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Topoisomerase I inhibition with topotecan: pharmacologic and clinical issues

B Arun1, E P Frenkel

  • 1University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 56, Houston, TX 77030, USA. barun@mdanderson.org

Expert Opinion on Pharmacotherapy
|May 5, 2001
PubMed

Insights

Topoisomerase I (topo-I) inhibitors, like topotecan, show promise in cancer treatment by disrupting DNA replication. Clinical trials indicate antitumor activity, with myelosuppression as the primary dose-limiting toxicity.

Area of Science:

  • Oncology
  • Pharmacology

Background:

  • Topoisomerase I (topo-I) inhibitors represent a novel class of anticancer agents.
  • These inhibitors function by impeding DNA replication in cancer cells, leading to cell death.
  • Most topo-I inhibitors are derived from the plant extract camptothecin.

Purpose of the Study:

  • To review the properties and clinical applications of topotecan, a camptothecin derivative.
  • To summarize current clinical trial findings regarding topotecan's efficacy and toxicity.
  • To explore the potential of combining topotecan with other chemotherapeutic agents.

Main Methods:

  • Review of pharmacokinetic data for topotecan.
  • Analysis of results from Phase I and Phase II clinical trials.
  • Evaluation of dose-limiting toxicities (DLTs) and non-haematologic toxicities.

Main Results:

  • Topotecan exhibits a linear pharmacokinetic profile within the 0.5-3.5 mg/m(2) dose range.
  • Antitumor activity has been observed in ovarian cancer, non-small cell lung cancer (NSCLC), and hematologic malignancies.
  • The primary DLT is non-cumulative myelosuppression; other toxicities are generally mild.

Conclusions:

  • Topotecan demonstrates therapeutic potential across various human tumor types.
  • The recommended Phase II dose is 1.5 mg/m(2)/day intravenously for 5 days.
  • Ongoing trials are investigating combination therapies to enhance topotecan's benefits, with myelosuppression remaining a key DLT.

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