This proposal details a risk reduction clinical trial on a population of familial polyposis coli (FPC) patients utilizing 13-cis-retinoic acid as the active agent. At the same time the specific biochemical effects of retinoid treatment upon both colonic polyps and skin dibroblasts will be studied. The incidence of colo-rectal carcinoma approaches 100 percent in FPC patients if surgery is not performed and even then there remains a significant possibility of rectal cancer. In addition a number of families show the extra-colonic associated manifestations of Gardner's syndrome. These include soft tissue tumors which occur in 27 percent of all members of the families and especially fibromas which can be life-threatening. Retinoids have been demonstrated to have both anti-proliferative and anti-tumorigenic effects upon epithelial cell types and to modify specific biochemical processes known to be altered in FPC. The effect of the administration of 13-cis-retinoic acid upon the growth of colorectal polyps and extra-colonic tumors will be determined. At the same time the effect of retinoid treatment on specific biochemical processes which are, a) believed to be important in or reflect abnormal growth and are b) altered in FPC, will be studied: 1. Clonogenicity: The clonogenicity of cells is a measure of their malignant potential. It has been demonstrated that retinoid acid markedly inhibits the clonogenic potential of certain malignant cells. The clonogenicity of cells obtained from polyps of untreated and retinoid treated FPC patients will be determined to assess the ability of retinoids to inhibit the growth potential of these cells. 2. Biochemical effects on polyps: The biochemical basis for the actions of retinoids are not well defined. However differentiation of certain cell types by retinoic acid appears to involve cyclic AMP-dependent protein kinase (cAMP-dPK) and in other cells retinoids appear to alter cell surface glycoprotein synthesis. Since both cAMP-dPK and glycoprotein synthesis are altered in the mucosa of FPC patients the effects of retinoid treatment upon these parameters will be determined. 3. In vitro growth control and transformation of skin fibroblasts: Abnormal growth and response to tumor promoters and carinogens appears to occur in FPC family derived fibroblasts. Since retinoids have been found to antagonise the actions of tumor promoters and carcinogens and inhibit cell growth, the effect of treatment upon these parameters in skin-derived fibroblasts will be studied.
| Quinlan, D C; Davidson, A; Watne, A L (1987) Dynamics of glycoprotein metabolism in familial polyposis coli-derived colonic epithelial tissue. Semin Surg Oncol 3:174-8 |
| Slomski, C A; Durham, J P; Watne, A L (1986) Glycosyltransferase levels in familial polyposis coli. J Surg Res 40:406-10 |
