Cellular pharmacology of dichloro(ethylenediamine)platinum(II) in cisplatin-sensitive and resistant human ovarian carcinoma cells.
The cellular pharmacology of the tritium-labeled cisplatin analogue dichloro(ethylenediamine)platinum(II) ([3H]DEP) was compared in cisplatin-sensitive 2008 and resistant 2008/C13*5.25 human ovarian carcinoma cells. The cellular content of total [3H], ultrafiltrable [3H], and free native [3H]DEP was measured during and following incubation with 5 microM [3H]DEP. While the rate constant for [3H]DEP uptake in the resistant cells was reduced to 25% of that in the sensitive cells, DNA intrastrand adduct formation was reduced even further to 11%, indicating the presence of defects in both uptake and the ability of intracellular drug to access or react with DNA. The latter could not be accounted for by enhanced repair. Together, these defects were sufficient to account for the 11-fold level of resistance. At steady state, the intracellular to extracellular concentration ratio for native [3H]DEP was 7.7 in the sensitive cells and 11.7 in the resistant cells, suggesting the presence of a trapping or concentrative mechanism. Thus, despite the slower initial influx, the resistant cells eventually accumulated more free [3H]DEP than the sensitive cells. We conclude that the resistant phenotype in these cells is accounted for primarily by impaired uptake and decreased reaction of [3H]DEP with DNA rather than by changes in efflux or DNA repair.
Jekunen
A P
AP
Department of Medicine, University of California, San Diego, La Jolla 92093-0812.
Hom
D K
DK
Alcaraz
J E
JE
Eastman
A
A
Howell
S B
SB
D002945:Cisplatin; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000378:metabolism*; D004351:Drug Resistance; D005260:Female; D006801:Humans; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; C002892:platinum ethylenediamine dichloride; D002945:Cisplatin