Efficacy and toxicity profile of oral topotecan in a panel of human tumour xenografts

  • De Cesare M
  • Zunino F
  • Pace S
 et al. 
  • 9

    Readers

    Mendeley users who have this article in their library.
  • 28

    Citations

    Citations of this article.

Abstract

On the basis of their mechanism of action (cell killing during DNA replication) and the potential reversibility of the drug effects, protracted therapy with camptothecins is reported to provide optimal antitumour effects. Furthermore, oral administration may be a useful modality for optimisation of treatment. The aim of this study was to compare the therapeutic profile of topotecan given orally or intravenously in human tumours xenografted into athymic nude mice. The drug topotecan was given according to an intermittent (every fourth day, four times) or daily (qd x 5/weekly x 5-10 weeks; only orally) schedule. Tumour growth inhibition and persistence of drug effects were assessed and compared with untreated mice. In a panel of seven tumour xenografts, oral topotecan was at least as effective on three and significantly more effective on four tumours. Using the intermittent schedule, the maximum tolerated dose (MTD) was comparable for the two routes (15 mg/kg), but the toxicity profile suggested a better tolerability in terms of lethal effects after oral administration. The daily oral treatment of low drug doses allowed a higher cumulative dose to be delivered with improved antitumour efficacy (2/10 cured in a large cell lung cancer) and no evidence of toxicity. In spite of the low bioavailability of oral topotecan (23.5%), the persistent plasma levels of the drug suggest that the time of exposure to the drug is more critical than the plasma concentrations for antitumour efficacy. This interpretation is consistent with the increased efficacy of prolonged daily treatment with low-dose levels. The results may have implications for the future design of clinical studies. (C) 2000 Elsevier Science Ltd.

Author-supplied keywords

  • Administration routes
  • Camptothecins
  • Human tumour xenograft
  • Nude mice
  • Preclinical studies
  • Topotecan

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document

Authors

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free