The future of cyclooxygenase-2 inhibitors and other inhibitors of the eicosanoid signal pathway in the prevention and therapy of lung cancer.
Recent advances in the understanding of the biology and molecular biology of lung cancer has provided targets for novel therapeutic and chemoprevention strategies. The eicosanoid/prostaglandin signal pathway is involved in the metabolism of membrane phospholipids to end products that are involved in apoptosis, proliferation, differentiation, and angiogenesis. Abnormalities in this pathway occur frequently in lung cancer, including the overexpression of cytoplasmic phospholipase A2, cyclooxygenase-2 (COX-2), prostaglandin E (PGE) synthase, PGE2, 5-lipoxygenase (LOX), 8-LOX, and 12-LOX. Increased levels of PGE2, 5-LOX, 8-LOX, and 12-LOX promote tumor proliferation and angiogenesis and inhibit apoptosis. On the other hand, levels of proapoptotic, antiangiogenic, and antiproliferative products are frequently decreased in lung cancer due to decreased levels of enzymes such as prostacyclin synthase. These abnormalities provide a rationale for the use of inhibitors of overexpressed enzymes or replacement of anticarcinogenic end products, and such agents have been studied in preclinical and clinical trials.
Bunn
Paul A
PA
Tobacco Related Malignancy Program, University of Colorado Cancer Center, Denver 80262, USA. paul.bunn@uchsc.edu
Keith
Robert L
RL