SCHEDULE-DEPENDENT TOPOISOMERASE II-INHIBITING DRUGS

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 n ot only to the observation that the activity of topoisomerase II varie s throughout the cell cycle but also to the finding that these drugs a re rapidly cleared from the cell following exposure, permitting DNA re pair. Etoposide has been most clearly shown to be schedule dependent i n clinical studies. The response rates of patients with small cell lun g cancer receiving a 24-h infusion was only 10% as compared with 89% w hen the same dose was given over 5 days. Pharmacokinetic studies perfo rmed in these patients demonstrated that although the total systemic e xposure (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 mu g/ml) was doubled in the 5-day arm. Haematological tox icity was the same in both arms of the study, as was the duration of e xposure to higher plasma levels (>5 mu g/ml), suggesting that this tox icity may be associated with higher plasma concentrations, whereas ant i-tumour activity is related to prolonged exposure to low levels of dr ug. This was confirmed in a subsequent study, where prolongation of tr eatment to 8 days compared to 5 days resulted in a similar exposure to low plasma concentrations and no difference in response rates or surv ival. Haematological toxicity in this study was worse in the 5-day arm , which also had an increased exposure to high levels of drug (>5 mu g /ml). More recently, interest has focused on even more prolonged etopo side administration, typically involving small daily doses repeated fo r 14-21 days. Although this schedule shows high activity in relapsed s mall-cell lung cancer and lymphoma, it is associated with significant toxicity (around one-third of patients experience grade III/IV leukope nia or neutropenia), which may be related to the observation that the etoposide dose delivered per course in these studies is higher than th at obtained with standard dosing over 3-5 days. Further randomised stu dies are required to determine the optimal dose and schedule of etopos ide.