title: Lung cancer chemoprevention with celecoxib in former smokers.
abstract: Ample studies suggest that the cyclooxygenase-2 (COX-2)/prostaglandin E(2) (PGE(2)) pathway plays a pivotal role in carcinogenesis and that COX-2 inhibition may help prevent lung cancer. Therefore, we conducted a randomized, double-blind, placebo-controlled trial of the COX-2-selective inhibitor celecoxib (400 mg bid for 6 months) in former-smokers (age ≥ 45, ≥ 30 pack-years of smoking, ≥ 1 year of sustained abstinence from smoking). We assessed the impact of celecoxib on cellular and molecular events associated with lung cancer pathogenesis; the primary endpoint was bronchial Ki-67 labeling index (Ki-67 LI) after 6 months of treatment. Of 137 randomized subjects, 101 completed both baseline and 6-month bronchoscopies and were evaluable for the primary endpoint analysis. The beneficial effect on Ki-67 LI was greater in the celecoxib arm (versus placebo) in a mixed-effects analysis (P = 0.0006), and celecoxib significantly decreased Ki-67 LI by an average of 34%, whereas placebo increased Ki-67 LI by an average of 3.8% (P = 0.04; t test). In participants who crossed over to the other study arm at 6 months (all of whom had received 6 months of celecoxib at the end of a 12 months treatment period), the decreases in Ki-67 LI correlated with a reduction and/or resolution of lung nodules on computed tomography. Celecoxib significantly reduced plasma c-reactive protein and interleukin-6 mRNA and protein and increased 15(S)-hydroxy-eicosatetraenoic acid levels in bronchoalveolar lavage (BAL) samples. The baseline ratio of COX-2 to 15-hydroxyprostaglandin dehydrogenase mRNA in BAL cells was a significant predictive marker of Ki-67 response to celecoxib (P = 0.002). Our collective findings support the continued investigation of celecoxib for lung cancer chemoprevention in former smokers at a low risk of cardiovascular disease.
authors: Pulmonary and Critical Care Section, New Mexico VA Health Care System/University of New Mexico, Albuquerque, New Mexico 87108, USA. jenny.mao@va.gov
authors: Jenny T
authors: JT
authors: Mao
authors: Michael D
authors: MD
authors: Roth
authors: Michael C
authors: MC
authors: Fishbein
authors: Denise R
authors: DR
authors: Aberle
authors: Zuo-Feng
authors: ZF
authors: Zhang
authors: Jian Yu
authors: JY
authors: Rao
authors: Donald P
authors: DP
authors: Tashkin
authors: Lee
authors: L
authors: Goodglick
authors: E Carmack
authors: EC
authors: Holmes
authors: Robert B
authors: RB
authors: Cameron
authors: Steven M
authors: SM
authors: Dubinett
authors: Robert
authors: R
authors: Elashoff
authors: Eva
authors: E
authors: Szabo
authors: David
authors: D
authors: Elashoff
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D018893:Bronchoalveolar Lavage; D002097:C-Reactive Protein / Q000378:metabolism; D000068579:Celecoxib; D018592:Cross-Over Studies; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D015850:Interleukin-6 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008175:Lung Neoplasms / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000627:therapeutic use*; D012907:Smoking / Q000009:adverse effects*; D013449:Sulfonamides / Q000627:therapeutic use*; D015996:Survival Rate; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D052246:Cyclooxygenase 2 Inhibitors; D015850:Interleukin-6; D019394:Ki-67 Antigen; D011720:Pyrazoles; D013449:Sulfonamides; D002097:C-Reactive Protein; D000068579:Celecoxib