Bisdioxopiperazine, (+)-1,2-Bis(3,5-Dioxopiperazinyl-1-yl)propane (ICRF 187), enhances the antiproliferative effect of cisplatin on human ovarian cancer cells

The bisdioxopiperazine ICRF 187 is a potent intracellular chelating agent which effectively diminishes Adriamycin cardiotoxicity without compromising its antitumor activity. Our study aimed at verifying whether ICRF 187 can modulate the cytotoxic action of cisplatin (CDDP) on ovarian cancer cells. We used the A2780 ovarian cancer cell line and a subline resistant to CDDP (A2780-CDDP) obtained in our laboratory by continuous exposure of the parental cells to progressively increasing CDDP doses. In both cell lines ICRF 187 (0.1-0.5 μg/ml) used in combination with CDDP (0.01-1 μg/ml) produced a dose-dependent reduction of CDDP IC₅₀ (the concentration inhibiting 50% of cell growth). Moreover, when ICRF 187 was used in combination with CDDP, analysis of the data by the isobole method showed that the combination of the two drugs produced a synergistic antiproliferative activity in both cell lines, with a CDDP potentiation up to fivefold. Our in vitro data show that ICRF 187 can synergize with CDDP. Prospective clinical trials are now needed to verify whether the addition of ICRF 187 to CDDP-containing regimens will result in an improved clinical response in ovarian cancer.