CIRCUMVENTION OF ACQUIRED TETRAPLATIN RESISTANCE IN A HUMAN OVARIAN-CARCINOMA CELL-LINE BY A NOVEL TRANS PLATINUM COMPLEX, JM335 [TRANS AMMINE (CYCLOHEXYLAMINE) DICHLORO DIHYDROXO PLATINUM (IV)]

Acquired resistance to tetraplatin [d,1-trans-1,2-diaminocyclohexane t etrachloroplatinum (IV)] has been generated in vitro in the human ovar ian carcinoma cell line PXN94; the derived line, PXN94tetR, was 24-fol d resistant to tetraplatin. Intracellular tetraplatin accumulation was reduced in PXN94tetR compared with PXN94 by an average of 1.3-fold ac ross the concentration range 1-100 mu M (2 hr exposure). There was no significant difference in glutathione levels between the 2 cell lines. PXN94tetR was 1.6-fold more resistant to cadmium chloride than PXN94, suggesting that metallothionein levels may be elevated. However, no s ignificant difference was observed between PXN94 and PXN94tetR in the levels of total platinum bound to DNA or DNA interstrand cross-links i mmediately after tetraplatin exposure (10-100 mu M x 2 hr). There was also no significant difference between the 2 cell lines in the rate of removal of total platinum or interstrand cross-links from DNA followi ng 2 hr exposure to 25 mu M tetraplatin. Hence the major mechanism of acquired tetraplatin resistance in PXN94tetR appears to be increased t olerance of platinum-DNA adducts. PXN94tetR was partially cross-resist ant to the bifunctional alkylating agents melphalan, chlorambucil and mitomycin C. Partial cross-resistance was also observed to Adriamycin, bleomycin, etoposide, Ei-fluorouracil and vinblastine; however, no el evation in P-glycoprotein levels was apparent in PXN94tetR. No cross-r esistance was observed to taxotere. PXN94tetR was partially cross-resi stant to cisplatin, carboplatin and several novel cis platinum complex es. In contrast, resistance was completely circumvented by the novel t rans platinum complex JM335 [trans ammine (cyclohexylamine) dichloro d ihydroxo platinum (IV)]. (C) 1994 Wiley-Liss, Inc.