Schedule-Dependent Synergistic Cytotoxicity of Arabinofuranosylcytosine with Adriamycin or 3,6-Bis(5-chloro-2-piperidinyl)-2,5-piperazinedione in Cultured Cells

The purpose of this study was to demonstrate that in vitro cell culture systems could serve a useful purpose in providing some guidelines in formulating drug schedules for combination cancer chemotherapy in the clinic. Using monolayer cultures of Chinese hamster ovary cells as the test system, we screened the combinations of 1-β-D-arabinofuranosylcytosine (ara-C) + adriamycin, ara-C + 3,6-bis(5-chloro-2-piperidinyl)-2,5-piperazinedione, melphalan + 5-fluorouracil, and melphalan + ara-C as to the effect of drug sequence on the plating efficiency of these cells. Schedule-dependent therapeutic synergism was observed only when ara-C treatment was followed by either adriamycin or 3,6-bis(5-chloro-2-piperidinyl)-2,5-piperazinedione but not vice versa. No synergistic effects were observed in the combination of melphalan with 5-fluorouracil or ara-C. The basis for this synergism appeared to be that ara-C was primarily acting as a synchronizing agent to set up the cells in S phase so that subsequent treatment with an S-phase-specific drug, such as adriamycin or 3,6-bis(5-chloro-2-piperidinyl)-2,5-piperazinedione, would produce the maximum cell kill. On the other hand, the lack of synergism in the combinations of melphalan with 5-fluorouracil or ara-C was due to the lack of S-phase specificity for melphalan. On the basis of these data, we postulate that schedule-dependent synergism could be expected if the first agent renders the cells more sensitive (for example, by selectively blocking cells in one of the phases of the cell cycle) to the action of the second drug.