title: Topoisomerase I inhibition with topotecan: pharmacologic and clinical issues.
abstract: Topoisomerase I (topo-I) inhibitors are a new class of anticancer agents with a mechanism of action aimed at interrupting DNA replication in cancer cells, the result of which is cell death. Most, if not all, topo-I inhibitors are derivatives of the plant extract camptothecin. Topotecan is a derivative of camptothecin which has been structurally modified to increase water solubility. The pharmacokinetic profile of topotecan is usually characterised by a two-compartment model and is linear in the dose range of 0.5 - 3.5 mg/m(2). Current clinical trials suggest antitumour activity against a variety of human tumour types, including ovarian cancer, non-small cell lung cancer (NSCLC) and non-lymphocytic haematologic malignancies. The main dose-limiting toxicity (DLT) is non-cumulative myelosuppression. Non-haematologic toxicities are usually mild. Based on several Phase I studies, the recommended Phase II dose was 1.5 mg/m(2)/day iv. for 5 days. Current Phase I and Phase II trials are evaluating the combination of topotecan with other chemotherapeutic agents to increase the therapeutic benefits of topotecan. The DLT in these trials is mainly myelosuppression.
authors.affiliation: University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 56, Houston, TX 77030, USA. barun@mdanderson.org
authors.forename: B
authors.initials: B
authors.lastname: Arun
authors.forename: E P
authors.initials: EP
authors.lastname: Frenkel
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D019772:Topotecan