The effect of
glutathione depletion (GSH) on the efficacy of
SR 2508 was evaluated in two murine
tumor models with single large doses of radiation or with low doses administered in an accelerated fractionated schedule. To deplete
tumor GSH,
buthionine sulfoximine (BSO) was administered in the animals
drinking water (10 mM) following two i.p.
injections of 450 mg/kg. This treatment decreased RIF and MCA
tumor GSH concentrations by 95% and 80%, respectively. Mice (C3H/Sed) received BSO for 48-72 hr before the first dose of radiation, and were maintained on BSO
drinking water for the duration of the fractionated course of
therapy.
SR 2508 (200-1000 mg/kg) was injected 45 min prior to each fraction of radiation. Radiation was administered as a single dose of 15 Gy or 20 Gy, for RIF and MCA
tumors, respectively. Alternatively, animals received a fractionated course of
radiotherapy which consisted of 2.5 Gy/fraction for the RIF, and 3 Gy/fraction for the MCA
tumors, b.i.d. for five days (total of 10 fractions).
Tumor response with and without BSO, and with and without
SR 2508, was determined by regrowth delay. BSO pretreatment increased the efficacy of
SR 2508 with single dose radiation in the MCA but not RIF
tumor.
SR 2508 administered with fractionated radiation produced lower enhancement ratios (SER) than with a single radiation dose. However, BSO significantly enhanced the efficacy of
SR 2508 with fractionated radiation. BSO increased the maximum SER for
SR 2508 (3 mM/fraction) from 1.2 to 1.4 in the RIF
tumor, and from 1.4 to 1.8 in the MCA
tumor. BSO also increased the toxicity of
SR 2508 by
a factor of 2. However, the ability of BSO to increase the efficacy of low doses of sensitizer at clinically relevant doses of radiation suggests that this combined modifier treatment may be of clinical benefit.