LY293111 Improves Efficacy of Gemcitabine Therapy on Pancreatic Cancer in a Fluorescent Orthotopic Model in Athymic Mice

Abstract

Pancreatic cancer has an abysmal prognosis because of late diagnosis and lack of effective therapeutics. New drugs are desperately needed. The present study determined the effect of the LTB4 receptor antagonist, LY293111, on tumor growth and metastases in a fluorescent orthotopic model of pancreatic cancer. Pancreatic cancer cells (S2-013) with stable expression of enhanced green fluorescent protein were implanted into the duodenal pancreatic lobe of athymic mice. Animals were allocated to four groups (eight mice per group): control (no treatment); LY293111; gemcitabine; and LY293111 + gemcitabine. Monitoring of the surgical procedure and follow-up examinations at 2, 3, and 4 weeks after implantation to monitor tumor growth and metastases were performed using a fluorescence microscope and the reversible skin-flap technique. A staging and scoring system was developed to evaluate tumor progression, based on the TNM classification. Control animals developed end-stage disease with invasive cancer, metastases, and cachexia. Tumor growth and incidence of metastases were significantly reduced in all treated mice. However, combined treatment with LY293111 and gemcitabine was most effective. LY293111 is a novel therapeutic agent for pancreatic cancer, which improves the efficacy of gemcitabine. It is well tolerated and can be administered orally and, therefore, provides a new hope for patients suffering from pancreatic adenocarcinoma.