calcimycin and Carcinoma--Non-Small-Cell-Lung

Preclinical data suggest that the cyclooxygenase (COX)-2/prostaglandin (PG) E2 signaling pathway plays an essential role in conferring the malignant phenotype in non-small cell lung cancer. We hypothesized that treatment with oral celecoxib, a selective COX-2 inhibitor, would favorably alter biomarkers of lung cancer risk. This study evaluated the feasibility of COX-2 inhibition as a form of chemoprevention for lung cancer.. Heavy active smokers were enrolled into a pilot study and treated with celecoxib. Bronchoscopy with bronchoalveolar lavage was performed both before and after 1 month of celecoxib treatment to recover alveolar macrophages (AMs) and lining fluid for study. After harvest, AMs were immediately stimulated in vitro with the calcium ionophore A23187. AMs obtained from smokers before treatment and from nonsmoking control subjects were also cultured overnight with SC58236, a selective COX-2 inhibitor, with or without lipopolysaccharide stimulation.. Treatment with celecoxib significantly reduced calcium ionophore-stimulated PGE2 production from AMs recovered from smokers. AMs recovered from smokers, but not nonsmokers, were primed to produce high levels of PGE2 and interleukin (IL-10) when stimulated with lipopolysaccharide, and SC58236 significantly abrogated the production of these factors. Moreover, both plasma and bronchoalveolar lavage fluid obtained from treated subjects significantly reduced the production of PGE2 that resulted when a lung cancer cell line, A549, was stimulated with IL-1beta or A23187.. Our findings suggest that oral celecoxib is capable of inhibiting the overproduction of PGE2, as well as modulating the production of IL-10 in the lung microenvironment in individuals at risk for lung cancer.

Topics: Aged; Bronchoalveolar Lavage; Bronchoscopy; Calcimycin; Carcinoma, Non-Small-Cell Lung; Case-Control Studies; Celecoxib; Cyclooxygenase Inhibitors; Dinoprostone; Feasibility Studies; Female; Humans; Interleukin-10; Ionophores; Lipopolysaccharides; Lung Neoplasms; Macrophages, Alveolar; Male; Middle Aged; Pilot Projects; Pyrazoles; Smoking; Sulfonamides; Tumor Cells, Cultured

We studied neutrophil functions in a patient with colony-stimulating activity (CSA)-producing lung cancer. A 59-year-old man had an abnormal chest X-ray and leucocytosis, predominantly with neutrophils. Pneumonectomy was performed, and the histological diagnosis of the tumour was large-cell carcinoma of the lung. The tumour induced marked granulocytosis in tumour-transplanted nude mice, and the conditioned media of the tumour contained very strong human-active CSA. Superoxide release and membrane depolarization in neutrophils stimulated by the chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine, were markedly enhanced in the patient. These findings suggest that CSA produced by the tumour primed neutrophil functions in vivo in the patient.

Topics: Animals; Calcimycin; Carcinoma, Non-Small-Cell Lung; Colony-Stimulating Factors; Humans; Lung Neoplasms; Male; Membrane Potentials; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neoplasm Transplantation; Neutrophils; Superoxides