Evidence that glutathione may determine the differential cell-cycle phase toxicity of a platinum (IV) antitumor agent.
Intracellular thiol group concentrations were monitored during the cell cycle of synchronous cultured Chinese hamster ovary (CHO) cells. Cyclic fluctuations in nonprotein thiol levels were observed that correlated with a cyclic change in cellular sensitivity to the platinum-based chemotherapy drug iproplatin (CHIP). Intracellular protein-bound nonprotein disulfide concentrations were inversely related to nonprotein thiol levels. Protein-bound thiol groups varied in concentration during the cell cycle, but the cyclic pattern did not relate to changes in nonprotein thiol to disulfide groups or to cellular sensitivity to CHIP toxicity. Cultured CHO cells were depleted of intracellular glutathione (GSH) with the use of buthionine sulfoximine. These cells were significantly more sensitive to CHIP toxicity than were control cultures. In addition, although control synchronous CHO cells showed considerable differential cell-cycle phase sensitivity to treatment with CHIP, the sensitivity of GSH-depleted synchronous cells did not alter during the cell cycle.
Edwards
P G
PG
Richard Dimbleby Department of Cancer Research, United Medical School, St. Thomas' Hospital, London, England.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019328:Buthionine Sulfoximine; D002453:Cell Cycle; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000032:analysis
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D013438:Sulfhydryl Compounds; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; C023359:iproplatin; D005978:Glutathione