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.

Ras-induced invasion and metastasis are regulated by a leukotriene B4 receptor BLT2-linked pathway

“…In accordance with our findings regarding the role of the BLT2-linked cascade in Ras-induced invasiveness and metastasis, mounting evidence has implicated LTB 4 and its receptor BLTs in cancer progression (Hennig et al, 2005;Heukamp et al, 2006). LTB 4 , a ligand for BLTs, has been suggested to stimulate cell proliferation in various cancer cell types, including colon and pancreatic cancer cell lines, and LTB 4 receptors are overexpressed in these cancer cells (Bortuzzo et al, 1996;Tong et al, 2002;Woo et al, 2002).…”

“…Blocking of BLTs, preferentially BLT1, by LY293111, inhibits proliferation and induces apoptosis in pancreatic cancer and lymphoma cells (Tong et al, 2002). In addition, Hennig et al (2005) reported that treatment with LY293111 reduces tumor growth and the incidence of metastasis in athymic mice, suggesting a potential role for BLTs in tumor progression in vivo. More recently, Rocconi et al (2008) suggested that expression of BLT2, but not BLT1, in ovarian cancer tissues correlates with advanced stage III/IV disease and is associated with poor clinical outcomes.…”

“…Another arachidonate metabolic enzyme, 5-lipoxygenase (5-LO) and its bio-products, including the leukotrienes, have also been implicated in cancer cell proliferation and progression (Nie et al, 2001;Romano and Claria, 2003;Ding et al, 2005;Hennig et al, 2005). Unlike COX, however, role of the 5-LO and LT products in the tumor-associated invasion and metastasis are not yet shown.…”

Potency of non-steroidal anti-inflammatory drugs in chemotherapy

“…It was also reported that 5-LOX expression may be involved in the development of BCR-ABL-induced chronic myeloid leukaemia (55). Moreover, the 5-LOX pathway may be involved in the metastatic process of pancreatic, intestinal and prostate cancers (56,57). The inhibition of 5-LOX expression and activity promotes cell apoptosis and tumour growth arrest.…”

A Photon Counting Technique for Quantitatively Evaluating Progression of Peritoneal Tumor Dissemination

“…Fluorescence-based imaging (26)(27)(28)(29)(30)(31)(32)(33)(34)(35) and photon counting analysis (36)(37)(38)(39)(40)(41)(42)(43) modalities are well developed and allow specific, highly sensitive and quantitative measurements of a wide range of tumor-related variables in mice. Herein, we have shown that photon counting technique is an effective technology in living mice.…”