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 s ome chemotherapeutic agents and to radiation. Depletion of cellular GS H has been demonstrated to result in enhanced toxicity of these drugs, and this approach is being explored in the clinic as a form of bioche mical modulation, using the drug buthionine sulfoximine (BSO). The fac t that some drug-resistant cell lines have increased glutathione level s, and that enhancing GSH concentrations in animal tissues protects ag ainst a variety of xenobiotic agents, suggest a different potential ap proach 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 decreas ed bone marrow GSH, but that OTZ significantly increased it in this se tting. Interestingly, OTZ administration significantly depleted tumor GSH levels to the same level as did BSO. OTZ could offer a selective b iochemical modulation of GSH.