L-buthionine sulfoximine potentiates the antitumor effect of 4-hydroperoxycyclophosphamide when administered locally in a rat glioma model

OBJECTIVE: L-buthionine sulfoximine (BSO) inhibits glutathione synthesis an d may modulate tumor resistance to some alkylating agents, but it has not b een proven effective in the treatment of intracranial neoplasms. To evaluat e this drug for the treatment of brain tumors, we studied the use of BSO fo r potentiating the antineoplastic effect of 4-hydroxyperoxycyclophosphamide (4-HC) in the rat 9L glioma model. METHODS: The survival of male Fischer 344 rats with intracranial 9L gliomas was measured after implantation of controlled-release polymers containing one of the following: no drug, ESO, 4-HC, or both BSO and 4-HC. The efficac y of intracranial 4-HC treatment was assessed with and without serial syste mic intraperitoneal BSO injections. Tissue glutathione levels were measured in the brains, tumors, and livers of animals treated with intraperitoneal injections or local delivery of BSO. RESULTS: The median survival of animals treated with intracranial polymers containing 4-HC was 2.3 times greater than that of controls. This survival benefit was doubled by local delivery of BSO. In contrast, systemic BSO the rapy did not improve survival time. In animals that were treated systemical ly, both liver and tumor glutathione levels were significantly lower than t hey were in control animals. In the locally treated animals, glutathione le vels were reduced in the brain tumor but not in the liver. CONCLUSION: These results demonstrate that local but not systemic delivery of BSO enhances the antineoplastic effect of 4-HC in this rat 9L glioma mod el. In addition, because local delivery of BSO within the brain did not dep lete glutathione levels systemically, this method of treatment may be safer than systemic administration of BSO.