Time-schedule dependency of S 16020, a new topoisomerase II inhibitor

S 16020 is a new olivacine derivative which has been shown to intercalate i nto DNA and to stabilize the cleavable complex formed by DNA and purified t opoisomerase II. The aim of the present study was to estimate the impact of time exposure on the in vitro activity of S 16020. This was done on seven cancer cell lines of human origin (head and neck, kidney, and ovary). Doxor ubicin was used as a reference drug. The cytotoxic activity of S 16020 rema ined stable during at least 3 h. A loss of activity of about 30% was appare nt after 6 or 24 h preincubation. This relative loss of activity reached ab out 50% after 72 h preincubation. Considering all tested cell lines, the av erage IC50 decrease was 89+/-8% for S 16020 with incubation times between 1 and 72 h. An exposure index (EI) was calculated to evaluate the effect of time on the cytotoxic efficacy. The reference time was 1 h exposure. The Fl values were corrected to take into account the loss of drug activity. For the majority of cell lines Fl values were greater than 1 for both drugs, pa rticularly after a 6 h exposure time. This means that, in this case as comp ared to the shorter exposure (1 h), increasing time has a relative detrimen tal effect on drug efficacy. For the two cancer cell lines of ovarian origi n, Fl values remained close to 1 for both drugs whatever the total exposure time. This means that, in this case, time and concentration have symetrica l effects on cell survival. The pharmacological information provided by the present study may be useful in designing future clinical trials on this po tentially interesting new topoisomerase II inhibitor. As a consequence of t hese data, 1 and 3 h drug administration schedules are currently tested dur ing phase I trials. [(C) 1999 Lippincott Williams & Wilkins.].