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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #204032
Title: Inhibition of Lung Carcinogenesis by 1alpha,25-dihydroxyvitamin D3 and 9-cis Retinoic Acid in the A/J Mouse Model: Evidence of Retinoid Mitigation of Vitamin D Toxicity

Author
item MERNITZ, HEATHER - HNRCA AT TUFTS
item Smith, Donald
item Wood, Richard
item Russell, Robert
item Wang, Xiang-Dong

Submitted to: International Journal of Cancer
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/13/2006
Publication Date: 1/4/2007
Citation: Mernitz, H., Smith, D., Wood, R., Russell, R., Wang, X. 2007. Inhibition of Lung Carcinogenesis by 1alpha,25-dihydroxyvitamin D3 and 9-cis Retinoic Acid in the A/J Mouse Model: Evidence of Retinoid Mitigation of Vitamin D Toxicity. International Journal of Cancer. 120: 1402-1407.

Interpretive Summary: The active forms of vitamin A and vitamin D show promise as potential chemopreventive agents. We examined 9-cis-retinoic acid (9cRA) and 1alpha,25-dihydroxyvitamin D3 (1,25D), alone and in combination, for their potential to inhibit carcinogen-induced lung cancer in mice. Mice (n=14/group) were treated with 9cRA (7.5, 15, or 30 mg/kg diet), 1,25D (2.5 or 5.0 ug/kg diet), or a combination of 9cRA (15 mg/kg diet) plus 1,25D (2.5 ug/kg diet) for three weeks before and 17 weeks after carcinogen injection. Compared to carcinogen-injected controls, mice receiving 9cRA supplementation had a significantly lower tumor number at all doses (decreased 68%-85%), with body weight loss at the higher doses of 9cRA. Mice receiving 1,25D supplementation had significantly lower tumor incidence (decreased 36% and 82%) and tumor number (decreased 85% and 98%), but experienced significant body weight loss, calcium deposits in the kidneys, elevated kidney expression of an enzyme responsible for the breakdown of vitamin D, and decreased fasting plasma 1,25D levels. These data demonstrate that these active vitamin A and vitamin D compounds, alone or combined, can inhibit the process of lung cancer in a mouse model. Addition of the vitamin A compound to vitamin D treatment was able to prevent the weight loss and kidney calcification associated with vitamin D treatment alone without diminishing the chemopreventive effectiveness of the vitamin D against lung cancer. The underlying mechanism behind this effect does not appear to be related to an effect of vitamin A on the breakdown of vitamin D.

Technical Abstract: 9-cis-retinoic acid (9cRA) and 1alpha,25-dihydroxyvitamin D3 (1,25D) show promise as potential chemopreventive agents. We examined 9cRA and 1,25D, alone and in combination, for their potential to inhibit carcinogen (NNK)-induced lung carcinogenesis in A/J mice. 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 ug/kg diet), or a combination of 9cRA (15 mg/kg diet) plus 1,25D (2.5 ug/kg diet) for three weeks before and 17 weeks after carcinogen injection. Lung tumor incidence, tumor multiplicity, plasma 1,25D levels, and kidney expression of vitamin D 24-hydroxylase (CYP24) were determined. Compared to carcinogen-injected controls, mice receiving 9cRA supplementation had significantly lower tumor multiplicity at all doses (decreased 68%-85%), with body weight loss at the higher doses of 9cRA. Mice receiving 1,25D supplementation had significantly lower tumor incidence (decreased 36% and 82%) and tumor multiplicity (decreased 85% and 98%), but experienced significant body weight loss, kidney calcium deposition, elevated kidney CYP24 expression, and decreased fasting plasma 1,25D levels. Although there was no apparent influence on chemopreventive efficacy, addition of 9cRA to 1,25D treatment effectively prevented the weight loss and kidney calcification associated with 1,25D treatment alone. These data demonstrate that 9cRA and 1,25D, alone or combined, can inhibit lung tumor promotion in the A/J mouse model. Combining 1,25D with 9cRA has the potential to mitigate the toxicity of 1,25D, while preserving the significant effect of 1,25D treatment against lung carcinogenesis. The underlying mechanism behind this effect does not appear to be related to retinoid modulation of vitamin D catabolism.