Following a period of fasting, feeding a normal diet results in a burst of DNA synthesis in the crypts of the colonic epithelium. This is due largely to a prompt entry of cells, blocked in G1, into S. Peak levels of S cellularity exceed 4 times the fasting, and 2 times the normal fed, control values. Refeeding a low residue diet (soluble casein, glucose and corn oil) results in a return to control levels of proliferative activity, but no hyperplasia. However, in jejunum and ileum, refeeding is followed by a return to near control levels of proliferation with only a slight overshoot in S phase cellularity. During the fasting period, the ileal crypt proliferative compartment (Pc‐zone) and total crypt cellularity decline significantly. These changes are accompanied by an increase in the total cycle time, due to an equivalent lengthening of the G1 and S phases. Following refeeding, there is a reduction in the cycle time and a gradual return to the control values for the Pc‐zone size and cellularity. In the colon, fasting has no effect on the Pc‐zone size or total crypt cellularity. There is an approximate doubling of the cycle time due solely to an increase in G1. Following refeeding there is an increase in the Pc‐zone size and crypt cellularity and a marked shortening of the cycle time. Evidence that a G1 cycle blockade is induced in the colon by fasting is given by a lengthening of the G1 period and by stathmokinetic studies employing vincristine.
The nutritional effects of butyrate on the colonic mucosa and studies of transformed cells suggest that butyrate has anti-colon cancer effects. If butyrate has antineoplastic effects, mucosal growth contrasts between normal subjects and those with a history of colonic neoplasia would parallel changes in growth characteristics caused by butyrate in a colon neoplasia population. To test this hypothesis, rectal biopsies from a survey of colonoscopy patients (n = 50) with and without a history of colonic neoplasia (controls) were compared. Similarly, rectal biopsies were compared from subjects (n = 44) with a colon neoplasia history in an acarbose-placebo crossover trial. Control subjects in the colonoscopy survey had higher bromodeoxyuridine (BrdU) uptake than subjects with a history of neoplasia (P = 0.05). The control subjects also had a higher correlation of BrdU and Ki-67 labeling (P = 0.003). Both findings were paralleled by acarbose use. Acarbose augmented BrdU uptake (P = 0.0001) and improved the correlation of BrdU and Ki-67 labeling (P = 0.013). Acarbose also augmented fecal butyrate (P = 0.0001), which was positively correlated with Ki-67 labeling (P = 0.003). p52 antigen had an earlier pattern of crypt distribution in subjects with a history of colon neoplasia but was not affected by acarbose use. Lewis-Y antigen was expressed earlier in the crypt with acarbose but had similar expression in the colonoscopy survey groups. The use of acarbose to enhance fecal butyrate concentration produced mucosal changes paralleling the findings in control subjects as opposed to those with neoplasia, supporting the concept of an antineoplastic role for butyrate.
Recent studies have shown that the rate of colonic cell renewal can be altered through fasting and refeeding, which produces a marked depression and transient stimulation, respectively. In the present study, the role of physical versus nutritional stimulation in the colonic fasting-refeeding response and the renewal of the functional colonic compartment were evaluated via a nondestructive colonic ligation procedure. The results reported herein suggest that physical stimulation by lumenal factors is in part required to initiate the colonic hyperplasia seen after refeeding. Blood-borne nutritional factors, in the absence of physical stimulation, cannot alone stimulate colonic cell production. Additional evidence is presented which suggests that this physical stimulation may be manifested through the lumenal distension produced by the newly ingested food materials. The results are discussed from the viewpoint of influencing the functional colonic compartment and physiological capacity.
The cellular kinetics of human mammary tumors were studied by in vitro methods. These techniques include single 3HTdR labeling to measure the 3HTdR LI, double labeling with 3HTdR and 14CTdR to measure DNA synthesis time, and an estimation of the growth fraction by the PDP index. Calculations of the potential doubling time and cell cycle time were made from these measurements. The 3HTdR LI of primary malignant tumors was greater than that of benign tumors, but only half that of metastatic lesions. There was considerable heterogeneity in the 3HTdR LI of primary tumors, but the DNA synthesis times were relatively invariant. Estimation of the growth fraction by the PDP index also revealed extensive heterogeneity, but the primary tumors were not different from metastases. There appear to be subsets of tumors with high and low proliferative values that correlate with some clinical parameters, such as age and nodal positivity. This material provides a data base for stratification of patients for future protocols and the use of cell kinetics in treatment programs.
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