Reference SummaryHuerta S, Cancer Res 2002 Feb 1;62(3):741-6

Title

 1alpha,25-(OH)(2)-D(3) and its synthetic analogue decrease tumor load in the Apc(min) Mouse.

Authors

 Huerta S; Irwin RW; Heber D; Go VL; Koeffler HP; Uskokovic MR; Harris DM

Journal

 Cancer Res

Volume

 62

Issue

 3

Year

 2002

Pages

 741-6

Abstract

 Both calcium and vitamin D are thought to be able to inhibit colon carcinogenesis. To better define the effects of vitamin D, we studied 1alpha,25-(OH)(2)-D(3) and a noncalcemic synthetic analogue of vitamin D(3) (VD(3)) in the Apc(min) mouse. Female Apc(min) mice 4-5 weeks old were randomized to four groups: a VD(3)-treated group (n = 11) were given injections of 0.01 microg of 1alpha,25-(OH)(2)-D(3) i.p. three times per week; an analogue-treated group (n = 10) received 5 microg of 1alpha,25-(OH)(2)-16-ene-19-nor-24-oxo-D(3) i.p. three times per week; and a control group (n = 12) received sham injections of PBS. A sulindac-treated group (n = 10) was used as a positive control. Doses of these compounds were chosen based on previous toxicity studies in mice and rats. After 10 weeks of treatment, mice were killed and two observers (S. H., R. W. I.), blinded to treatment, scored polyp number and size. Tumor number was not affected with 1alpha,25-(OH)(2)-D(3) or vitamin D analogue administration. A significant decrease in total tumor load (sum of all polyp areas) over the entire gastrointestinal tract was seen in the analogue (36% decrease; P < 0.05) and the VD(3) groups (46%; P < 0.001). There was a significant decrease in polyp number (49%; P < 0.001) and polyp area (70%; P < 0.001) in the sulindac group. Reverse transcription-PCR of the total RNA derived from intestinal tissue revealed expression of the vitamin D receptor throughout the small intestine and the colon. Serum calcium levels in the analogue group were not elevated at week 4 of treatment and only moderately elevated (22%) by week 8 (P < or =0.001). In contrast, serum calcium in the VD(3) group was significantly elevated (P < or =0.001) at weeks 4 (23%) and 8 (45%). Food intake and growth rate were significantly lower in the VD(3) group (26%, P < 0.001, and 27%, P < 0.001, respectively) at week 10. In contrast, food intake and growth rate were similar for the control, sulindac, and analogue groups. Our results indicate that a noncalcemic analogue of vitamin D can significantly decrease intestinal tumor load in Apc(min) mice without severe toxic side effects and suggest that these compounds may have utility as chemopreventive agents in groups at high-risk for colon cancer.

Links

 J:74361 – MGI References
11830528 – National Library of Medicine/PubMed

Strain Notes

Strain Note
C57BL/6J-ApcMin/+ Mice were generated from inhouse breeding colony, original breeding pairs were purchased from The Jackson Laboratory.

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6J-ApcMin/+ Intestine - Large Intestine polyp
  • vitamin D3 analogue (1alpha,25-(OH)2-16-ene-19-nor-24-oxo D3) (Ro 26-9114)
 Intestine - Large Intestine

observed
C57BL/6J-ApcMin/+ Intestine - Large Intestine polyp
  • vitamin D3 (1alpha,25-(OH)2-D3) (VD3)
 Intestine - Large Intestine

observed
C57BL/6J-ApcMin/+ Intestine - Large Intestine polyp
  • sulindac
 Intestine - Large Intestine

observed
C57BL/6J-ApcMin/+ Intestine - Large Intestine polyp Intestine - Large Intestine

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Distal polyp
  • vitamin D3 analogue (1alpha,25-(OH)2-16-ene-19-nor-24-oxo D3) (Ro 26-9114)
 Intestine - Small Intestine - Distal

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Distal polyp
  • vitamin D3 (1alpha,25-(OH)2-D3) (VD3)
 Intestine - Small Intestine - Distal

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Distal polyp
  • sulindac
 Intestine - Small Intestine - Distal

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Distal polyp Intestine - Small Intestine - Distal

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Medial polyp
  • vitamin D3 analogue (1alpha,25-(OH)2-16-ene-19-nor-24-oxo D3) (Ro 26-9114)
 Intestine - Small Intestine - Medial

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Medial polyp
  • vitamin D3 (1alpha,25-(OH)2-D3) (VD3)
 Intestine - Small Intestine - Medial

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Medial polyp
  • sulindac
 Intestine - Small Intestine - Medial

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Medial polyp Intestine - Small Intestine - Medial

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Proximal polyp
  • vitamin D3 analogue (1alpha,25-(OH)2-16-ene-19-nor-24-oxo D3) (Ro 26-9114)
 Intestine - Small Intestine - Proximal

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Proximal polyp
  • vitamin D3 (1alpha,25-(OH)2-D3) (VD3)
 Intestine - Small Intestine - Proximal

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Proximal polyp
  • sulindac
 Intestine - Small Intestine - Proximal

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Proximal polyp Intestine - Small Intestine - Proximal

observed
C57BL/6J-ApcMin/+ Intestine polyp
  • vitamin D3 analogue (1alpha,25-(OH)2-16-ene-19-nor-24-oxo D3) (Ro 26-9114)
 Intestine

observed
C57BL/6J-ApcMin/+ Intestine polyp
  • vitamin D3 (1alpha,25-(OH)2-D3) (VD3)
 Intestine

observed
C57BL/6J-ApcMin/+ Intestine polyp
  • sulindac
 Intestine

observed
C57BL/6J-ApcMin/+ Intestine polyp Intestine

observed