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

S 16020 is a new olivacine derivative which has been shown to intercalate into DNA and to stabilize the cleavable complex formed by DNA and purified topoisomerase 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). Doxorubicin was used as a reference drug. The cytotoxic activity of S 16020 remained stable during at least 3 h. A loss of activity of about 30% was apparent after 6 or 24 h preincubation. This relative loss of activity reached about 50% after 72 h preincubation. Considering all tested cell lines, the average IC50 decrease was 89+/-8% for S 16020 with incubation times between 1 and 72 h. An exposure index (El) was calculated to evaluate the effect of time on the cytotoxic efficacy. The reference time was 1 h exposure. The El values were corrected to take into account the loss of drug activity. For the majority of cell lines EI values were greater than 1 for both drugs, particularly after a 6 h exposure time. This means that, in this case as compared to the shorter exposure (1 h), increasing time has a relative detrimental effect on drug efficacy. For the two cancer cell lines of ovarian origin, El values remained close to 1 for both drugs whatever the total exposure time. This means that, in this case, time and concentration have symmetrical effects on cell survival. The pharmacological information provided by the present study may be useful in designing future clinical trials on this potentially interesting new topoisomerase II inhibitor. As a consequence of these data, 1 and 3 h drug administration schedules are currently tested during phase I trials.