PRECLINICAL PHASE-II STUDIES IN HUMAN TUMOR XENOGRAFTS - A EUROPEAN MULTICENTER FOLLOW-UP-STUDY

Background: The EORTC New Drug Development Office has initiated a mult icenter collaborative program to evaluate the use of human tumor xenog rafts to predict phase II clinical activity. A first study confirmed t he efficacy of doxorubicin and inactivity of amsacrine against human t umor xenografts (Boven et al., Cancer Res: 52, 5940, 1992). In the fol low-up study reported here, the activities of cisplatin, AZQ (diaziquo ne), pazelliptine and retelliptine have been evaluated against a panel of 40 established tumor lines grown subcutaneously in nude mice. Desi gn: The xenografts used represent carcinomas of the breast, colon, hea d + neck, ovary, small cell lung cancer (SCLC), non-small cell lung ca ncer (NSCLC) and melanoma. Drugs were administered intravenously on da ys 0 and 7. Doses were for cisplatin 5 mg/kg, AZQ 3-7 mg/kg, pazellipt ine 20-80 mg/kg and retelliptine 6-12.5 mg/kg and were selected to giv e a median loss of about 10%-15% body weight. Results: When activity w as defined as a specific growth delay > 1 and a tumor growth inhibitio n > 50%, then cisplatin demonstrated activity in 15 of 40 xenografts t ested (3 of 5 breast, 1 of 6 colon, 0 of 5 head + neck, 2 of 6 NSCLC, 4 of 7 SCLC, 1 of 5 melanoma and 4 of 6 ovarian cancers); AZQ was acti ve in 23 of 38 xenografts (2 of 3 breast, 2 of 7 colon, 4 of 5 head neck, 3 of 6 NSCLC, 6 of 6 SCLC, 2 of 5 melanoma, 4 of 6 ovarian cance rs); pazelliptine was active in 2 of 38 xenografts (1 of 5 breast canc ers, 1 of 5 melanoma) while retelliptine was active in 1 of 39 xenogra fts (a breast cancer xenograft) tested. Conclusions: These results are reasonably consistent with the clinical activity of cisplatin, but ov erpredict the clinical efficacy of AZQ. Since pazelliptine and retelli ptine are investigational compounds, the clinical phase II studies wil l provide a prospective test for this model. The results of the presen t study and the previous one indicate that the human tumor xenograft m odel could be suitable for predicting the activity of novel compounds to be developed for treatment of cancer patients.