Initial testing of topotecan by the pediatric preclinical testing program

Hernan Carol, Peter J. Houghton, Christopher L. Morton, E. Anders Kolb, Richard Gorlick, C. Patrick Reynolds, Min H. Kang, John M. Maris, Stephen T. Keir, Amy Watkins, Malcolm A. Smith, Richard B. Lock

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Background. Topotecan is a smallmolecule 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 volumemeasure; and (3) a time to event (fourfold increase in tumor volume for solid tumor models, 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 IC50 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.

Original languageEnglish (US)
Pages (from-to)707-715
Number of pages9
JournalPediatric Blood and Cancer
Volume54
Issue number5
DOIs
StatePublished - May 2010

Fingerprint

Topotecan
Pediatrics
Heterografts
Neoplasms
Disease-Free Survival
Neuroblastoma
Type I DNA Topoisomerase
Ewing's Sarcoma
Wilms Tumor
Rhabdomyosarcoma
Poisons
Growth
Tumor Burden
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Inhibitory Concentration 50
Leukemia
Clinical Trials

Keywords

  • Developmental therapeutics
  • Preclinical testing
  • Topotecan

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Medicine(all)

Cite this

Carol, H., Houghton, P. J., Morton, C. L., Kolb, E. A., Gorlick, R., Reynolds, C. P., ... Lock, R. B. (2010). Initial testing of topotecan by the pediatric preclinical testing program. Pediatric Blood and Cancer, 54(5), 707-715. https://doi.org/10.1002/pbc.22352

Initial testing of topotecan by the pediatric preclinical testing program. / Carol, Hernan; Houghton, Peter J.; Morton, Christopher L.; Kolb, E. Anders; Gorlick, Richard; Reynolds, C. Patrick; Kang, Min H.; Maris, John M.; Keir, Stephen T.; Watkins, Amy; Smith, Malcolm A.; Lock, Richard B.

In: Pediatric Blood and Cancer, Vol. 54, No. 5, 05.2010, p. 707-715.

Research output: Contribution to journalArticle

Carol, H, Houghton, PJ, Morton, CL, Kolb, EA, Gorlick, R, Reynolds, CP, Kang, MH, Maris, JM, Keir, ST, Watkins, A, Smith, MA & Lock, RB 2010, 'Initial testing of topotecan by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 54, no. 5, pp. 707-715. https://doi.org/10.1002/pbc.22352
Carol H, Houghton PJ, Morton CL, Kolb EA, Gorlick R, Reynolds CP et al. Initial testing of topotecan by the pediatric preclinical testing program. Pediatric Blood and Cancer. 2010 May;54(5):707-715. https://doi.org/10.1002/pbc.22352
Carol, Hernan ; Houghton, Peter J. ; Morton, Christopher L. ; Kolb, E. Anders ; Gorlick, Richard ; Reynolds, C. Patrick ; Kang, Min H. ; Maris, John M. ; Keir, Stephen T. ; Watkins, Amy ; Smith, Malcolm A. ; Lock, Richard B. / Initial testing of topotecan by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2010 ; Vol. 54, No. 5. pp. 707-715.
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abstract = "Background. Topotecan is a smallmolecule 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 volumemeasure; and (3) a time to event (fourfold increase in tumor volume for solid tumor models, 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 IC50 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.",
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AU - Reynolds, C. Patrick

AU - Kang, Min H.

AU - Maris, John M.

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AU - Watkins, Amy

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AU - Lock, Richard B.

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