Luminal and humoral influences on human rectal epithelial cytokinetics

Multiple genetic and environmental steps may underpin the development of human colorectal neoplasia, and experimental evidence suggests that promoters of colorectal cancer also induce colorectal epithelial cell hyperplasia. In vitro crypt cell production rate (CCPR) was measured to determine the effect of calcium, epidermal growth factor (EGF), vitamin D3 metabolites and synthetic analogues on human rectal epithelial cell proliferation. In a double-blind trial of oral calcium supplementation, CCPR was reduced by 49% in patients with familial adenomatous polyposis (FAP), but there was no effect on established neoplasia. In control tissue, the active form of vitamin D3 (1,25(OH)2D3) reduced rectal CCPR by 57% at 1 microM, 55% at 10 nM and 45% at 100 pM. Likewise, in tissue taken from patients with FAP, 1,25(OH)2D3 reduced CCPR by 52%. Vitamin D3 has profound effects on calcium metabolism, but synthetic analogues can avoid these. The effects of a synthetic analogue (MC-903) on human rectal CCPR were therefore studied. MC-903 (10(-7) M) reduced CCPR in control tissue by 51%, and in FAP tissue by 52% at 10(-6) M and 51% at 10(-7) M. In addition, MC-903 and a related analogue, EB 1089, produced a clear-cut dose-dependent inhibition of both HT-29 and Caco2 colorectal cancer cells maintained in culture. Hence, vitamin D3 and its analogues can reduce the rate of cell proliferation in normal, premalignant and malignant colorectal epithelial cells and might therefore have future therapeutic uses as chemoprotective or chemotherapeutic agents. Lastly, EGF increases CCPR by 102% in FAP tissue that expresses the EGF receptor. Thus, human colorectal cell proliferation is influenced by a variety of luminal and humoral agents and a greater understanding of these actions should help plan future treatments.