Biomedical subjects

R P Bird

Publications and source records attributed to R P Bird.

At least 19 recordsLinked to original sources

PubMed2006

Novel mucilage fraction of Sinapis alba L. (mustard) reduces azoxymethane-induced colonic aberrant crypt foci formation in F344 and Zucker obese rats.

Seeds of Sinapis alba Linn. (commonly called yellow or white mustard) and their components have been reported to possess anticancer properties. In this study, we evaluated the efficacy of a novel mucilaginous fraction of mustard seeds in inhibiting colonic preneoplastic changes in animal models of sporadic and obesity-associated colon cancer. In two separate studies, male Sprague-Dawley or female Zucker obese rats, injected with azoxymethane (15 or 10 mg/kg body wt. once a week for 2 weeks, respectively), were fed AIN-93G diets with or without 5% mustard mucilage (MM) (w/w) for 8 weeks. Our aim was to measure the ability to modulate the number of aberrant crypt foci (ACF), putative preneoplastic lesions of the colon. The data were classified into total numbers of ACF and large ACF (crypt multiplicity of 4 or more). We report here that 5% MM significantly (p<0.05) decreased the number of total (approximately 21% inhibition) and large (approximately 50% inhibition) ACF in the colons of Sprague-Dawley rats compared to that in untreated controls. In addition, 5% MM supplemented diet significantly lowered (p<0.05) the number of total (approximately 63% inhibition) and large (approximately 60% inhibition) colonic ACF in Zucker obese rats compared to untreated obese rats, and had no effect on fasting plasma cholesterol or triglyceride levels. These results demonstrate the possible role of MM as a functional food against sporadic and obesity-associated colon cancer, and provide impetus to conduct research to understand the underlying mechanism(s) of action.

Adhesives↗

PubMed2006

Alleviation of hepatic steatosis accompanied by modulation of plasma and liver TNF-alpha levels by Trigonella foenum graecum (fenugreek) seeds in Zucker obese (fa/fa) rats.

OBJECTIVE: Oral supplements of fenugreek (Trigonella foenum graecum) seeds (Fen) have been shown to treat glucose and lipid homeostasis in several metabolic disorders; however, its ability to alleviate obesity-associated pathologies is not known. The main objective of this study was to evaluate the effect of Fen in Zucker obese rats (Ob), an animal model of obesity and related disorders, such as dyslipidemia and hepatic steatosis. METHODS: Female Zucker (6-week-old) Ob and lean (Ln) rats were randomly grouped (n = 8 rats/group) to receive either basal or 5% Fen-supplemented AIN-93G diets for 8 weeks, and then were euthanized. Histopathology and biochemical parameters in the liver together with plasma biochemistry were assessed. RESULTS: Obese rats had significantly higher (P < 0.05) body and liver weight, as well as plasma insulin, lactate, cholesterol, triglyceride and tumor necrosis factor (TNF)-alpha compared to their Ln counterparts. Fen significantly reduced (P < 0.05) the liver-weight of Ob rats in comparison to Ob rats fed basal diet (Control), while no effect was observed in the Ln rats. Fen treatment resulted in a lower P-value (P < 0.05). In addition, Ob rats on Fen-supplemented diets had fasting plama cholesterol and TNF-alpha levels, and significantly higher (P < 0.05) triglycerides in comparison to the control rats. Hepatic triglyceride level was significantly lower (P < 0.05) in Ob rats fed Fen supplemented diets in comparison to control. The levels of bound and soluble liver TNF-alpha (26 and 17 kDa, respectively) and TNF receptor-II (TNFR-II, 75 kDa) proteins were significantly lower (P < 0.05) in Ob than in Ln rats. Fen significantly lowered (P < 0.05) both the soluble and bound forms of TNF-alpha protein while significantly elevating (P < 0.05) TNFR-II in the livers of Ob rats compared to Ob Controls. CONCLUSION: These results demonstrate unequivocally that in a short-term preclinical evaluation, dietary Fen supplementation reduced the triglyceride accumulation in the liver, a hallmark feature of hepatic steatosis without affecting the plasma insulin or glucose levels in Zucker obese rats and suggest that TNF-alpha may play an important role in this process.

