ANTITUMOR-ACTIVITY OF ORALLY-ADMINISTERED AMMINE AMINE PLATINUM (IV) DICARBOXYLATE COMPLEXES AGAINST A PANEL OF HUMAN OVARIAN-CARCINOMA XENOGRAFTS

The antitumour activity of a series of ten novel ammine/amine platinum (IV) dicarboxylates of general formula [Pt(IV) Cl2 (OCOR1) NH3 (RNH2) ] where R1 was an aliphatic or aromatic substituent and R an aliphatic or alicyclic substituent, was evaluated, after oral administration, t o nude mice bearing various human ovarian carcinoma xenografts. The tu mours were chosen to encompass a wide range in responsiveness to the c linically used platinum-based drugs cisplatin and carboplatin, with tu mour growth delays varying from less than 10 days to greater than 60 d ays. Against two tumour lines, the platinum (IV) ammine/amine dicarbox ylate JM221 (R1=C3H7; R= cC6H11) exhibited similar antitumour activity whether administered by the oral or intraperitoneal route. Experiment s have been performed using four xenografts to provide a direct compar ison of the antitumour effects of three platinum (IV) ammine/amine but yrates (JM216, R=cC6H11; JM225, R=cC5H9; JM269, R=cC7H13; R1=C3H7 for all three) administered by the oral route versus cisplatin and carbopl atin administered by the intravenous route at equitoxic q7dx4 schedule s. All three dicarboxylates exhibited oral activity broadly comparable to cisplatin and carboplatin and significantly superior to tetraplati n (Ormaplatin; a 1,2 diaminocyclohexane-containing platinum drug curre ntly undergoing clinical evaluation). Average specific growth delay va lues across the four xenografted lines were 3.45 for cisplatin, 3.9 fo r carboplatin, 3.2 for JM216, 3.3 for JM225, 3 for JM269 and only 0.55 for tetraplatin. Thus the ammine/amine platinum (IV) dicarboxylates r epresent a novel class of platinum drug for oral administration capabl e of exhibiting broadly comparable activity to cisplatin and carboplat in in a panel of human ovarian carcinoma xenografts.