The cyclooxygenase inhibitor ibuprofen and the FLAP inhibitor MK886 inhibit pancreatic carcinogenesis induced in hamsters by transplacental exposure to ethanol and the tobacco carcinogen NNK.
OBJECTIVE
Pancreatic cancer is the fourth leading cause of cancer death in men and women. Smoking is a documented risk factor for pancreatic cancer, and the risk is increased in smokers who also consume alcohol. Arachidonic acid (AA)-metabolizing enzymes have been implicated in aggressive clinical behavior of pancreatic cancer while mutations in the Ki- ras gene have been associated with prolonged survival and responsiveness to therapy. Using a hamster model of exocrine pancreatic cancer induced by transplacental exposure to ethanol and the tobacco-carcinogen NNK, we have analyzed these tumors for mutations in the ras and p53 genes and tested the modulating effects of the COX inhibitor, ibuprofen, and the FLAP inhibitor, MK886, on the development of pancreatic cancer in this animal model.


METHODS
Hamsters were given 10% ethanol in the drinking water from the fifth to the last day of their pregnancy and a single dose of NNK on the last day. Starting at 4 weeks of age, groups of offspring were given either the COX inhibitor ibuprofen (infant Motrin oral suspension) or the FLAP-inhibitor MK886 (dissolved in carboxymethylcellulose orally) for life while a group of offspring not receiving any treatment served as positive controls.


RESULTS
None of the induced pancreatic cancers demonstrated mutations in the Ki-, N-, or H- ras or p53 genes. The development of pancreatic cancer in offspring who had been given ibuprofen or MK886 was reduced by 50% or 30%, respectively.


CONCLUSIONS
In conjunction with the documented over-expression of COX-2 and LOX in human pancreatic cancer, our findings suggest an important role of the AA-cascade in the genesis of this cancer type and indicate that pharmacological or dietary measures that reduce AA-metabolism may be useful for the prevention and clinical management of pancreatic cancer.
Schuller
H M
HM
Experimental Oncology Laboratory, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA. hmsch@utk.edu
Zhang
L
L
Weddle
D L
DL
Castonguay
A
A
Walker
K
K
Miller
M S
MS
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D006224:Cricetinae; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D017931:DNA Primers / Q000737:chemistry; D000431:Ethanol / Q000633:toxicity; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D007052:Ibuprofen / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use*; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008297:Male; D008431:Maternal-Fetal Exchange / Q000187:drug effects; D008647:Mesocricetus; D009602:Nitrosamines / Q000633:toxicity; D010179:Pancreas / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011247:Pregnancy; D002722:Chlorobenzenes
D016718:Arachidonic Acid; D016861:Cyclooxygenase Inhibitors; D017931:DNA Primers; D000431:Ethanol; D007052:Ibuprofen; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D009602:Nitrosamines; C060893:MK-886; D002722:Chlorobenzenes; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone