Optimum scheduling during combination chemotherapy of murine leukemia. Additional examples of schedule-dependent synergism between S-phase-specific antimetabolites and agents inducing mitotic or pre-mitotic (G2) arrest.

In an extension of our prior studies with methotrexate and vinca alkaloids, three additional drug combinations incorporating an S-phase-specific antimetabolite and an agent inducing blockade at mitosis or G2 were found to exhibit potent schedule-dependent synergism against the L1210 leukemia. Combinations employed include cytosine arabinoside with vindesine and methotrexate with teniposide (VM-26) or the -deaza-pteridine derivative, NSC 181,928. Synergism was observed following sequential administration (antimetabolite given 24 h before the second agent), but effects following simultaneous administration or sequential administration in the reverse order (antimetabolite given 24 h after the second agent) were only additive.