CIRCADIAN VARIATIONS OF EPITHELIAL-CELL PROLIFERATION IN HUMAN RECTALCRYPTS

Background/Aims: Evidence (almost exclusively from animal studies) sug gests that proliferation within the colorectal mucosa undergoes circad ian variations. The epithelial cells that line the human colorectal cr ypt occupy definite positions along the longitudinal axis according to their proliferative potential and degree of differentiation. Thus, ci rcadian rhymicity was investigated in humans to locate the areas along the longitudinal crypt axis in which diurnal fluctuation might occur. Methods: Rectal mucosal biopsy specimens were obtained every 4 hours for a 24-hour span from each of 23 subjects (8 healthy volunteers and 15 with histories of sporadic adenomatous polyps). [H-3]thymidine hist oautoradiography was used to determine ratios of S-phase to total cell s (total labeling index) in the crypt. Glands were also divided into 5 equal compartments from base (compartment 1) to mouth (compartment 5) , and labeling indices were calculated for each. Results: Important te mporal variations were confined to compartment 2 (F = 5.15, P = 0.0003 ) and total labeling indices (F = 3.57, P = 0.005). Despite individual variations, proliferation was generally higher at night and lower dur ing afternoon. Upper-crypt proliferative rates (compartments 4 and 5) remained decidedly stable (F = 0.5, P = NS). Normal subjects and patie nts with polyps displayed similar circadian behaviors. Conclusions: Ci rcadian fluctuation in proliferation is confined to the area of the cr ypt normally associated with replication. Upper-crypt indices, includi ng those that were higher than normal (a colon-cancer risk marker) are stable over 24 hours. These findings should be useful in planning che moprevention trials and chemotherapeutic regimens.