Animals↗

PubMed2001

Correspondence re: Y. Yamada et al., frequent beta-catenin gene mutations and accumulations of the protein in the putative preneoplastic lesions lacking macroscopic aberrant crypt foci appearance, in rat colon carcinogenesis. Cancer Res., 60: 3323-3327, 2000; and sequential analysis of morphological and biological properties of beta-catenin-accumulated crypts, provable premalignant lesions independent of aberrant crypt foci in rat colon carcinogenesis. Cancer Res., 61: 1874-1878, 2001.

Explore the source record for details and available documents.

Animals↗

PubMed2000

The significance of aberrant crypt foci in understanding the pathogenesis of colon cancer.

Animal models provide a unique opportunity to study the biology of the disease process, and to test hypotheses linking environmental factors in the etiology and prevention of colon cancer. The concept of cancer prevention is to retard, regress or eliminate precancerous lesions. To actuate this concept, it is important to identify and enumerate preneoplastic lesions of various growth dimensions. The study of the precancerous stages in the colon is possible by the identification of aberrant crypt foci (ACF) in rodent colons treated with a carcinogen. The growth, morphological and molecular features of ACF support the contention that ACF are putative preneoplastic lesions. The ACF system is used extensively to identify modulators of colon carcinogenesis. Among the various endpoints being used in cancer research, ACF are the only endpoints which provides a quantitative approach to assess the disease process and the underlying cellular and molecular events as affected by cancer preventive or promoting agents. Many dietary components have been classified as tumor promoters or inhibitors based on their ability to change the tumor outcome. Whether they affect the growth of very early or advanced preneoplastic lesions is not known and can be explored by using ACF system. This information will provide a better understanding of cancer pathogenesis and will lead to the development of different cancer preventive strategies for high-risk individuals and the general population.

Animals↗

PubMed2000

Evidence for the involvement of dietary lipids on the modulation of transforming growth factor-beta1 in the platelets of male rats.

Transforming growth factor beta1 (TGF-beta1), a multifunctional cytokine participates in the proliferation and differentiation of various cell types. Platelets are an important source of TGF-beta1 and are physiologically linked to a variety of chronic illnesses including cancer, heart disease and inflammation. It is well known that dietary lipids modulate platelet function. Whether dietary lipids affect growth factor status of platelets is not known. This study addresses the effect of dietary lipids on TGF-beta1 status of the platelets. Male 8 month-old Sprague Dawley rats were allocated to different diet groups. The high fat diets ( 18% by weight) comprising of high fat beef tallow (HFB), high fat corn oil (HFC), high fat fish oil (HFF) and high fat olive oil (HFO) and one low fat diet containing low fat soybean oil (LFS) (5% by weight) were fed to the experimental animals for 6 weeks. The TGF-beta1 status in the platelet lysate was assessed by using the CCL-64 mink lung cell bioassay and by Western blot analysis. Platelet lysates were evaluated for their ability to inhibit the growth of the CCL-64 mink lung cells, unexpectedly platelet lysates stimulated growth. The stimulatory effect of platelet lysate was in the order HFF > HFO > HFB > HFC > LFS. Acidification of the lysates to activate the latent form of TGF-beta1 resulted in the loss of the growth stimulatory potential of the platelet lysates in all the groups. Western blot analysis of the platelet lysates to detect the level of TGF-beta1 protein demonstrated that HFB diet group had the highest level of TGF-beta1 and the HFC diet group had the lowest level of TGF-beta1 and were significantly different (p < 0.05) as compared to the other three diet groups. These findings demonstrate that dietary lipids varying in their fatty acid composition, profoundly affect the level of growth modulating constituents of the platelets. Further studies are warranted to refine our understanding of the effect of dietary constituents on the physiology of the platelets.

