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Copyright by Eunyoung Park 2007 - The University of Texas at Austin

Copyright by Eunyoung Park 2007 - The University of Texas at Austin

food intake decreased

food intake decreased after tumor injection in both experiments (Fig. 5.1 B and D). In addition, only one mouse in the chemotherapy study, consuming 200,000 IU vitamin A/kg diet, showed skin redness and desquamation. No mice in the chemoprevention study showed any signs of vitamin A toxicity. These data show that high levels of vitamin A supplementation do not adversely affect body weight and food intake or cause toxicity in mice. The effect of retinol on liver metastases incidence in the chemotherapy study. Because visible metastases were not always apparent and to confirm that the visual metastases were indeed true metastases of human origin, liver sections were subjected to immunohistochemical analysis for the presence of CK 20, a marker of human colon cells. This also allowed us to visualize micrometastases. As can be seen in Fig. 5.2A, dietary supplementation with 50,000, 100,000 or 200,000 IU vitamin A/kg diet decreased the incidence of metastasis. The number of metastases per dietary group is displayed in Table 5.2. The greatest degree of inhibition was achieved by the consumption of the 200,000 IU vitamin A/kg diet. These mice exhibited a metastasis rate 45.2% less (P = 0.14) than that exhibited by mice consuming the control diet (Table 5.2 and Fig. 5.2C). These data indicate that dietary supplementation with vitamin A trends to inhibit the metastases of human colorectal cancer cells in a nude mouse xenograft chemotherapy model, confirming our in vitro observations. 105

The effect of retinol on tumor multiplicity in chemoprevention study. Because the incidence of metastasis was very high and visual tumors were apparent in the chemoprevention study, we determined metastasis multiplicity, defined here as the number of metastatic tumors per liver, per mouse. Supplementation with 200,000 IU vitamin A/kg diet significantly reduced tumor multiplicity from 56.57 ± 21.99 to 9.86 ± 3.8 (P = 0.03) (Fig. 5.3) which decreased tumor multiplicity to 17% of control. These data indicate that dietary vitamin A supplementation, prior to tumor cell injection, reduces the number of metastases per liver. In a previous study, we showed that retinol decreased MMP-2, -9 and PI3K activity resulting in inhibition of human colon cancer cell invasion in vitro (144,174). To determine if the activity of these enzymes were decreased by dietary vitamin A supplementation, liver metastases were stained with MMP-2, -9, total Akt, and phospho- Akt. Phospho-Akt corrected for total Akt represents PI3K activity. These four antibodies were pre-examined for positive staining in different tissues (data not shown). Liver metastases introduced by intrasplenic injection of human colon cancer cells showed no staining for MMP-2 and -9 (Fig. 5.4 B and C). Metastasized tumors showed positive total and phospho-Akt staining. However, vitamin A supplementation did not change the level of total or phospho-Akt (Fig. 5.4 D to F). DISCUSSION The liver is the major storage site for vitamin A and the target organ for colon cancer metastasis. Previously, we showed that retinol decreased ATRA resistant colon 106

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