Enhanced potentiation of cisplatin cytotoxicity in human ovarian carcinoma cells by prolonged glutathione depletion.
We have determined the effect of extended glutathione (GSH) depletion on cis-diamminedichloroplatinum(II) (DDP) cytotoxicity in parent and DDP-resistant human ovarian carcinoma cells. Cells were exposed to 50 microM buthionine sulfoximine (BSO) for 48 h and exposed to DDP for the last 24 h of this time. This treatment protocol sensitized 2008 cells to DDP. The dose modification factor (DMF) defined as IC50 control cells/IC50 GSH depleted cells was 1.6 +/- 0.5 (N = 9). DDP-resistant cells selected by acute, high dose DDP exposure were also sensitized by this treatment; the DMF in the 3-6-fold resistant 2008/DDP cells was 2.4 +/- 1.2 (N = 9). The sensitization was not significantly greater in the resistant cells than in the parent cells (P greater than 0.05). When the rebound of GSH following BSO exposure was reexamined, the GSH levels were found to rise rapidly following trypsinizing and plating. BSO treatment following DDP exposure had no effect on DDP cytotoxicity in 2008 and 2008/DDP cells. These results indicate that simply depleting GSH prior to DDP exposure is not sufficient for sensitizing these cells to DDP. In contrast to the potentiation of nitrogen mustard cytotoxicity, exposure to GSH depletion must be maintained during DDP treatment for enhancement of DDP cytotoxicity to occur.
Andrews
P A
PA
Cancer Center, University of California, San Diego, La Jolla 92093.
Schiefer
M A
MA
Murphy
M P
MP
Howell
S B
SB
D019328:Buthionine Sulfoximine; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D003536:Cystadenocarcinoma / Q000473:pathology*; D004357:Drug Synergism; D005260:Female; D005978:Glutathione / Q000502:physiology*; D006801:Humans; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione; D002945:Cisplatin