Abstract

PURPOSE. IRL-1620, a selective ETB receptor agonist, has been reported to selectively enhance tumor blood flow and potentiate the efficacy of chemotherapeutics in various tumor models. Improved tumor perfusion is associated with a net increase in tumor oxygenation, which may be exploited to increase the effectiveness of radiotherapy. Since tumor oxygenation increases the radiation-induced cellular damage, IRL-1620 may be helpful to increase radiation sensitivity of tumor. The present study was conducted to determine whether administration of IRL-1620 prior to radiation enhances the efficacy of radiotherapy.

STUDY DESIGN. Male Swiss albino mice (6–8 weeks old; 25–30 g) were used for the study. Tumor was induced by the subcutaneous inoculation of Dalton’s Lymphoma cells (1 million) on the right hind limb. Tumor volume was measured using a digital caliper. Animals with a tumor volume of about 1cc were selected for the study and were divided into six groups (10 mice per group). Group I: No treatment; Group II: IRL-1620 (9 nmol/kg, 5 doses on alternate days); Group III: Radiation (5 × 4 Gy using Cobalt-60 Teletherapy unit (Theratron 780, Canada) on alternate days administered at 1 Gy/min); Group VI: IRL-1620 (1 nmol/kg) + radiation, 5 doses on alternate days; Group V: IRL-1620 (3 nmol/kg) + radiation, 5 doses on alternate days; Group VI: IRL-1620 (9 nmol/kg) + radiation, 5 doses on alternate days. Mice were shielded with lead except for a 3-cm-diameter circular field where the tumor was centered. IRL-1620 was administered via tail vein 15 minutes prior to radiation administration. Tumor diameter was measured twice a week for a total of 70 days.

RESULTS. Tumor bearing mice without any treatment showed a progressive increase in tumor volume and all the animals died by 53 days after tumor induction. Radiation alone did not significantly reduce tumor volume when compared to controls (possible due to hypoxic condition). There was no significant increase in the survival. All the animals (10 out of 10) died by 56 days after tumor induction. Animals treated with radiation 15 min after administration of 9 nmol/kg IRL-1620 reduced the tumor volume significantly and there was significant increase in life span. It was found that only 4 out 10 animals died by 70 days after tumor induction. Animals treated with radiation 15 min after administration of 3 nmol/kg IRL-1620 delayed the development of tumors. It was found that 7 out 10 animals died by 70 days after tumor induction. Animals treated with radiation 15 min after administration of 1 nmol/kg IRL-1620 along with radiation delayed tumor development. It was found that 9 out 10 animals died by 70 days after tumor induction.

CONCLUSION. It is concluded that IRL-1620 significantly enhanced the efficacy of radiation treatment in Dalton’s Lymphoma cells induced tumor model by reducing tumor volumes and increasing the survival.

Disclosures: Spectrum Pharmaceuticals, Inc.; SPPI.; Research funded by Spectrum Pharmaceuticals.

ACKNOWLEDGEMENTS. Authors are grateful to Ramadasan Kuttan, PhD and Rajeshkumar NV, PhD for their assistance in guiding and coordinating this project. This study was funded in part by Spectrum Pharmaceuticals, and Chicago Labs, Inc.

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