Modulation of aberrant crypt foci by dietary fat and caloric restriction: the effects of delayed intervention.

Recent investigations have established that caloric restriction (CR) reduces end tumor incidence in the rat colon. The present study was conducted to determine whether CR at the level of 20% of the ad libitum (AL) intake and dietary fat would alter the growth of intermediate preneoplastic colonic aberrant crypt foci (ACF). F344 rats were given injections of 15mg/kg azoxymethane, fed AL for 11 weeks, and then allocated to 1 of 4 dietary groups (n-20/group): high fat (23% w/w) or low fat (5% w/w) AL (HFAL, LFAL), or high fat or low fat CR (HFCR, LFCR). After 4 weeks only the HFAL and HFCR groups had identifiable adenomas with incidences of 50 and 30%, respectively. There was a significant positive correlation between total fat consumed/day (grams) and the number of ACF with 4-6 crypts focus. After 12 weeks of feeding, the total number of ACF was lower (P < or = 0.05) in the CR groups relative to the AL groups in both the high and low fat diets. The number of ACF with 4-6 crypts/focus and > 6 crypts/focus were lower in the LFCR group compared to the LFAL group, whereas the number of ACF with 1-3 crypts/focus was lower in the HFCR group compared to the HFAL group. CR was the main variable affecting the number and growth of ACF at week 12. Positive correlations were demonstrated between increased mean daily intake of energy and the number of total ACF/colon, ACF with 4-6 crypts/focus, and ACF with > 7 crypts/focus at week 12. Cell proliferation indices did not correlate with ACF or tumor incidence data. These findings demonstrated that (a) dietary fat affects tissue growth characteristics more rapidly than CR, (b) CR alters the development of ACF depending on the level of fat and experimental duration, and (c) ACF with varying growth features respond differently to CR and dietary fat. These findings also suggest that subtle dietary manipulations in fat and caloric content used at the later stages of colon carcinogenesis can modulate tumor development.