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Sequential oral 9-nitrocamptothecin and etoposide: a pharmacodynamic- and pharmacokinetic-based phase I trial

George R Simon1, Richard M Lush, Jana Gump

  • 1Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, SRB-2, Tampa, 33612-9416, USA.

Molecular Cancer Therapeutics
|August 25, 2006
PubMed
Abstract

Insights

This study found that sequential administration of topoisomerase I inhibitor 9-nitrocamptothecin and topoisomerase II inhibitor etoposide is tolerable and active in advanced malignancies. However, peripheral blood mononuclear cells may not accurately predict drug-induced changes in tumor topoisomerase levels.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Drug resistance to topoisomerase I inhibitors is linked to reduced enzyme levels.
  • Topoisomerase II inhibitors may be more effective when topoisomerase II levels are induced by topoisomerase I inhibitors.

Purpose of the Study:

  • To evaluate the safety and efficacy of sequential administration of 9-nitrocamptothecin (a topoisomerase I inhibitor) followed by etoposide (a topoisomerase II inhibitor).
  • To assess the pharmacokinetic profiles and treatment-induced modulation of topoisomerase I and II expression.

Main Methods:

  • A phase I/II study involving patients with advanced or metastatic malignancies.
  • Sequential administration of 9-nitrocamptothecin (days 1-3) followed by etoposide (days 4-5) at escalating doses.
  • Pharmacokinetic analyses and measurement of topoisomerase I and II expression in peripheral blood mononuclear cells.

Main Results:

  • The combination therapy was tolerable, with dose-limiting toxicities including neutropenia, thrombocytopenia, nausea, vomiting, diarrhea, and fatigue.
  • Objective response was observed in 4% of patients and stable disease in 29%, despite prior treatments.
  • Contrary to expectations, topoisomerase IIalpha levels decreased, and topoisomerase I levels were not significantly altered by 9-nitrocamptothecin.

Conclusions:

  • Sequential administration of 9-nitrocamptothecin and etoposide demonstrates tolerability and activity in advanced malignancies.
  • Peripheral blood mononuclear cells may not serve as reliable biomarkers for drug-induced modulation of topoisomerase levels in tumor tissues.
  • Further research is needed to validate these findings in larger patient cohorts.

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