Initial testing of cisplatin by the pediatric preclinical testing program

Abstract

Cisplatin is one of the most widely used drugs for the treatment of solid tumors in adults and children. Here, we report the activity of cisplatin against the PPTP panels of childhood cancer xenografts. Cisplatin was evaluated against 23 cell lines, and 40 xenografts representing brain tumors, neuroblastoma, rhabdoid tumors, sarcoma, Wilms tumor, and acute lymphoblastic leukemia (ALL). The IC(50) concentration in vitro was determined for 96 hr exposure. Solid tumors were grown subcutaneously in immune-deficient mice, and tumor dimensions measured weekly. ALL xenografts were inoculated intravenously and the percent human CD45(+) cells in the peripheral blood determined weekly. The antitumor activity of cisplatin (7 mg/kg administered intraperitoneally on Days 0 and 21) was evaluated using time to event (EFS T/C), tumor growth delay (tumor volume T/C), and objective response measures. The median IC(50) concentration in vitro was 0.87 microM (0.24-4.29 microM), and cisplatin exhibited broad range activity. Cisplatin induced significant differences in EFS distributions compared to controls in 20/28 solid tumors and 4/8 ALL models. Objective responses were observed in 7/28 solid tumor models (25%): partial responses in three rhabdomyosarcomas and one Ewing's sarcoma; complete responses in one rhabdoid tumor and the medulloblastoma; and a maintained complete response in one Wilms tumor. No objective responses were observed in the ALL panel. Cisplatin exhibits significant antitumor activity against a broad range of solid tumor xenograft models and limited activity against ALL xenografts. This preclinical pattern of activity is generally consistent with cisplatin's clinical activity.