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Schedule-dependent Synergism of Combinations of Hydroxyurea with Adriamycin and 1-ß-D-Arabinofuranosylcytosine with Adriamycin

Clinical Pharmacology Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20205

The lethal effects of combinations of adriamycin (ADR) and either hydroxyurea (HU) or 1-ß-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.

¹ To whom requests for reprints should be addressed, at Hematology-Oncology Section, Department of Medicine, The Medical College of Wisconsin, 8700 W. Wisconsin Avenue, Milwaukee, Wis. 53226.

Received 3/17/81. Accepted 7/ 1/81.

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