Animals↗

PubMed1999

Energy restriction modulates the development of advanced preneoplastic lesions depending on the level of fat in the diet.

Our objective was to investigate the ability of preneoplastic colonic lesions at different stages of development to respond to the growth-retarding effects of energy restriction (ER). Male Fischer 344 rats were given three injections of azoxymethane (15 mg/kg s.c.) and fed a high-fat corn oil diet for 16 weeks. This duration allowed aberrant crypt foci (ACF) to develop and acquire different growth states. ACF growth was assessed by enumerating the number of crypts per focus. At Week 16, 10 animals were killed and their colons were enumerated for ACF (baseline). The remaining animals were then allocated to four dietary groups: high-fat (23% wt/wt), low-fat (5% wt/wt), high-fat energy-restricted (HFER), or low-fat energy-restricted (LFER). After the animals were fed the experimental diets for six weeks, ER decreased the total number of ACF regardless of the level of fat. At Week 12, the LFER diet retarded the appearance of advanced ACF, but this was not the case for the HFER diet. Consequently, the level of fat was identified as the significant variable in affecting the number of ACF with different crypt multiplicity. The animals fed the LFER diet had the fewest tumors and microadenomas per rat. The HFER diet was ineffective in modulating tumor outcome. To our knowledge, these findings are the first to suggest that ER modulated the development of advanced ACF and colonic tumors depending on the level of fat in the diet.

Analysis of Variance↗

PubMed1998

Modulation of colonic xenobiotic metabolizing enzymes by feeding bile acids: comparative effects of cholic, deoxycholic, lithocholic and ursodeoxycholic acids.

Primary and secondary bile acids such as cholic (CHA), deoxycholic (DCA) and lithocholic (LCA) acids have been shown to increase colon tumorigenesis. It has been suggested that inhibition of xenobiotic metabolizing enzymes such as glutathione S-transferase (GST) and UDP-glucuronyltransferase (UGT) by bile acids may be a factor in the development of colon cancer. While enzyme inhibition has been demonstrated in vitro, it is unclear whether feeding bile acids modulates colonic GST and UGT in vivo. To test this notion, male, Sprague-Dawley rats (n = 100) were assigned to a control (CON) or test diets containing 0.2% CHA, DCA, LCA or ursodeoxycholic acid (UDCA). After 5 weeks, colonic tissue was harvested and used for enzyme and cell proliferation measurements. The response to bile acids varied with the enzyme measured and appeared isoenzyme specific. GST-alpha activity was lower in the bile acid fed groups compared with CON. While GST-mu was lower in the LCA-fed group, GST-pi was lower in the DCA-, CHA- and UDCA-fed groups. Unlike GST, both UGT and NADPH-cytochrome P-450 reductase (CYC) activities were increased by bile acids. The proliferative response of the colonic epithelium varied with the bile acids and was regionally specific. These data demonstrate that feeding bile acids alters the activity of colonic phase I and II enzymes; however, the physiological effect of these enzymatic perturbations is yet to be determined.

Animals↗

PubMed1998

Comparative effects of secondary bile acids, deoxycholic and lithocholic acids, on aberrant crypt foci growth in the postinitiation phases of colon carcinogenesis.

