Acquired resistance to
tetraplatin [d,1-trans-1,2-diaminocy-clohexane tetrachloroplatinum (IV)] has been generated in vitro in the human ovarian
carcinoma cell line PXN94; the derived line, PXN94tetR, was 24-fold resistant to
tetraplatin. Intracellular
tetraplatin accumulation was reduced in PXN94tetR compared with PXN94 by an average of 1.3-fold across the concentration range 1-100 microM (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 significant difference was observed between PXN94 and PXN94tetR in the levels of total
platinum bound to
DNA or
DNA interstrand cross-links immediately after
tetraplatin exposure (10-100 microM 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 following 2 hr exposure to 25 microM
tetraplatin. Hence the major mechanism of acquired
tetraplatin resistance in PXN94tetR appears to be increased tolerance of
platinum-
DNA adducts. PXN94tetR was partially cross-resistant to the bifunctional
alkylating agents melphalan,
chlorambucil and
mitomycin C. Partial cross-resistance was also observed to
Adriamycin,
bleomycin,
etoposide,
5-fluorouracil and
vinblastine; however, no elevation in
P-glycoprotein levels was apparent in PXN94tetR. No cross-resistance was observed to
taxotere. PXN94tetR was partially cross-resistant to
cisplatin,
carboplatin and several novel
cis platinum complexes. In contrast, resistance was completely circumvented by the novel trans
platinum complex
JM335 [trans ammine (
cyclohexylamine) dichloro dihydroxo
platinum (IV)].