The role of platinum uptake and glutathione levels in L1210 cells sensitive and resistant to cisplatin, tetraplatin or carboplatin.
Three L1210 murine leukemia variants resistant to cisplatin, tetraplatin or carboplatin were compared with their sensitive parent line for differences in platinum accumulation, efflux and glutathione (GSH) content. All three resistant lines had reduced platinum accumulation compared with the sensitive line following exposure to each of the three drugs. There was no difference in the efflux of platinum between the sensitive and resistant lines indicating that reduced platinum accumulation was due to impaired uptake mechanisms. However, in cell survival experiments it was apparent that the resistant lines could tolerate higher intracellular platinum levels than the sensitive line. Intracellular GSH measurements revealed comparable levels in all but the L1210/carboplatin line which had a 2-fold elevation during the first 24 hours of culture. However, depletion of intracellular GSH with buthionin sulphoximine over a 72 hour period did not sensitize the resistant lines to the drugs. These studies have demonstrated that impaired platinum uptake is one of the mechanisms contributing to platinum drug resistance, while perturbations in GSH levels do not appear to play a role in these cell lines.
Nicolson
M C
MC
Biochemical Pharmacology, Drug Development Section, Institute of Cancer Research, Sutton, Surrey, U.K.
Orr
R M
RM
O'Neill
C F
CF
Harrap
K R
KR
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D016190:Carboplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004351:Drug Resistance; D005978:Glutathione / Q000378:metabolism*; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D010984:Platinum / Q000493:pharmacokinetics*; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010984:Platinum; D016190:Carboplatin; D005978:Glutathione; D002945:Cisplatin; C049777:ormaplatin