PREDICTIVE VALUE OF PROLIFERATION, DIFFERENTIATION AND APOPTOSIS AS INTERMEDIATE MARKERS FOR COLON TUMORIGENESIS

In order to determine the prognostic significance of proliferation, di fferentiation, and apoptosis as intermediate markers for colon tumor d evelopment, these indices were measured during the promotion phase of tumorigenesis, Two hundred and sixty male Sprague-Dawley rats were pro vided with one of two fats (corn oil and fish oil) and two fibers (pec tin and cellulose) plus or minus the carcinogen azoxymethane (AOM) and killed at two time points (18 and 36 wk) in a 2x2x2x2 factorial desig n, In vivo cell proliferation was measured immunohistochemically using incorporation of bromodeoxyuridine into DNA, Differentiation was asse ssed by binding of Dolichos biflorus agglutinin (DBA) to colonocytes. Apoptosis was measured by immunoperoxidase detection of digoxigenin-la beled genomic DNA, Adenocarcinoma incidence results at week 36 were 70 .3% for corn oil + AOM and 56.1% for fish oil + AOM treatment (P < 0.0 5); no main effect of fiber was observed. At week 18, AOM treatment in creased the number of cells per crypt column in the proximal colon com pared with saline controls (P = 0.0358) and increased the proliferativ e zone in the distal colon compared with controls (P = 0.0073), Howeve r, changes in cell proliferation at week 18 did not predict the benefi cial effect of fish oil versus corn oil, In contrast, DBA binding (the marker for differentiation) was higher in fish oil versus corn oil fe d animals in both the proximal and distal colon and in each portion of the crypt (P = 0.0001), There were a greater number of apoptotic cell s/crypt column in the proximal colon (P = 0.0019) and distal colon (P = 0.0358) with fish oil compared with corn oil, and indices of apoptos is also predicted certain fat/fiber interactions, Measurements of diff erentiation and apoptosis had greater prognostic value to detect dieta ry effects on tumor incidence than did measurements of cell proliferat ion.