New advances in lung cancer chemotherapy : Topotecan and the role of topoisomerase I inhibitors

Objective tumor responses and survival rates with standard chemotherapy options for small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) have been disappointing. However, several promising new classes of agents have emerged in recent years, including the taxanes, mitotic spindle inhibitors, antimetabolites, and topoisomerase I and II inhibitors. The molecular target of several of these new agents is topoisomerase I, an enzyme that is essential for DNA replication and is up-regulated in tumor cells. Inhibition of this enzyme by drugs such as topotecan and irinotecan leads to cell death and is the basis for their anticancer activity. The process of DNA replication is halted by the covalent binding of the drug in a topoisomerase I drug/DNA ternary reaction intermediate. The pharmacokinetics of the approved regimen - a 30-min infusion daily for 5 days at 21-day intervals - are well defined, with proportional increases in the area under the plasma concentration-time curve, peak plasma concentration, and steady state concentration following application of higher doses. The antitumor activities of both the intravenous and oral formulations of topotecan have been tested in clinical trials. Topotecan is well tolerated and has demonstrated good efficacy in patients with relapsed SCLC when administered as monotherapy or in combination regimens as first-line or second-line therapy. Preliminary trials also indicate that topotecan is well tolerated and has activity in the first-line treatment of NSCLC. In this article an overview of new agents in lung cancer chemotherapy is provided, with particular attention paid to the topoisomerase I inhibitors. A review of topotecan - the first topoisomerase I inhibitor to be approved for second-line therapy in SCLC - is presented as an illustration of the promise these new agents hold for the treatment of SCLC and NSCLC.