Induction and modulation of lung tumors: genomic and transcriptional alterations in cigarette smoke-exposed mice.
Cigarette smoke plays a major role in the epidemiology of lung cancer, and smoke components have extensively been investigated in carcinogenicity and chemoprevention studies in experimental animals. However, it is much more difficult to reproduce the tumorigenicity of the whole complex mixture in preclinical models. The authors review here some results obtained in their laboratories, dealing with the induction of lung tumors, and genomic and transciptional alterations in smoke-exposed mice. The authors were successful in inducing lung tumors in 4 strains of mice exposed whole-body to environmental cigarette smoke, including Swiss albino, A/J, SKH-1 hairless, and p53 mutant (UL533 x A/J)F1 mice. However, the tumorigenic response was rather weak in all strains. Much more intense were the smoke-induced alterations of a variety of intermediate biomarkers, such as cytogenetic end points in pulmonary alveolar macrophages, bone marrow and peripheral blood erythrocytes; apoptosis, p53 oncoprotein, and proliferating cell nuclear antigen in the bronchial epithelium; bulky DNA adducts, 8-hydroxy-2-deoxyguanosine; multigene expression, and thiobarbituric acid-reactive aldehydes in whole lung and several other organs. Smoke-induced genomic and transcriptional alterations were suitable for evaluating their modulation by chemopreventive agent, as shown in studies using the thiol N-acetylcysteine and the nonsteroidal anti-inflammatory drug sulindac.
De Flora
Silvio
S
Department of Health Sciences, University of Genoa, Genoa, Italy. sdf@unige.it
Izzotti
Alberto
A
D'Agostini
Francesco
F
Bennicelli
Carlo
C
You
Ming
M
Lubet
Ronald A
RA
Balansky
Roumen M
RM
D000111:Acetylcysteine / Q000627:therapeutic use; D000230:Adenocarcinoma / Q000209:etiology* / Q000235:genetics / Q000517:prevention & control; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D015415:Biomarkers; D002273:Carcinogens / Q000009:adverse effects* / Q000378:metabolism; D018890:Chemoprevention; D004195:Disease Models, Animal; D004336:Drug Antagonism; D020869:Gene Expression Profiling; D019570:Inhalation Exposure; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics / Q000517:prevention & control; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D015162:Micronucleus Tests; D013045:Species Specificity; D013467:Sulindac / Q000627:therapeutic use; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D014158:Transcription, Genetic / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D002273:Carcinogens; D014028:Tobacco Smoke Pollution; D013467:Sulindac; D000111:Acetylcysteine