Effect of the cisplatin-procaine complex DPR in combination with several anticancer agents on murine P388 leukemic cells in vitro and in vivo.

We evaluated in vitro the antiproliferative activity of DPR (Fig. 1), a new cisplatin-derived compound, in combination with five conventional anticancer drugs: the antimetabolites 5-fluorouracil (5FU) and methotrexate (MTX), the alkylating agent mitomycin C (MMC), the antimicrotubule agent taxol (TAX) and the intercalating agent of the antracycline group doxorubicin (DOX), against murine P388 leukemic cells. MTT assay was used to determine growth inhibition after incubation of cells for 72 hours in the presence of single or combined drugs. The additive, synergistic or antagonistic nature of the combined drug effect was determined using the isobole method. In our cellular model, synergism was the prevailing result observed when DPR was combined with MMC. Conversely, antagonism was observed when DPR was combined with TAX. When DPR was administered together with the other antineoplastic drugs, the final effect was dependent on the concentrations of single agents. The study in vitro of the association between DPR and MMC was extended in vivo in BDF-1 female mice bearing i.p. P388 leukemic cells. Our data in vivo confirmed those obtained in vitro, demonstrating the therapeutic advantage of the association of ineffective doses of DPR (2 and 7 mg/kg) and MMC (3.2 mg/kg) over the administration of MMC alone.