Preclinical antitumor activity of orally administered platinum (IV) complexes

Abstract

Several novel platinum (IV) mixed ammine/amine dicarboxylate dichlorides of general structure [Pt(IV)Cl₂ (OCOY)₂ NH₃(XNH₂)], where Y is aliphatic or aromatic and X is alicyclic or aliphatic, known to be particularly well absorbed following oral administration, were evaluated by that route for their antitumor activity. Testing of the Pt(IV) derivatives took place concomitantly with i.v. administered cisplatin and carboplatin in two s.c. staged tumor models, the murine M5076 sarcoma and human A2780 ovarian carcinoma. Based upon repetitive experiments which included an evaluation of different vehicles and treatment schedules, each of the orally administered Pt(IV) dicarboxylates was reproducibly active in the M5076 tumor, producing mean maximum gross log cell kill (LCK) values of between 1.5 and 2.0, and lifespan increases, reflected by mean maximum treated/control median survival (T/C) values, of 139–151%. Cisplatin and carboplatin given i.v. yielded mean maximum LCK of 3.5 and 2.5, respectively, as well as mean maximum T/C values of 166% and 164%, respectively, in the same tumor model. The best of the derivatives in the M5076 experiments, JM-216 [ammine/cyclohexylamine diacetato dichloride Pt(IV), produced LCK values that averaged only 0.5 lower than that of carboplatin, and increases in lifespan not significantly different than that of carboplatin. Against the A2780 tumor, the Pt(IV) dicarboxylates produced individual best effects of between 0.8–1.1 LCK, based on data from two or three experiments. The mean maximum LCK values for cisplatin and carboplatin were 1.8 and 2.2 LCK, respectively. JM-225, ammine/cyclopentylamine diacetato dichloride Pt(IV), was active in two of three experiments, including one result comparable to that of carboplatin. The Pt(IV) mixed ammine/amine dicarboxylate dichlorides represent a novel class of Pt derivative capable of expressing oral antitumor activity in both murine and human tumor models.