title: Chemopreventive effects of the p53-modulating agents CP-31398 and Prima-1 in tobacco carcinogen-induced lung tumorigenesis in A/J mice.
abstract: Lung cancer is the leading cause of cancer deaths worldwide. Expression of the p53 tumor suppressor protein is frequently altered in tobacco-associated lung cancers. We studied chemopreventive effects of p53-modulating agents, namely, CP-31398 and Prima-1, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung adenoma and adenocarcinoma formation in female A/J mice. Seven-week-old mice were treated with a single dose of NNK (10 µmol/mouse) by intraperitoneal injection and, 3 weeks later, were randomized to mice fed a control diet or experimental diets containing 50 or 100 ppm CP-31398 or 150 or 300 ppm Prima-1 for either 17 weeks (10 mice/group) or 34 weeks (15 mice/group) to assess the efficacy against lung adenoma and adenocarcinoma. Dietary feeding of 50 or 100 ppm CP-31398 significantly suppressed (P < .0001) lung adenocarcinoma by 64% and 73%, respectively, after 17 weeks and by 47% and 56%, respectively, after 34 weeks. Similarly, 150 or 300 ppm Prima-1 significantly suppressed (P < .0001) lung adenocarcinoma formation by 56% and 62%, respectively, after 17 weeks and 39% and 56%, respectively, after 34 weeks. Importantly, these results suggest that both p53 modulators cause a delay in the progression of adenoma to adenocarcinoma. Immunohistochemical analysis of lung tumors from mice exposed to p53-modulating agents showed a significantly reduced tumor cell proliferation and increased accumulation of wild-type p53 in the nucleus. An increase in p21- and apoptotic-positive cells was also observed in lung tumors of mice exposed to p53-modulating agents. These results support a chemopreventive role of p53-modulating agents in tobacco carcinogen-induced lung adenocarcinoma formation.
authors.affiliation: Center for Cancer Prevention and Drug Development, Hematology-Oncology Section, Department of Medicine, Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
authors.forename: Jagan Mohan R
authors.initials: JM
authors.lastname: Patlolla
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.forename: Yuting
authors.initials: Y
authors.lastname: Zhang
authors.forename: Misty
authors.initials: M
authors.lastname: Brewer
authors.forename: Altaf
authors.initials: A
authors.lastname: Mohammed
authors.forename: Dhimant
authors.initials: D
authors.lastname: Desai
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Stan
authors.initials: S
authors.lastname: Lightfoot
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001372:Aza Compounds / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D018890:Chemoprevention; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D051379:Mice; D008805:Mice, Inbred A; D009602:Nitrosamines; D011743:Pyrimidines / Q000627:therapeutic use*; D011897:Random Allocation; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects*; D062789:Tobacco Products
chemical_list: D016588:Anticarcinogenic Agents; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009602:Nitrosamines; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C451219:2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one; C402665:CP 31398
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