Depletion of intracellular
glutathione (GSH) can enhance
misonidazole (MISO) radiosensitizing efficacy both in vivo and in vitro. However, such treatments may also enhance the systemic toxicity in animals. The purpose of the present study was to test various ways of depleting GSH levels in a variety of experimental mouse
tumors, to measure the improvement in the efficacy of MISO and its less toxic analog
SR 2508 by this depletion, and to determine the effect of daily GSH depletion on the toxicity of MISO and
SR 2508. GSH levels were measured daily for 5 days in
tumors, livers and brains of mice injected daily with
buthionine sulfoximine (BSO), with or without
diethylmaleate (DEM). To investigate
tumor variability we studied 5 different
tumors: EMT-6, RIF-1, KHT, SCC VII, and
B16 melanoma. The efficacy of MISO and
SR 2508 was evaluated using the KHT and SCC VII
tumors either by the regrowth delay assay or by the in vivo/in vitro clonogenic assay. The
drug toxicity was evaluated by
weight loss and by death. Daily doses of 3 mmole/kg BSO depleted
tumor levels of GSH to 20 to 40% of controls by 6 hr after each injection. Injection of DEM (300 mg/kg) 6 hr after BSO further enhanced the depletion. Administration of MISO or
SR 2508 at the time of maximum GSH depletion enhanced the MISO efficacy by factors of 2.5 to 8 for depletion to 8% of controls by BSO + DEM, but no enhancement of
SR 2508 was seen with
tumors at 20% GSH levels achieved with BSO alone in the preliminary experiment. The chronic toxicity of MISO was enhanced not at all or by
a factor of up to 2 for BSO and BSO + DEM respectively. Further studies are needed before it can be concluded that GSH depletion by BSO alone may be a useful adjunct to the clinical use of radiosensitizers.