EVALUATION OF THE TIME-SCHEDULE DEPENDENCY FOR THE CYTOTOXIC ACTIVITYOF THE NEW VINCA ALKALOID DERIVATIVE, S-12363 (VINFOSILTINE)

S 12363 is a new vinca alkaloid derivative obtained by appending an op tically active alpha-aminophosphonate at the C23 position of 04-deacet yl vinblastine. The present study concerns four different human tumour cell lines, which represent the spectrum of vinca alkaloid clinical a ctivity. The influence of time exposure on S 12363 growth inhibition w as studied in vitro. Cells were exposed to the drug during the followi ng exposure times : 5, 15, 30 min and 1, 3, 6, 12, 24, 48, 72, 144 h. The concentrations of S 12363 applied were between 1 x 10(-2) and 1 x 10(3) nmol/l. The cytotoxic effects were assessed by using the methylt etrazolium (MTT) semi-automated test. Considering the IC(50) values in terms of concentration (C) x time (T), I (C x T)50, it was shown that for an equal growth inhibitory effect (50% of cell death) the increas ed exposure times required higher cumulative drug exposures. More prec isely, only very long exposure (greater than 24 h) resulted in very hi gh I (C x T)50. The drug exposure ratios which correspond to I (C x T) 50 values for 144 h divided by the I (C x T)50 values for 0.25 h range d between 2.8 and 18.3. If T and C had symmetrical effects on the fina l growth inhibition, the I (C x T)50 ratios should have been equal to one. For all cell lines investigated there were similar dose-response curves following two types of S12363 exposure: a single day exposure o r three successive daily exposures, the total C x T values being the s ame in both experimental situations. The basic pharmacological informa tion provided by the present study may encourage further clinical tria ls of this potentially interesting new vinca alkaloid.