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Inhibition of lung carcinogenesis by 9‐cis retinoic acid and 1α,25‐dihydroxyvitamin D 3 in the A/J mouse model: Evidence of retinoid antagonism of vitamin D
Author(s) -
Mernitz Heather,
Smith Donald E.,
Wood Richard J.,
Russell Robert M.,
Wang XiangDong
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a149-a
Subject(s) - retinoid , retinoic acid , carcinogenesis , vitamin d and neurology , medicine , endocrinology , antagonism , lung , vitamin , lung cancer , carcinogen , chemistry , pharmacology , cancer , biochemistry , receptor , gene
9‐cis‐retinoic acid (9cRA) and 1α,25‐dihydroxyvitamin D 3 (1,25D) are potential chemopreventive agents against lung cancer. However, direct evidence of the efficacy of these agents against lung tumor development in vivo is lacking. We examined 9cRA and 1,25D, alone and in combination, for their potential to inhibit lung carcinogenesis in the A/J mouse lung cancer model. A/J mice (n=14/group) were treated with 9cRA (7.5, 15, or 30 mg/kg diet), 1,25D (2.5 or 5.0 μg/kg diet), a combination of 9cRA (15 mg/kg diet) plus 1,25D (2.5 or 5.0 μg/kg diet), or standard semi‐purified diet for three weeks prior to a single dose carcinogen injection (100 mg NNK/kg body weight), and 17 weeks thereafter. Results showed that mice receiving 9cRA supplementation had significantly lower tumor multiplicity at all doses (68%–85% lower), but no significant changes in tumor incidence. 1,25D treatment resulted in a dose‐dependent decrease in tumor incidence (36% and 82% reductions) and highly significant declines in tumor multiplicity (85% and 98% reductions). The addition of 9cRA to 1,25D treatment did not enhance the tumor inhibitory effects of 1,25D, but appeared to reduce the significant weight loss and kidney calcium deposits associated with 1,25D treatment alone. There were no significant differences in plasma 1,25D concentrations between relevant groups, suggesting that this retinoid antagonism of vitamin D toxicity did not involve alteration of vitamin D metabolism. Additional research into the molecular mechanism behind this interaction is currently underway. Work supported by the NIH grant R01CA104932 and USDA 1950‐51000‐064.