title: The role of murine tumour models and their acquired platinum-resistant counterparts in the evaluation of novel platinum antitumour agents: a cautionary note.
abstract: Two murine tumour models, the L1210 leukaemia and the ADJ/PC6 plasmacytoma, have featured prominently in the preclinical development of platinum drugs. Mindful of the unequivocal need to discover new platinum-based drugs exhibiting activity in cisplatin/carboplatin refractory and relapsed cancers, and to devise clinically-predictive screening models, we have generated resistance in vivo in the ADJ/PC6 plasmacytoma to cisplatin (19- to 21-fold), to carboplatin (25-fold), iproplatin (greater than 14-fold) and tetraplatin (10-fold). The chemo-sensitivity profiles of these tumours have been compared with L1210 leukaemia lines resistant to either cisplatin (10-fold) or tetraplatin (34-fold). In cross-resistance studies, the L1210 and ADJ/PC6 resistant variants provided conflicting predictions of structures likely to circumvent cisplatin-acquired resistance. In particular, the L1210/cisplatin resistant model exhibited cross-resistance to carboplatin and iproplatin, whereas the diaminocyclohexane (DACH)-containing complex, tetraplatin, was even more active in the cisplatin resistant tumour than in the 'wild-type' tumour. The ADJ/PC6/cisplatin resistant tumour, however, was cross-resistant, not only to carboplatin and iproplatin, but also to tetraplatin. These data provide an important caveat on the adoption of single acquired resistant animal tumour models for platinum drug development.
authors.affiliation: Drug Development Section, Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: P M
authors.initials: PM
authors.lastname: Goddard
authors.forename: M R
authors.initials: MR
authors.lastname: Valenti
authors.forename: K R
authors.initials: KR
authors.lastname: Harrap
mesh_terms: D000818:Animals; D016190:Carboplatin / Q000627:therapeutic use; D002461:Cell Line, Transformed; D002945:Cisplatin / Q000627:therapeutic use*; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005260:Female; D007938:Leukemia / Q000188:drug therapy; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use; D010954:Plasmacytoma / Q000188:drug therapy
chemical_list: D009944:Organoplatinum Compounds; C011076:platinum(II) 1,2-diaminocyclohexane malonate; C023359:iproplatin; D016190:Carboplatin; D002945:Cisplatin; D008558:Melphalan; C049777:ormaplatin