The role of glutathione (GSH) in determining sensitivity to platinum drugs in vivo in platinum-sensitive and -resistant murine leukaemia and plasmacytoma and human ovarian carcinoma xenografts.
Numerous studies performed in vitro have suggested a role for glutathione (GSH) in determining the sensitivity/resistance of tumour cells to various platinum-based drugs. Few studies have extended these findings into the in vivo setting. We have measured GSH levels in two murine (ADJ/PC6 plasmacytoma and L1210 leukaemia and their acquired platinum-drug-resistant sublines) and five human ovarian carcinoma (PXN/100, PXN/109T/C, SKOV3, HX/62 and OVCAR-3) tumour models of varying sensitivity to cisplatin. Results showed that relatively high GSH levels may be involved, at least partially, in determining platinum drug resistance in vivo in at least some of the tumour models studied (ADJ/PC6 carboplatin and tetraplatin resistant tumours; L1210 cisplatin and tetraplatin resistant tumours and the HX/62 and OVCAR-3 human ovarian carcinoma xenografts). However, in other tumours (e.g., the acquired cisplatin resistant ADJ/PC6 plasmacytoma) non-GSH mediated mechanisms of resistance (such as enhanced DNA repair) probably account for the resistance. Pretreatment of animals with oral buthionine sulfoximine (BSO), which resulted in approximately 70% depletion in tumour GSH levels, failed to potentiate the antitumour efficacy of either cisplatin (using the ADJ/PC6 and L1210 models) or the 1,2-diaminocyclohexane (DACH) platinum-drug, tetraplatin (using the ADJ/PC6 model). These BSO plus or minus cisplatin data suggest a limited role for such combinations in the clinic.
Goddard
P
P
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, U.K.
Valenti
M
M
Kelland
L R
LR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019328:Buthionine Sulfoximine; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004351:Drug Resistance; D005260:Female; D005978:Glutathione / Q000502:physiology*; D006801:Humans; D007939:Leukemia L1210 / Q000473:pathology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D010954:Plasmacytoma / Q000473:pathology*; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione; D002945:Cisplatin; C049777:ormaplatin