Synergy of topotecan in combination with vincristine for treatment of pediatric solid tumor xenografts

Joyce Thompson, E. Olusegun George, Catherine A. Poquette, Pamela J. Cheshire, Lois B. Richmond, Siebold S.N. De Graaf, Margaret Ma, Clinton F. Stewart, Peter J Houghton

Research output: Contribution to journalArticle

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Abstract

Topotecan and vincristine were evaluated alone or in combination against 13 independent xenografts and 1 vincristine-resistant derivative, representing childhood neuroblastoma (n = 6), rhabdomyosarcoma (n = 5), or brain tumors (n = 3). Topotecan was given by i.v. bolus on a schedule found previously to be optimal. Drug was administered daily for 5 days on 2 consecutive weeks with cycles repeated every 21 days over a period of 8 weeks. Doses of topotecan ranged from 0.16 to 1.5 mg/kg to simulate clinically achievable topotecan lactone plasma systemic exposures. Vincristine was administered i.v. every 7 days at a fixed dose of 1 mg/kg. Given as a single agent, vincristine induced complete responses (CRs) in all mice bearing two rhabdomyosarcomas (Rh28 and Rh30) and some CRs in Rh12- bearing mice (57%) but relatively few CRs (<29%) in other tumors. As a single agent, topotecan induced CR in a low proportion of tumor lines. A dose- response model with a logit link function was used to investigate whether the combination of topotecan and vincristine resulted in greater than expected responses compared with the activity of the agents when administered alone. Only CR was used to evaluate tumor responses. The combination resulted in significantly greater than expected CRs than individual agents in nine tumor lines (four neuroblastoma, three brain tumors, and two rhabdomyosarcomas). Similar event-free (failure) distributions were shown in SJ-GBM2 glioblastoma xenografts, whether vincristine was administered on day 1 or day 5 of each topotecan course. To determine whether the increased antitumor activity with the combination was attributable to a change in drug disposition, extensive pharmacokinetic studies were performed. However, little or no interaction between these two agents was determined. Toxicity of the combination was marked by prolonged thrombocytopenia and decreased hemoglobin. However, approximately 75 and 80% of the maximum tolerated dose of each single agent, topotecan (1.5 mg/kg) or vincristine (1 mg/kg), could be given in combination, resulting in a combination toxicity index of ~1.5. These results show that the therapeutic effect of combining topotecan with vincristine was greater than additive in most tumor models of childhood solid tumors, and toxicity data suggest that this can be administered to mice with only moderate reduction in the dose levels for each agent.

Original languageEnglish (US)
Pages (from-to)3617-3631
Number of pages15
JournalClinical Cancer Research
Volume5
Issue number11
StatePublished - Nov 1 1999
Externally publishedYes

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Topotecan
Vincristine
Heterografts
Pediatrics
Neoplasms
Rhabdomyosarcoma
Neuroblastoma
Brain Neoplasms
Maximum Tolerated Dose
Therapeutic Uses
Lactones
Glioblastoma
Thrombocytopenia
Pharmaceutical Preparations
Appointments and Schedules
Hemoglobins
Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Thompson, J., George, E. O., Poquette, C. A., Cheshire, P. J., Richmond, L. B., De Graaf, S. S. N., ... Houghton, P. J. (1999). Synergy of topotecan in combination with vincristine for treatment of pediatric solid tumor xenografts. Clinical Cancer Research, 5(11), 3617-3631.

Synergy of topotecan in combination with vincristine for treatment of pediatric solid tumor xenografts. / Thompson, Joyce; George, E. Olusegun; Poquette, Catherine A.; Cheshire, Pamela J.; Richmond, Lois B.; De Graaf, Siebold S.N.; Ma, Margaret; Stewart, Clinton F.; Houghton, Peter J.

In: Clinical Cancer Research, Vol. 5, No. 11, 01.11.1999, p. 3617-3631.

Research output: Contribution to journalArticle

Thompson, J, George, EO, Poquette, CA, Cheshire, PJ, Richmond, LB, De Graaf, SSN, Ma, M, Stewart, CF & Houghton, PJ 1999, 'Synergy of topotecan in combination with vincristine for treatment of pediatric solid tumor xenografts', Clinical Cancer Research, vol. 5, no. 11, pp. 3617-3631.
Thompson J, George EO, Poquette CA, Cheshire PJ, Richmond LB, De Graaf SSN et al. Synergy of topotecan in combination with vincristine for treatment of pediatric solid tumor xenografts. Clinical Cancer Research. 1999 Nov 1;5(11):3617-3631.
Thompson, Joyce ; George, E. Olusegun ; Poquette, Catherine A. ; Cheshire, Pamela J. ; Richmond, Lois B. ; De Graaf, Siebold S.N. ; Ma, Margaret ; Stewart, Clinton F. ; Houghton, Peter J. / Synergy of topotecan in combination with vincristine for treatment of pediatric solid tumor xenografts. In: Clinical Cancer Research. 1999 ; Vol. 5, No. 11. pp. 3617-3631.
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