SCHEDULE-DEPENDENT ENHANCEMENT OF ANTITUMOR-ACTIVITY OF ETHYLDESHYDROXY-SPARSOMYCIN IN COMBINATION WITH CLASSICAL ANTINEOPLASTIC AGENTS

The efficacy of the protein synthesis inhibitor ethyldeshydroxy-sparso mycin (EDSM) as a biochemical response modifier of several antitumor a gents against L1210 leukemia and sie melanoma is described. Seven drug s with different intracellular targets were selected for this combinat ion study. Tumor implantation and drug treatment were both i.p., and t he time interval between the administration of EDSM and the cytostatic agent was varied. Our results show that in the B16 tumor model EDSM i s not able to potentiate any of these drugs, whereas antagonism is see n in combination with doxo-rubicin (DX). In the L1210 tumor model, how ever, no loss of activity is seen for this specific combination. The e ffect of the combination of cytosar (Ara-C), 5-fluorouracil (5-FU) or vincristine (VCR) with EDSM in the L1210 model is strongly time interv al dependent. Loss of 5-FU antitumor activity is seen when EDSM is giv en 3 or 24 h after 5-FU; however, no effect is observed when EDSM is g iven 6 h after 5-FU. Enhancement of the 5-FU activity is not noticed. The VCR activity is potentiated when EDSM is given at least 6 h after VCR administration, which increases the antitumor response from 32 to >60 days and the percentage survivors from 33 to 83% (p = 0.04). In co mbination with Ara-C, potentiation of antitumor activity is seen only when EDSM is given 24 h after Ara-C, which increases the antitumor res ponse from 32 to >55 days and the percentage survivors from 11 to 50% (p = 0.008). No modulatory effects are found when EDSM is combined wit h carmustine or DX. Our results suggest that EDSM changes the antitumo r efficacy of selected antitumor agents (Ara-C and VCR) in a schedule- dependent way and that potentiation is largely restricted to cell-cycl e phase-specific cytostatic agents.