title: The binding of cis-dichlorodiammineplatinum(II) to extracellular and intracellular compounds in relation to drug uptake and cytotoxicity in vitro.
abstract: The biological consequence of the binding of cis-dichlorodiammineplatinum(II) (cis-DDP) to serum protein as well as to cellular components in general, was studied on human NHIK 3025 cells in vitro. As expected, we found that the cytotoxicity of cis-DDP was lost by binding to serum protein, and that protein-bound platinum was impermeable to the cells. As we have previously shown that electropermeabilisation may transiently increase the influx of cis-DDP, we applied this technique in an attempt to increase the efflux of cis-DDP or any other cytotoxic intermediates. Our data demonstrate that if cells are electropermeabilised shortly after treatment with cis-DDP, cell survival increased. This indicates that cis-DDP in an active form is released from the cells; furthermore, the plasma membrane represents a barrier against efflux, as it has also been shown to be against influx of active cis-DDP. Thus, our data are consistent with the idea that there must be an intracellular pool of either cis-DDP, or some biologically active intermediates, in cells treated with this drug. Additionally, our data indicate that the binding rate of cis-DDP to biological molecules is much quicker intracellularly than in the extracellular environment: We found the biological half-life at 37 degrees C to be about 2.1 h in human serum and about 11 min inside our cells.
authors.affiliation: Department of Tissue Culture, Norwegian Radium Hospital, Montebello, Oslo.
authors.forename: J E
authors.initials: JE
authors.lastname: Melvik
authors.forename: J M
authors.initials: JM
authors.lastname: Dornish
authors.forename: E O
authors.initials: EO
authors.lastname: Pettersen
mesh_terms: D001665:Binding Sites; D001692:Biological Transport; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000378:metabolism* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D013054:Spectrophotometry, Atomic; D013997:Time Factors; D014594:Uterine Neoplasms
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; D002945:Cisplatin