THE ROLE OF MURINE TUMOR-MODELS AND THEIR ACQUIRED PLATINUM-RESISTANT COUNTERPARTS IN THE EVALUATION OF NOVEL PLATINUM ANTITUMOR AGENTS - A CAUTIONARY NOTE

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 (> 14-fold) and tetraplatin (10-fold). The chemosensitivity 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.