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Synergistic Activity of Doxorubicin and the Bisdioxopiperazine (+)-1,2-Bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF 187) against the Murine Sarcoma S180 Cell Line¹

The Division of Medical Oncology, New York University School of Medicine, New York, New York 10016

The bisdioxopiperazine (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF 187) abrogates doxorubicin cardiotoxicity in every mammalian species tested, but its effect on doxorubicin antitumor activity remains poorly understood. In order to better define the anthracycline-bisdioxopiperazine interaction, the ability of murine sarcoma S180 cells to form colonies in soft agar and their capability to proliferate in microtiter wells were assayed after exposure to drug at varying doses and schedules. Incubation of cell suspensions for 1 h with doxorubicin, 0.1 µg/ml, with or without (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane, 80 µg/ml, produces additive cytotoxicity for the combination. Prolonged incubation (24 h) with the same drugs produces synergistic cytotoxic and antiproliferative effects at 1- and 2-log order reductions in dose. These studies indicate that the antineoplastic activity of the single agents doxorubicin and (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane is enhanced when the drugs are used in combination, and that this phenomenon is highly dose and schedule dependent.

¹ This work was supported in part by NIH Grant P30-CA-16087-109 and by a grant from the Long Island League against Cancer.

² Recipient of the Rita and Stanley H. Kaplan Cancer Center fellowship. To whom requests for reprints should be addressed at Department of Oncology, Northwest 460, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467.

Received 7/ 2/85. Revised 11/13/85. Accepted 11/14/85.

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