The objective of this study was to investigate the effect of deoxycholic (DCA) and lithocholic (LCA) acids on the postinitiation phases of colon cancer. Male Sprague-Dawley rats (n = 170) were injected with azoxymethane (2 injections at 15 mg/kg body wt sc given 1 wk apart) and fed a control (CON) AIN-93 diet. Two weeks after the second azoxymethane injection, 10 animals were killed and aberrant crypt foci (ACF) were enumerated. The remaining animals were randomly assigned to four diet groups: 1) CON, 2) DCA, 3) LCA, and 4) high fat (HF, a positive control group). Bile acid diets consisted of 0.2% by weight DCA or LCA; HF diets consisted of 20% fat (5% soybean oil + 15% beef tallow by weight). Animals were killed at Weeks 3, 12, and 20 (from 1st carcinogen injection), and number and growth features of ACF and adenomatous lesions were enumerated in the colon. At Week 12, ACF number and small, medium, and large (1-3, 4-6, and > or = 7 crypts/focus, respectively) ACF were higher in the HF group than in the DCA, LCA, and CON groups (p < or = 0.05). By Week 20, ACF number and small, medium, and large ACF were similar in the LCA and HF groups, whereas the response was similar in the DCA and CON groups. Average crypt multiplicity was higher in the HF and LCA groups than in the DCA and CON groups (p < or = 0.05). Microadenoma (MA) incidence was higher in the HF group than in the CON and LCA groups (p < or = 0.05). Regional distribution patterns for ACF number were similar to MA and tumor distribution patterns within the CON, DCA, and HF groups. In the LCA group, ACF number and MA showed a proximal predominance in regional distribution, whereas tumors showed a distal predominance. HF diets provided the most stimulatory environment, immediately enhancing the number and growth of ACF and MA incidence. In conclusion, HF and LCA diets exerted distinct effects on postinitiation phases of colon cancer, whereas the DCA diet did not.

Animals↗

PubMed1998

Diverse effect of fish oil on the growth of aberrant crypt foci and tumor multiplicity in F344 rats.

The main objective of the present study was to investigate the amenability of preneoplastic lesions at different developmental stages to the growth-regulatory effects of two types of dietary lipids. F344 male rats were given three injections of azoxymethane (15 mg/kg) and fed a low-fat corn oil diet for 12 weeks to allow preneoplastic lesions or aberrant crypt foci (ACF) to develop. At this time, the colons of rats had a large number of ACF exhibiting various crypt multiplicities (number of crypts/focus). These rats were then randomly allocated to three dietary groups: high-fat corn oil (HFC), high-fat fish oil (HFF), and low-fat corn oil (LFC). The number and crypt multiplicity of ACF and adenomatous lesions were determined after 6 and 12 weeks of dietary intervention. After six weeks, the HFF group had the highest number of ACF of all crypt multiplicities and microadenomas among the dietary groups. After 12 weeks of feeding, the HFC diet increased the number of tumors without significantly changing the number of ACF. In contrast, the HFF diet increased significantly (p < 0.05) the number of ACF with higher crypt multiplicity without affecting the number of tumors. Consequently, the total number of tumors per group in decreasing order was as follows: HFC > LFC > HFF. These findings suggest that dietary lipids varying in fatty acid composition, namely corn oil and fish oil, exerted a growth-enhancing and -inhibiting effect, respectively, on different preneoplastic stages in a selective and differential manner. Most notably, transition of microscopic preneoplastic lesions to macroscopic lesions (microadenomas or adenomas) appears to be retarded by an HFF diet.

Animals↗

PubMed1998

Tumor-enhancing effects of cholic acid are exerted on the early stages of colon carcinogenesis via induction of aberrant crypt foci with an enhanced growth phenotype.

