Schedule-dependent topoisomerase II-inhibiting drugs

Abstract

A number of topoisomerase II-acting drugs have been described, but few demonstrate schedule-dependent anti-tumour activity. The activity of the epipodophyllotoxins etoposide and teniposide and the acridine dye derivative amsacrine is clearly schedule-dependent, and this related not only to the observation that the activity of topoisomerase II varies throughout the cell cycle but also to the finding that these drugs are rapidly cleared from the cell following exposure, permitting DNA repair. Etoposide has been most clearly shown to be schedule dependent in clinical studies. The response rates of patients with small-cell lung cancer receiving a 24-h infusion was only 10% as compared with 89% when the same dose was given over 5 days. Pharmacokinetic studies performed in these patients demonstrated that although the total systemic exposure (area under the plasma concentration-time curve, AUC) was the same in both arms of the study, the duration of exposure to low levels of drug (> 1 microgram/ml) was doubled in the 5-day arm. Haematological toxicity was the same in both arms of the study, as was the duration of exposure to higher plasma levels (> 5 micrograms/ml), suggesting that this toxicity may be associated with higher plasma concentrations, whereas anti-tumour activity is related to prolonged exposure to low levels of drug. This was confirmed in a subsequent study, where prolongation of treatment to 8 days compared to 5 days resulted in a similar exposure to low plasma concentrations and no difference in response rates or survival. Haematological toxicity in this study was worse in the 5-day arm, which also had an increase exposure to high levels of drug (> 5 micrograms/ml). More recently, interest has focused on even more prolonged etoposide administration, typically involving small daily doses repeated for 14-21 days. Although this schedule shows high activity in relapsed small-cell lung cancer and lymphoma, it is associated with significant toxicity (around one-third of patients experience grade III/IV leukopenia or neutropenia), which may be related to the observation that the etoposide dose delivered per course in these studies is higher than that obtained with standard dosing over 3-5 days. Further randomised studies are required to determine the optimal dose and schedule of etoposide.