Novel trans platinum complexes: comparative in vitro and in vivo activity against platinum-sensitive and resistant murine tumours.
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.
Goddard
P M
PM
CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
Orr
R M
RM
Valenti
M R
MR
Barnard
C F
CF
Murrer
B A
BA
Kelland
L R
LR
Harrap
K R
KR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D007536:Isomerism; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010954:Plasmacytoma / Q000188:drug therapy; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; C089656:JM 335; D009944:Organoplatinum Compounds