The objective of the study was to establish whether cholic acid (CHA) enhanced colonic tumor incidence in the early phase of carcinogenesis. Male, Sprague-Dawley rats (n = 180) were injected twice with azoxymethane (AOM) (15 mg x kg(-1) body weight x week(-1), s.c., given 1 week apart). Following the first AOM injection, animals were randomly assigned to two groups, control AIN-93G diet (CON) or control diet containing 0.2% CHA by weight (CHA). Three weeks after the first injection, 20 animals (10 animals/group) were killed and aberrant crypt foci (ACF) were enumerated. The remaining animals were further subdivided and animals randomly assigned to CON or CHA diets, creating four treatments: CON-CON, CON-CHA, CHA-CHA, and CHA-CON. After 3, 12, and 20 weeks (following the first carcinogen injection), the animals were killed and the number and crypt multiplicity of ACF enumerated. Macroscopic tumors were evaluated at week 20. Total ACF were not different between groups. Average crypt multiplicity and medium (4-6 crypts/focus) and large (> or = 7 crypts/focus) ACF were greater in CHA-CHA and CHA-CON compared with CON-CON and CON-CHA (p < 0.01). Transient exposure to CHA (CHA-CON) was sufficient to induce development of ACF with an accelerated growth phenotype and elicit a tumor-enhancing effect. CHA-CHA had the highest tumor incidence (82.8%, p < 0.05) followed by CHA-CON (56.7%, p < 0.05), and tumor multiplicity and number of tumors per rat in CHA-CON were similar to CHA-CHA (2.29 and 1.3 versus 2.33 and 1.9, respectively). Delayed intervention with CHA (CON-CHA) produced a tumor outcome similar to CON-CON (31 and 30%, respectively), it did not enhance colonic tumor incidence. Taken collectively these results suggest CHA was effective in enhancing colon carcinogenesis during early phases and ineffective in post-initiation phases.

Animals↗

PubMed1997

A novel methodological approach to study the level of specific protein and gene expression in aberrant crypt foci putative preneoplastic colonic lesions by Western blotting and RT-PCR.

Aberrant crypt foci (ACF) represent microscopic preneoplastic lesions, present in the carcinogen-treated rodent colons. The cellular and molecular changes occurring within these lesions may provide important clues to the sequence of events leading to advanced preneoplastic or neoplastic lesions. The main objective of this investigation was to determine whether intact mRNA and protein can be isolated from fixed tissue and studied. A pure population of ACF was harvested from colonic tissue that had been preserved in 70% ethanol or 10% buffered formalin, by using a dissecting microscope and plucking the ACF out using fine forceps. The standard procedure of isolating RNA was performed successfully on ACF and normal tissue preserved in 70% ethanol. The expression of a housekeeping gene, beta-actin was demonstrated. Analysis of ethanol-preserved ACF for phosphorylated proteins was carried out by immunoblotting. The present study demonstrated that ACF are easily harvested from fixed tissues and that intact RNA and protein can be isolated from ACF or normal epithelium which can be used in techniques such as immunoblotting and RT-PCR.

Animals↗

PubMed1997

Phenobarbital and 3-methylcholanthrene treatment alters phase I and II enzymes and the sensitivity of the rat colon to the carcinogenic activity of azoxymethane.

It has been hypothesized that cancer risk may be influenced by phase I and II drug-metabolizing enzyme systems. This study attempted to determine the relationship between colon phase I and II enzyme activity and the subsequent induction of aberrant crypt foci (ACF), preneoplastic lesions by azoxymethane (AOM), a colon-specific carcinogen. Phenobarbital (PB) and 3-methylcholanthrene (MC) treatment (prototype hepatic inducers of phase I and II enzymes) provided the framework to study the induction of phase I and II enzymes in the rat colonic mucosa. Following induction for five consecutive days, the animals were given a single injection of AOM. Phase I and II enzymes were determined fluorometrically and spectrophotometrically and ACF were identified microscopically. Phase I and II xenobiotic metabolizing enzymes were induced in the rat colonic mucosa by prototype hepatic inducers. A lower number of ACF and crypt multiplicity was observed in animals induced with MC than in those in the non-induced and PB groups. Altered levels of phase I and II enzymes in the colon during preinitiation stages were associated with modulation in the growth of ACF, putative preneoplastic lesions.

Animals↗

PubMed1996

Inability of low- or high-fat diet to modulate late stages of colon carcinogenesis in Sprague-Dawley rats.

