compounds. However, responses are transitory and relapses are commonly observed. We examined the ability of verapam il, 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, Fr ance, and adapted to the treatment of nude mice implanted with these t umours. Although Pgp encoded by the MDR1 (multidrug resistance) gene i s not the only mechanism for multidrug resistance (MDR), and not all d rags included in this regimen are recognised by Pgp, we anticipated a therapeutic benefit. Four different SCLC lines, expressing the MDR1 ge ne 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-4 1T and SCLC-6T tumours were used after having undergone, respectively, five and nine cycles of in vivo passage and CyCAV treatment of the tu mour-bearing nude mice, to reinforce their chemoresistance. The effica cy of the CyCAV regimen, associated with or without verapamil (given 2 4 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 o bserved. Verapamil modestly delayed the plasma clearance of ADM. Two d aily injections of 10 mg/kg of verapamil, administered at a 3 h interv al, proved to be effective, whereas the same total dose administered a s a bolus was not. These results indicate that the association of some reversers of MDR, including drugs possibly interacting with Pgp, migh t potentiate SCLC combined chemotherapy.