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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)]
Author(s) -
Mellish Kirste J.,
Barnard Chris F. J.,
Kelland Lloyd R.,
Harrap Ken R.
Publication year - 1994
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910590114
Subject(s) - platinum , chemistry , cisplatin , carboplatin , biochemistry , chemotherapy , medicine , catalysis
Acquired resistance to tetraplatin [d, I ‐ trans ‐1,2‐diaminocyclohexane 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 μM (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 μM 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 μM 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)].