The main objective of the present proposal was to investigate the effect of feeding a low- or high-fat diet in the early and late stages of colon carcinogenesis. Sprague-Dawley male rats were injected with azoxymethane (20 mg/kg/week) for 2 weeks. One week later they were randomly allocated to eat a low-fat (4% beef tallow + 1% corn oil) or a high-fat (18.6% beef tallow + 4.7% corn oil) diet (LF or HF). After 10 weeks of feeding, 10 animals per group were killed, and their colons were evaluated for tumors. The remaining animals in each group were divided further into LF and HF groups. The four experimental groups consisted of groups receiving LF or HF diet throughout the study (LF-LF or HF-HF) and the groups fed LF or HF diet for the first 10 weeks, then assigned the alternate diet for the remainder of the duration (LF-HF or HF-LF). By week 26, the remaining animals were killed, and their colons were evaluated for the number, location and size of tumors. The tumor incidence in the HF-HF and HF-LF groups were higher than the LF-LF and LF-HF groups (81.6 and 84.8% versus 71.4 and 60.0%). Tumor multiplicity ranged from 1.86 +/- 0.26 to 2.54 +/- 0.33 in all groups. The average size of tumors and total tumor area/rat were affected significantly by the time at which the diet was fed. Average size and total tumor area in the animals fed HF diet during early stages (HF-HF and HF-LF) were significantly higher than those fed the LF diet during the early stages. Late intervention by specific diets did not affect tumor outcome. Sequential enumeration of aberrant crypt foci of different growth features representing early preneoplastic stages corroborated the findings of the tumor outcome. It was concluded that early preneoplastic stages were more sensitive than their advanced counterparts to the dietary interventions of the present study.

Animals↗

PubMed1996

Different genetic susceptibility to aberrant crypts and colon adenomas in mice.

Aberrant crypt foci (ACFs) are the earliest identifiable epithelial lesions thought to precede the development of a subset of colon tumors. To assess their predictive value to adenoma development, we have tested in mice whether the development of ACFs and adenomas is controlled by the same genes. Therefore we used the CcS/Dem series of recombinant congenic strains, in which the effect of multiple susceptibility genes might be studied separately. We investigated susceptibility to ACFs in nine CcS/Dem strains and their parental strains, BALB/cHeA and STS/A, 4 weeks after s.c. injection of 1,2-dimethylhydrazine (20 mg/kg body weight). For the strains BALB/cHeA, STS/A, and CcS-19, we also examined the number of ACFs 2, 8, and 12 weeks after treatment. Susceptibility to adenomas was measured as the number of adenomas 6 weeks after 26 weekly s.c. injections of 1,2-dimethylhydrazine (15 mg/kg body weight). The nine CcS/Dem strains, the BALB/ cHeA strain, and the STS/A strain exhibited different patterns of susceptibility to ACFs and adenomas, demonstrating that different subsets of susceptibility genes are involved. Therefore, in evaluating the role of ACFs as a predictive marker for adenoma development, genetic factors must be taken into account.

1,2-Dimethylhydrazine↗

PubMed1996

Modulation of colonic aberrant crypt foci and proliferative indexes in colon and prostate glands of rats by vitamin E.

The effect of a high vitamin E diet on the early stages of colon carcinogenesis and on the proliferative indexes in the colon and in the prostate glands was investigated in rats. F344 male rats were injected with azoxymethane (AOM, 15 mg/kg sc). One week later, animals were randomly allocated into two dietary groups (n = 8 rats/group): normal vitamin E (50 IU/kg diet) and high vitamin E (200 IU/kg diet). The basal diet was the AIN-76 diet modified to contain high corn oil (23% wt/wt). After eight weeks of feeding, concentrations of vitamin E in plasma, liver, and prostate were analyzed. Enumeration of aberrant crypt foci (ACF) in colons and proliferative indexes of colons and prostate glands were determined. The total number of ACF and the average number of aberrant crypts (AC) per focus were similar in both dietary groups. ACF were classified as small (1-3 crypts/focus), medium (4-6 crypts/focus), or large (> or = 7 crypts/focus). Only the ACF in the small category showed a significant treatment effect, with values being lower in the high vitamin E group than in the control group (p < or = 0.05). No significant difference was observed in colonic proliferative indexes assessed by enumeration of metaphase cells, S phase cells, or cells exhibiting proliferative cell nuclear antigen (PCNA). The PCNA labeling index in the prostate glands and the activity of prostatic acid phosphatase in plasma were higher in high vitamin E-fed rats (p < or = 0.05) than in control animals. The present study demonstrates that additional vitamin E does not inhibit the induction and growth of ACF; also it enhances the proliferative status of the prostate glands.

