Two pairs of cis/trans
platinum complexes,
JM118 (cis-ammine(
cyclohexylamine) dichloro
platinum(II)) and its trans counterpart, JM334 and
JM149 (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 L1210 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,
iproplatin,
tetraplatin and
JM149)-resistant L1210 sublines whereas at least partial cross-resistance was observed to the cis isomer
JM149 in the acquired
carboplatin and
iproplatin-resistant lines (in addition to being 11-fold resistant in the line selected for resistance to
JM149 itself). In vivo, JM355 showed activity against both the ADJ/
PC6 and L1210 models of acquired
cisplatin resistance. Furthermore, JM355 was active against an ADJ/
PC6 subline possessing resistance to
iproplatin and a L1210 subline possessing resistance to its cis isomer
JM149. Interestingly, the trans
platinum(II) counterpart of
JM335(JM334) was inactive in vivo. These data indicate that the trans
platinum(IV) complex
JM335 possess several in vitro growth inhibitory- and in vivo antitumour properties which are distinct from those observed for
cisplatin (or its cis isomer). Thus,
JM335 contravenes the original structure-activity rules determined for
platinum-containing compounds and, because of its level of activity against
cisplatin-resistant tumours, establishes the complex as of interest in the search for new
platinum drugs active against
cisplatin-resistant disease.