NOVEL TRANS PLATINUM COMPLEXES - COMPARATIVE IN-VITRO AND IN-VIVO ACTIVITY AGAINST PLATINUM-SENSITIVE AND RESISTANT MURINE TUMORS

Two pairs of cis/trans platinum complexes, JM118 (cis-ammine(cyclohexy lamine) dichloro platinum(II)) and its trans counterpart, JM334 and JM 149 (cis-ammine(cyclohexylamine) dichloro-dihydroxo platinum(IV)) and its trans counterpart JM335 have been evaluated (both in vitro and in vivo) against two murine tumour models of historical importance in the discovery of novel platinum drugs; the ADJ/PC6 plasmacytoma and the L 1210 leukaemia and sublines selected for resistance to platinum drugs. In vitro, results showed that the trans complexes induced comparable growth inhibitory properties to those observed for cisplatin and their respective cis isomers. Moreover, retention of activity was observed in a series of 5 acquired platinum drug (cisplatin, carboplatin, iprop latin, tetraplatin and JM149)-resistant L1210 sublines whereas at leas t partial cross-resistance was observed to the cis isomer JM149 in the acquired carboplatin and iproplatin-resistant lines (in addition to b eing 11-fold resistant in the line selected for resistance to JM149 it self). In vivo, JM335 showed activity against both the ADJ/PC6 and L12 10 models of acquired cisplatin resistance. Furthermore, JM335 was act ive against an ADJ/PC6 subline possessing resistance to iproplatin and a L1210 subline possessing resistance to its cis isomer JM149. Intere stingly, the trans platinum(II) counterpart of JM335(JM334) was inacti ve in vivo. These data indicate that the trans platinum(IV) complex JM 335 possesses several in vitro growth inhibitory- and in vivo antitumo ur properties which are distinct from those observed for cisplatin (or its cis isomer). Thus, JM335 contravenes the original structure-activ ity rules determined for platinum-containing compounds and, because of its level of activity against cisplatin-resistant tumours, establishe s the complex as of interest in the search for new platinum drugs acti ve against cisplatin-resistant disease.