Use of nude mouse xenografts as preclinical drug screens: in vivo activity of established chemotherapeutic agents against melanoma and ovarian carcinoma xenografts.
To evaluate the utility of nude mouse xenografts as preclinical drug screens, the activity of ten established chemotherapeutic agents was evaluated against seven melanoma and three ovarian carcinoma xenografts. Xenografts were established using primary explants from patients who had not received chemotherapy and serially passaged as sc tumors in nude mice. In vivo drug activities for dactinomycin, carmustine, vinblastine, melphalan, amsacrine, cisplatin, bleomycin, mitomycin, doxorubicin, and etoposide were evaluated by 4 weekly ip injections of 10% less than LD10 doses. Plots of relative tumor growth versus time were nearly log-linear. Analysis of in vivo activity was performed using percent control growth (treated/control tumor volume) and by calculation of a novel growth delay index obtained by fitting growth curves to a quadratic regression model. Both modes of data analysis identified alkylating agents (melphalan, carmustine, and mitomycin) as the most active drugs against human melanomas. Melphalan, mitomycin, and cisplatin showed the greatest activity against ovarian xenografts. However, complete tumor regressions were noted only with melphalan, mitomycin, and cisplatin against a single ovarian tumor xenograft. Correlation analysis suggested xenograft tumor growth rate was an important determinant of drug response. These results suggest that preclinical, new-drug screening with melanoma xenografts would identify drugs such as alkylating agents as active, and may not provide an advantage over murine leukemia screens. However, screening with ovarian xenografts may more closely reflect clinical drug activity. Criteria for detecting active drugs in such systems are discussed.