The rexinoid LG100268 and the synthetic triterpenoid CDDO-methyl amide are more potent than erlotinib for prevention of mouse lung carcinogenesis.
Female A/J mice injected with the carcinogen vinyl carbamate develop atypical adenomatous hyperplasias in lungs 4 weeks after injection with the carcinogen. The number and severity of tumors then increase over time, making these mice a useful model for evaluating potential chemopreventive agents. The rexinoid LG100268 (LG268), a selective ligand for the retinoid X receptor, and the methyl amide of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) both significantly reduced the number, size, and severity of the histopathology of lung tumors in female A/J mice when fed in diet for 14 to 20 weeks. The total tumor burden was 85% to 87% lower in mice fed LG268 and CDDO-MA than in controls, and the percentage of high-grade tumors decreased from 59% in the controls to 25% or 30% with CDDO-MA and LG268. Erlotinib, which is used to treat lung cancer patients and is an inhibitor of the epidermal growth factor receptor, was less effective in this model. Immunohistochemical staining of geminin, a marker of cell cycle progression, was higher in lung sections from control mice than in mice treated with LG268. Because rexinoids and triterpenoids signal through different biological pathways, they should be tested in combination for the prevention of lung cancer.
Liby
Karen
K
Department of Pharmacology, Dartmouth Medical School, Hanover, NH 03755, USA. karen.liby@dartmouth.edu
Black
Candice C
CC
Royce
Darlene B
DB
Williams
Charlotte R
CR
Risingsong
Renee
R
Yore
Mark M
MM
Liu
Xi
X
Honda
Tadashi
T
Gribble
Gordon W
GW
Lamph
William W
WW
Sporn
Thomas A
TA
Dmitrovsky
Ethan
E
Sporn
Michael B
MB
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D000069347:Erlotinib Hydrochloride; D005260:Female; D008168:Lung / Q000187:drug effects*; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D009539:Nicotinic Acids / Q000627:therapeutic use*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use*; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use*
C530803:2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl amide; D016588:Anticarcinogenic Agents; D009539:Nicotinic Acids; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013764:Tetrahydronaphthalenes; D009828:Oleanolic Acid; D000069347:Erlotinib Hydrochloride; C095104:LG 100268