Effects of selective COX-2 and 5-LOX inhibition on prostaglandin and leukotriene synthesis in ductal pancreatic cancer in Syrian hamster

Abstract

Selective inhibition of eicosanoid synthesis seems to decrease carcinogenesis, however, the effect on liver metastasis in pancreatic cancer is still unknown. Ductal pancreatic adenocarcinoma was chemically induced by weekly injection of N-nitrosobis-2-oxopropylamine (BOP) in Syrian hamster. Animals received selective inhibition of cyclooxygenase-2 (Celebrex) and 5-lipoxygenase (Zyflo). In week 33, hamsters were sacrificed and incidence of pancreatic carcinomas as well as liver metastases were examined. Furthermore, size and number of liver metastases per animal were determined and concentration of PGF 1 α , PGE 2 and leukotrienes was measured in hepatic and pancreatic tissue. Combined therapy (Celebrex+Zyflo) significantly decreased incidence, number and size of liver metastases. Furthermore extra- and intrametastatic concentration of PGE 2 was reduced by this treatment in hepatic tissue. Single Cox-2-inhibition (Celebrex) decreased intrametastatic hepatic PGF 1 α and PGE 2 concentration while PGF 1 α concentration was reduced in non-metastatic liver (nml). Moreover 5-LOX-inhibition (Zyflo) decreased intrametastatic PGE 2 concentration as well as PGF 1 α and PGE 2 in nml. In pancreatic carcinomas highest LT-concentration was found after combined treatment and this therapy group was the only one revealing a significantly higher amount of LTs in carcinomas compared to tumour-free tissue. Hepatic LT-concentration was significantly lower in the control groups than in nml of the tumour groups. Combination of Cox-2-inhibition and 5-Lox-inhibition might be a suitable adjuvant therapy to prevent liver metastasis in human ductal pancreatic adenocarcinoma.