Glutathione (GSH) is known to play a role in cellular sensitivity to some chemotherapeutic agents and to radiation. Depletion of cellular
glutathione increases toxicity of these drugs, and this approach is being explored in the clinic as a form of biochemical modulation using the
drug buthionine sulfoximine. The fact that some
drug-resistant cell lines have increased GSH levels, and that enhancing
glutathione concentrations in animal tissues protects against a variety of
xenobiotic agents, suggests a different potential approach to improve anticancer
therapy. We previously showed a selective enhancement by the
cysteine "
pro-drug,"
L-2-oxothiazolidine-4-carboxylate (OTZ), of GSH concentration in some normal tissues of
tumor-bearing rats, whereas there is a paradoxic GSH depletion in
tumor. OTZ has been shown to protect animals from a variety of toxins, and in vitro studies showed a selective increase in GSH in normal cells that results in reduced sensitivity to some
chemotherapy drugs. This report describes evidence that OTZ provides this effect in an in vivo rat mammary
tumor model. We have examined the OTZ "activating"
enzyme,
5-oxoprolinase, in these
tumors and found it to be 4-fold lower than that of normal rat liver. This may explain at least the lack of increased GSH in
tumor in response to OTZ. A limited number of human
breast cancer samples show similar activity.