Distinctive potentiating effects of cisplatin and/or ifosfamide combined with etoposide in human small cell lung carcinoma xenografts

Combined modalities are currently used for cancer therapy, although their m echanisms of activity remain incompletely deciphered. The design of new dru g combinations suffers from our inability to anticipate accurately their ef ficacy or toxicity. They can be evaluated irt vivo, using human tumors graf ted into immunodeficient mice, as we did here with combined protocols used in the clinical setting. Xenografts of small cell lung carcinoma (SCLC) fro m 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 agent s 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, SCL C-41, and SCLC-96) and three after treatment (SCLC-74, SCLC-101, and SCLC-1 08). p53 was inactivated in all of them. Tumor growth inhibition, growth de lay, and the survival rate of tumor-bearing mice reflected individual SCLC chemosensitivity. As single agents, IFO inhibited tumor growth in a dose-de pendent manner, whereas CDDP and VP16 had little or no effect. Both CDDP an d IFO potentiated VP16, inducing complete regressions in the most sensitive SCLCs; VP16-IFO was more effective than VP16-CDDP, with complete regressio ns in six versus three of the eight tumors tested, respectively. CDDP-IFO w as 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-respon ses distinguished two classes of SCLCs, as sensitive or refractory, MDR1, g lutathione S-transferase pi, lung-related multidrug resistance protein, mul tidrug resistance protein, and topoisomerase II alpha mRNA expression was s tudied by semiquantitative reverse transcription. There was no correlation with SCLC sensitivity; topoisomerase II alpha and multidrug resistance prot ein was expressed in all cases, lung-related multidrug resistance protein a nd glutathione S-transferase pi in seven of eight, and MDR1 gene in four of eight. In conclusion, these SCLC xenografts displayed a pattern of chemoth erapy response close to that observed in patients. This model confirmed tha t in two-drug combinations, each component potentiated the effects of the o ther, with VP16-IFO tending to be the best two-drug combination, both of wh ich 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 betw een the extent of response and resistance markers.