Lethal and sublethal effects of the combination of doxorubicin and the bisdioxopiperazine, (+)-1,2,-bis (3-5-dioxopiperazinyl-1-yl) propane (ICRF 187), on murine sarcoma S180 in vitro

Doxorubicin and the bisdioxopiperazine, ICRF 187, synergistically inhibit proliferation of murine sarcoma S180 cells in vitro. Cell cycle analysis was employed to help discriminate cytokinetic from lethal effects of the drug combination. Twenty-four-hour incubation with either agent produced dose-dependent partial G₂M arrest. At high doses, ICRF 187 produced partial G₂M arrest, inhibition of cell division, and continued DNA synthesis at a higher ploidy, resulting in a second G₂M arrest of an 8n population. The addition of ICRF 187 to doxorubicin resulted in enhancement of cell cycle blockade at G₂M. The combination also produced enhanced lethality as measured by reduced colonyforming efficiency of drug-treated S180 cells. Measurement of (¹⁴C]doxorubicin accumulation in, and effux from, ICRF 187 pretreated cells failed to reveal an effect of pretreatment with the bisdioxopiperazine on anthracycline disposition by S180 cells, suggesting that the enhanced cytotoxic and cytostatic effects do not result from increased intracellular concentrations of doxorubicin. The positive interaction between the two drugs may represent site-specific enhancement of the anthracycline effect by ICRF 187 at an intracellular target site.