A new rexinoid, NRX194204, prevents carcinogenesis in both the lung and mammary gland.
OBJECTIVE
We evaluated the anti-inflammatory and growth-inhibitory properties of the novel rexinoid NRX194204 (4204) in vitro and then tested its ability to prevent and/or treat experimental lung and estrogen receptor (ER)-negative breast cancer in vivo.


METHODS
In cell culture studies, we measured the ability of 4204 to block the effects of lipopolysaccharide and induce apoptosis. For the lung cancer prevention studies, A/J mice were injected with the carcinogen vinyl carbamate and then fed 4204 (30-60 mg/kg diet) for 15 weeks, beginning 1 week after the administration of the carcinogen. For breast cancer prevention studies, mouse mammary tumor virus-neu mice were fed control diet or 4204 (20 mg/kg diet) for 50 weeks; for treatment, tumors at least 32 mm3 in size were allowed to form, and then mice were fed control diet or 4204 (60 mg/kg diet) for 4 weeks.


RESULTS
Low nanomolar concentrations of 4204 blocked the ability of lipopolysaccharide and tumor necrosis factor-alpha to induce the release of nitric oxide and interleukin 6 and the degradation of IKBalpha in RAW264.7 macrophage-like cells. In the A/J mouse model of lung cancer, 4204 significantly (P < 0.05) reduced the number and size of tumors on the surface of the lungs and reduced the total tumor volume per slide by 64% to 81% compared with the control group. In mouse mammary tumor virus-neu mice, 4204 not only delayed the development of ER-negative mammary tumors in the prevention studies but also caused marked tumor regression (92%) or growth arrest (8%) in all of the mammary tumors when used therapeutically.


CONCLUSIONS
The combined anti-inflammatory and anticarcinogenic actions of 4204 suggest that it is a promising new rexinoid that should be considered for future clinical trials.
Liby
Karen
K
Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Royce
Darlene B
DB
Risingsong
Renee
R
Williams
Charlotte R
CR
Wood
Matthew D
MD
Chandraratna
Roshantha A
RA
Sporn
Michael B
MB
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D002273:Carcinogens / Q000737:chemistry; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D008264:Macrophages / Q000378:metabolism; D008324:Mammary Tumor Virus, Mouse / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D011960:Receptors, Estrogen / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology*
C430898:AGN 194204; D000893:Anti-Inflammatory Agents; D016588:Anticarcinogenic Agents; D002273:Carcinogens; D005231:Fatty Acids, Unsaturated; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D013764:Tetrahydronaphthalenes