1,2-Diaminocyclohexane Platinum Derivatives of Potential Clinical Value

Abstract

Cisdiamminodichloroplatinum (DDP) has assumed an important role in clinical cancer chemotherapy either alone or, more often, in combination with bleomycin, adriamycin, Cytoxan (cyclophosphamide), vindesine, or the arabinosylcytosine (ara-C) derivatives. With these combinations, many investigators have reported on activity in germ cell tumors of the testis, carcinoma of the head and neck, penis, cervix, bladder, lung, esophagus, and ovary [1,7]. It has been used much less in the leukemias and lymphomas. Unfortunately, renal toxicity and severe nausea and vomiting have limited its usefulness, and compounds with less toxicity, greater antitumor effectiveness, and a broader spectrum of activity, including the leukemias and lymphomas, are being sought, particularly those lacking cross-resistance to DDP. As previously reported by various investigators [9, 13], the 1,2-diaminocyclohexane platinum derivatives seem to fit these criteria. In the experimental animal renal toxicity does not appear to be limiting [10], and in mouse leukemia there is no cross-resistance to DDP [2, 3]. The dichloro, malonato, and carboxyphthalato derivatives of 1,2-diaminocyclohexane platinum experimentally have shown a high degree of antitumor effectiveness [9, 13], marked synergism with ara-C derivatives, adriamycin, demethylepipodophyllotoxin ethylidene glucoside (VP-16) [2], and with cyclophosphamide, particularly in combination with various ribonucleotide reductase inhibitors such as hydroxyurea, guanazole, and MAIQ-1 [6]. Clinically, the malonato derivative has been reported by HILL et al. [8] to be clinically active in the acute leukemias, and by RIBAUD et al. [11] to produce remissions in patients whose disease had become clinically resistant to DDP.

This research was supported by NCI grant CA-18856, ACS grant CH27U, and The Hearst Foundation Grant