RESUMEN
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.
Asunto(s)
Glutatión/fisiología , Metionina Sulfoximina/análogos & derivados , Neoplasias Experimentales/radioterapia , Nitroimidazoles/uso terapéutico , Fármacos Sensibilizantes a Radiaciones , Animales , Butionina Sulfoximina , Etanidazol , Metionina Sulfoximina/uso terapéutico , Ratones , Ratones Endogámicos C3H , Dosificación RadioterapéuticaRESUMEN
Delay of tumor growth in RIF-1 fibrosarcomas in C3H mice was studied, comparing ip delivery of 5-fluorouracil (5-FU) or cisplatin (cis-DDP) versus collagen matrix-associated intratumoral delivery of drug with and without irradiation to a total dose of 1,500 cGy. For cis-DDP (6 mg/kg), the number of days required for treated tumors to attain three times their original treatment volume was 6.2 +/- 1.6 SE for ip drug and 7.0 +/- 1.3 for intratumoral drug matrix. The use of the vasoactive agent epinephrine (1 mg/kg) in the matrix resulted in a growth delay of 10.1 +/- 2.0 days. Irradiation given 60 minutes after drug administration enhanced the delay of tumor growth to 19.2 +/- 2.6 days for systemic drug and 16.7 +/- 2.5 days for matrix-associated drug. The delay of tumor growth for irradiation plus matrix-associated cis-DDP containing epinephrine was 33.0 +/- 5.4 days. X-rays alone caused a tumor growth delay of 11.2 +/- 1.3 days. Similar results were found for 5-FU at a dose of 50 mg/kg, although the epinephrine in the matrix was not as effective.