Combination vincristine and VP-16-213: evaluation of drug sequence

The combination of vincristine and VP-16-213 has been found to have synergistic antitumor activity in a murine system in vivo when the sequence of drug administration was vincristine followed by VP-16-213. To investigate the potential influence of drug scheduling on this synergistic combination, the reverse sequence of drug administration was evaluated. DBA/2 mice were inoculated with 10(6) P-388 murine leukemia cells, after which saline only, VP-16-213 only, vincristine only, or VP-16-213 followed at various time intervals by vincristine, were administered. Probable cure (survival greater than 60 days) was observed in 0/20, 0/20, 0/120, and 46/115 (40%), respectively (p less than 0.001). The proportion of animals attaining probable cure was greatest in the group receiving vincristine 4-72 hours after VP-16-213 (40-50%). Similar results had been obtained previously with the reverse drug sequence. In this animal model, the synergistic antitumor activity of vincristine and VP-16-213 does not appear to be schedule-dependent with respect to the sequence of drug administration.