The role of metallothionein, glutathione, glutathione S-transferases and DNA repair in resistance to platinum drugs in a series of L1210 cell lines made resistant to anticancer platinum agents.
The glutathione contents, glutathione S-transferase activities and metallothionein contents have been measured in a series of L1210 cell lines which show decreased sensitivities to platinum drugs. Resistance to cisplatinum cisDDP, cis-diamminedichloroplatinum (II)] and chip [ioproplatin, cisdichloro-bis-isopropylamine-trans dihydroxy platinum IV] was found to correlate with glutathione levels but not metallothionein. Conversely, resistance to tetraplatin was found to be correlated with metallothionein but not glutathione levels. However, depletion of glutathione by buthionine 1-sulphoximine sensitizes all cell lines to the effects of cisDDP, chip and tetraplatin [d,1-trans-tetrachloro-1,2-diamino-cyclohexanplatinum (IV)]. Inhibition of DNA repair by aphidicholin or caffeine also partially restored sensitivity to these platinum drugs. These results indicate the complexity of the changes occurring upon the development of drug resistance.
Hrubisko
M
M
CRC Dept of Experimental Chemotherapy, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, U.K.
McGown
A T
AT
Fox
B W
BW
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects*; D004351:Drug Resistance; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D007939:Leukemia L1210 / Q000235:genetics; D008668:Metallothionein / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D009944:Organoplatinum Compounds; D002110:Caffeine; C023359:iproplatin; D008668:Metallothionein; D005982:Glutathione Transferase; D005978:Glutathione; D002945:Cisplatin; C049777:ormaplatin