Initial testing of topotecan by the pediatric preclinical testing program.

Journal Article

BACKGROUND: Topotecan is a small molecule DNA topoisomerase I poison, that has been successful in clinical trials against pediatric solid tumors and leukemias. Topotecan was evaluated against the Pediatric Preclinical Testing Program (PPTP) tumor panels as part of a validation process for these preclinical models. PROCEDURES: In vivo three measures of antitumor activity were used: (1) an objective response measure modeled after the clinical setting; (2) a treated to control (T/C) tumor volume measure; and (3) a time to event (fourfold increase in tumor volume for solid tumor models, or > or =25% human CD45+ cells in the peripheral blood for acute lymphoblastic leukemia, ALL models) measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. RESULTS: Topotecan inhibited cell growth in vitro with IC(50) values between 0.71 and 489 nM. Topotecan significantly increased EFS in 32 of 37 (87%) solid tumor xenografts and in all 8 of the ALL xenografts. Seventy-five percent of solid tumors met EFS T/C activity criteria for intermediate (n = 17) or high activity (n = 7). Objective responses were noted in eight solid tumor xenografts (Wilms, rhabdomyosarcoma, Ewing sarcoma, neuroblastoma). Among the six neuroblastomas, three achieved a PR. For the ALL panel, two maintained CRs, three CRs, and two PRs were observed. CONCLUSIONS: Topotecan demonstrated broad activity in vitro and in vivo against both the solid tumor and ALL panels, with significant tumor growth delay generated in all the panels. These results further demonstrate the validity of the PPTP panel for preclinical testing of new drugs.

Full Text

Duke Authors

Cited Authors

  • Carol, H; Houghton, PJ; Morton, CL; Kolb, EA; Gorlick, R; Reynolds, CP; Kang, MH; Maris, JM; Keir, ST; Watkins, A; Smith, MA; Lock, RB

Published Date

  • May 2010

Published In

Volume / Issue

  • 54 / 5

Start / End Page

  • 707 - 715

PubMed ID

  • 20017204

Electronic International Standard Serial Number (EISSN)

  • 1545-5017

Digital Object Identifier (DOI)

  • 10.1002/pbc.22352

Language

  • eng

Conference Location

  • United States