In vivo selective modulation of tissue glutathione in a rat mammary carcinoma model.
Glutathione (GSH) is known to play a role in cellular sensitivity to some chemotherapeutic agents and to radiation. Depletion of cellular GSH has been demonstrated to result in enhanced toxicity of these drugs, and this approach is being explored in the clinic as a form of biochemical modulation, using the drug buthionine sulfoximine (BSO). The fact that some drug-resistant cell lines have increased glutathione levels, and that enhancing GSH concentrations in animal tissues protects against a variety of xenobiotic agents, suggest a different potential approach to improving anti-cancer therapy. We have examined the efficacy of the cysteine "pro-drug" L-2-oxothiazolidine-4-carboxylate (OTZ) at enhancing normal tissue versus tumor GSH. Animals were treated with OTZ or BSO, and the concentrations of GSH in normal tissues and tumor were measured. We found that the presence of the tumor itself decreased bone marrow GSH, but that OTZ significantly increased it in this setting. Interestingly, OTZ administration significantly depleted tumor GSH levels to the same level as did BSO. OTZ could offer a selective biochemical modulation of GSH.
Baruchel
S
S
Department of Oncology, Lady Davis Research Institute, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
Wang
T
T
Farah
R
R
Jamali
M
M
Batist
G
G
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D019328:Buthionine Sulfoximine; D004357:Drug Synergism; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid; D051381:Rats; D011916:Rats, Inbred F344; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D013844:Thiazoles; D053778:Thiazolidines; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid