Schedule-dependent synergism of combinations of hydroxyurea with adriamycin and 1-beta-D-arabinofuranosylcytosine with adriamycin.

Abstract

The lethal effects of combinations of adriamycin (ADR) and either hydroxyurea (HU) or 1-beta-d-arabinofuranosylcytosine (ara-C) were studied in relation to drug-scheduling interval in Sarcoma 180 cells grown in vitro. Drug lethality was determined by cell cloning in soft agar. Serial kinetic changes induced by a priming dose of HU or ara-C were monitored by flow cytometry and related to schedule-dependent cell killing by ADR. All drug exposures were for 1 hr. When ADR was given together with either HU or ara-C, cell log kill was additive. However, when ADR was given after exposure to either HU or ara-C, cell killing was increased up to 200- to 500-fold, respectively. Maximum schedule-dependent synergism was observed at a drug-scheduling interval of 2 hr; schedule-dependent synergism decreased as the interval between drugs was increased beyond 2 hr. Schedule-dependent synergism was not observed when the same drug combinations were given in reversed order. Drug-induced changes in the DNA histogram were not seen until 5 hr after HU exposure and 8 hr after ara-C exposure. Thus, the schedule-dependent synergism between ADR and either HU or ara-C cannot be explained by cell cycle blockade with synchronization of cells in S phase.