Prevention of mouse lung tumors by budesonide and its modulation of biomarkers.
Chemopreventive drugs have the potential to decrease the morbidity and mortality of lung cancer. The development of these drugs could be expedited by the application of surrogate end-point biomarkers that demonstrate chemopreventive efficacy. In this study, the ability of budesonide to prevent lung tumors in mice was characterized further and its effects on biomarkers were determined. Lung tumors were induced in female strain A mice by vinyl carbamate (16 mg/kg) administered once weekly for 2 consecutive weeks. Four weeks later the mice started to receive 0.6, 1.2 or 2.4 mg/kg budesonide continually in the diet until killed at week 20. Budesonide caused a dose-dependent decrease in the multiplicity of lung tumors of 25, 58 and 82%, respectively. Budesonide (2.4 mg/kg diet) administered starting at weeks 4, 10 or 16, decreased tumor multiplicity by 82, 66 and 30% at week 20. Administering 2.4 mg/kg budesonide at weeks 4-20 or 20-35 and killing the mice at week 35 did not significantly decrease the yield of tumors, although both treatment regimens did decrease the size of the tumors and the progression of adenomas to carcinomas. Thus, budesonide delayed the appearance of lung tumors and decreased their growth and progression to carcinomas. To determine the effect of limited exposure to budesonide on biomarkers, it was administered for only 7 days prior to death at week 35. Budesonide decreased the proliferating cell nuclear antigen labeling in lung adenomas, carcinomas, parenchyma and bronchial airways by 87.6, 59.0, 41.1 and 25.4%, respectively. Budesonide treatment also increased the protein level of the p21 and p27 genes and increased the mRNA level of p21. Thus, short-term treatment with budesonide modulated biological and molecular end-points in lung tumors that might be developed further as biomarkers for its clinical chemopreventive efficacy in the lung.
Department of Pathology, Medical College of Ohio, HEB, Room 200F, 3055 Arlington Avenue, Toledo, OH 43614-5806, USA. mpereira@mco.edu
Michael A
MA
Pereira
Yingzhe
Y
Li
William T
WT
Gunning
Paula M
PM
Kramer
Fadel
F
Al-Yaqoub
Ronald A
RA
Lubet
Vernon E
VE
Steele
Eva
E
Szabo
Lianhui
L
Tao
D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000236:Adenoma / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D019819:Budesonide / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008805:Mice, Inbred A; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D014520:Urethane / Q000031:analogs & derivatives*
D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017931:DNA Primers; D008840:Microfilament Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C058992:Tagln protein, mouse; D014520:Urethane; D019819:Budesonide; C017963:vinyl carbamate