Chemoprevention strategies with cyclooxygenase-2 inhibitors for lung cancer.
Clinical lung cancer is the ultimate event resulting from a series of genetic and epigenetic alterations in the respiratory epithelium at risk. According to the "field carcinogenesis" theory, these alterations can occur throughout the entire lung. In individuals with a genetic predisposition combined with a sufficient amount of procarcinogenic environmental influences, a few of these sites may eventually progress to malignancies. Recent advances in the understanding of tumor biology have identified new therapeutic targets for lung cancer chemoprevention, among which is cyclooxgygenase (COX)-2. Ample preclinical data suggest that the COX-2/prostaglandin E2 (PGE2) signaling pathway plays a pivotal role in conferring the malignant phenotype. Produced primarily by the action of COX on the free arachidonic acid liberated from membrane phospholipids, overproduction of PGE2, which is predominantly generated by upregulation of COX-2, is associated with a variety of mechanisms known to facilitate tumorigenesis. These mechanisms include abnormal expression of epithelial growth factors, epithelial and microvascular proliferation, resistance to apoptosis, and suppression of antitumor immunity. The lung is one of the major sites of PGE2 production, and previous studies have shown elevated PGE2 levels in bronchoalveolar lavage fluid of patients with bronchogenic carcinoma. In animal models, inhibition of COX-2 and PGE2 synthesis suppresses lung tumorigenesis. These preclinical data suggesting the antineoplastic effect of COX-2 inhibitors provide the basis for several ongoing pilot clinical trials to determine the feasibility of COX-2 inhibition in chemoprevention of bronchogenic carcinoma.
Mao
Jenny T
JT
Department of Medicine, David Geffen School of Medicine at UCLA, 37-131 CHS, University of California-Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095. jmao@mednet.ucla.edu
Cui
Xiaoyan
X
Reckamp
Karen
K
Liu
Ming
M
Krysan
Kostyantyn
K
Dalwadi
Harnisha
H
Sharma
Sherven
S
Hazra
Saswati
S
Strieter
Robert
R
Gardner
Brian
B
Dubinett
Steven M
SM
D017209:Apoptosis; D002471:Cell Transformation, Neoplastic; D018890:Chemoprevention; D002986:Clinical Trials as Topic; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D015232:Dinoprostone / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000503:physiopathology / Q000517:prevention & control*; D009389:Neovascularization, Pathologic; D015398:Signal Transduction; D015854:Up-Regulation
D052246:Cyclooxygenase 2 Inhibitors; D015232:Dinoprostone