Combination of aziridinylbenzoquinone and cis-platinum with radiation therapy in the 9L rat brain tumor model

Abstract

Purpose : We evaluated the potentiating effects of aziridinylbenzoquinone (AZQ) and cis-platinum on the prolongation of survival by radiation therapy in a rat brain tumor model. Methods and Materials : On day 10 following intracranial inoculation of the 9L gliosarcoma, Fischer 344 rats were treated with radiation therapy (Cesium-137 source irradiator) and/or chemotherapy delivered either systemically (intraperitoneal or intravenous), or intracranially directly into the tumor in a volume of 5 μl. Increased life spans were calculated relative to the median survival time for the control (ILS-C) or to the median survival time for radiation therapy only (ILS-RT) group. Results : Median survival time for untreated rats was 22 ± 3 days for seven experiments. Radiation therapy (16 Gy) produced a significant ( p < 0.002) improvement in survival, with an average ILS-C of 75 ± 19%. Systemic AZQ (1 or 5 intravenous injections of 0.5 mg/kg) produced ILS's of 0 and 23%, the latter being significant ( p = 0.002). When added to radiation therapy, there were further improvements (ILS-RT's of 47 and 72%), but these were not significant. Intratumor AZQ (40 or 50 pg intracranially) produced significant ILS-C's of 30 and 33% ( p = 0.01 and 0.0002, respectively). Added to radiation therapy, intracranial AZQ produced improvements (ILS-RT's of 5 and 102%), with only the latter being significantly improved ( p = 0.009). Cis-platinum (3 μg intracranially) produced ILS-C's of 13 and 6%, neither significantly different from controls. Added to radiation therapy, cis-platinum caused improvements (ILS-RT's of 18 and 64%), with only the latter significant ( p = 0.049). Conclusion : These results demonstrate that AZQ delivered systemically, and AZQ and cis-platinum delivered intracranially, can produce statistically significant improvements in the survival of rats burdened with the 9L brain tumor. The agents delivered intracranially significantly potentiated the prolongation of survival obtained by radiation therapy. This preclinical evidence suggests that combining radiation therapy with these cytotoxic chemotherapeutic agents may benefit patients with high-grade malignant brain tumors.