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[Cancer Research 62, 734-740, February 1, 2002]
© 2002 American Association for Cancer Research

Epidemiology and Prevention

Manipulation of Pulmonary Prostacyclin Synthase Expression Prevents Murine Lung Cancer1

Robert L. Keith, York E. Miller, Yasushi Hoshikawa, Mark D. Moore, Tracy L. Gesell, Bifeng Gao, Alvin M. Malkinson, Heiko A. Golpon, Raphael A. Nemenoff and Mark W. Geraci2

Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, Denver VA Medical Center, Denver, Colorado 80220 [R. L. K., Y. E. M.], and Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine [R. L. K., Y. E. M., Y. H., M. D. M., T. L. G., B. G., H. A. G., M. W. G.], Department of Pharmaceutical Sciences [A. M. M.], and Departments of Medicine and Pharmacology [R. A. N.], University of Colorado Health Sciences Center, Denver, Colorado 80262

Inhibition of cyclooxygenase (COX) activity decreases eicosanoid production and prevents lung cancer in animal models. Prostaglandin (PG) I2 (PGI2, prostacyclin) is a PGH2 metabolite with anti-inflammatory, antiproliferative, and antimetastatic properties. The instability of PGI2 has limited its evaluation in animal models of cancer. We hypothesized that pulmonary overexpression of prostacyclin synthase may prevent the development of murine lung tumors. Transgenic mice with selective pulmonary prostacyclin synthase overexpression were exposed to two distinct carcinogenesis protocols: an initiation/promotion model and a simple carcinogen model. The transgenic mice exhibited significantly reduced lung tumor multiplicity (tumor number) in proportion to transgene expression, a dose-response effect. Moreover, the highest expressing mice demonstrated reduced tumor incidence. To investigate the mechanism for protection, we evaluated PG levels and inflammatory responses. At the time of sacrifice following one carcinogenesis model, the transgenics exhibited only an increase in 6-keto-PGF1{alpha}, not a decrease in PGE2. Thus, elevated PGI2 levels and not decreased PGE2 levels appear to be necessary for the chemopreventive effects. When exposed to a single dose of butylated hydroxytoluene, transgenic mice exhibited a survival advantage; however, reduction in alveolar inflammatory response was not observed. These studies demonstrate that manipulation of PG metabolism downstream from COX produces even more profound lung cancer reduction than COX inhibition alone and could be the basis for new approaches to understanding the pathogenesis and prevention of lung cancer.




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