Schedule-dependent interaction of cytarabine plus doxorubicin or cytarabine plus mitoxantrone in acute myelocytic leukemia cells in culture

Schedule-dependent interaction of 1-β-D-arabinofuranosylcytosine (ara-C, cytarabine) plus doxorubicin or ara-C plus mitoxantrone was studied in vitro using HL-60 human acute myelocytic leukemia cell line. The cells were exposed for 1 hr to each drug simultaneously, or sequentially (up to a 28-hr interval), and cell kill effects were determined by clonogenic assay. The results were compared with controls in which cells were exposed to the individual drug only and seeded after appropriate intervals. Simultaneous exposure to two drugs produced lethal effects, but no more than those produced by doxorubicin or mitoxantrone alone. Ara-C followed by doxorubicin produced time-dependent increases in cell kill that was parallel to the doxorubicin alone control, indicative of no true potentiation. In contrast, ara-C followed by mitoxantrone produced striking increases in cell kill effects. Thus, ara-C followed by mitoxantrone resulted in more than 10-fold increases in cell kill at the intervals of≥8 hr between exposures, and the strong cell kill effects were maintained. Our data indicate that: (a) simultaneous exposure to ara-C and doxorubicin or mitoxantrone is less than additive; (b) ara-C followed by doxorubicin is probably only additive; and (c) ara-C followed by mitoxantrone is more than additive, and cell kill effects are sustained.