Acid Phosphatase↗

PubMed1996

Growth features of aberrant crypt foci that resist modulation by cholic acid.

Previously, we demonstrated that feeding rats a diet containing 0.2% cholic acid (CHA-diet) resulted in the elimination or remodelling of a number of aberrant crypt foci (ACF) in their primal stages (1-3 crypts/focus). The present investigation was conducted to determine if ACF with advanced growth features will respond differently than their primal counterparts to the CHA-diet. Sprague-Dawley male rats were injected with azoxymethane (20 mg/ kg) and were maintained on a control diet for 21 weeks. At week 21, three rats were killed and their colons were assessed for ACE. The remaining animals were randomly divided into two groups, which were fed a control diet or a CHA-diet respectively, After 3 weeks of feeding, the rats (n = 5) were killed and their colons were assessed for the number, size (area occupied by each focus) and crypt multiplicity (number of crypts/focus). The CHA-diet resulted in a significant (P </= 0.05) reduction in the number of ACF with 1-2 crypt multiplicity. When compared to the control group, the CHA group ACF with 1-2 crypts/focus were reduced by 70%; with 3-4 crypts/focus, a 48% reduction; and with >4 crypts/focus, a 50.4% reduction. Treatment with CHA resulted in a marked reduction in the population of ACF with 1-2 or 3-4 crypt multiplicity with area >5-1Ox10(-2) mm2. These findings demonstrate that ACF with advanced growth features are phenotypically different from their primal counterparts in resisting the responses elicited by the CHA-diet even at a late time point, and that morphological heterogeneity among ACF may represent different biological states.

Analysis of Variance↗

PubMed1995

Role of aberrant crypt foci in understanding the pathogenesis of colon cancer.

Aberrant crypt foci (ACF) are present in carcinogen treated rodent colons and in the colons of humans with a high risk for developing the disease. It is proposed that ACF are preneoplastic lesions. Quantification of the number and growth features of ACF has been employed to study modulators of colon carcinogenesis. In this review, examples are presented to support the concept that ACF are preneoplastic lesions and that sequential quantification of their number and growth features (crypt multiplicity) in animal colons may provide further insight into the pathogenesis of colon cancer. It is proposed that cellular and molecular heterogeneity among ACF with different growth and morphologic features will be invaluable in the identification of events critically associated with cancer development.

1,2-Dimethylhydrazine↗

PubMed1995

Further investigation of the effect of cholic acid on the induction, growth characteristics and stability of aberrant crypt foci in rat colon.

We previously reported that the colons of animals injected with azoxymethane (AOM) and fed a diet containing cholic acid (CHA) had lower numbers of aberrant crypt foci (ACF) than those in animals fed a control diet. To follow up on this observation, a series of studies was conducted to determine whether CHA affects the development of ACF in a dose- and time-dependent manner, and the possible mechanism(s) involved. Sprague Dawley male rats were injected with AOM (20 mg/kg s.c.), and one week later randomly allocated to groups fed diets containing 0, 0.05, 0.1 or 0.2% CHA by weight, for 4 weeks. Their colons were scored for the number size and location of ACF, number of crypts per ACF, and mitotic activity. It was observed that the number and size of ACF decreased with increasing levels of CHA. Mitotic activity was higher (P < 0.05) in the 0.2% CHA diet (CHA-diet) group compared to the 0% CHA group. To determine if timing of intervention with the CHA-diet was critical, rats were allocated to the CHA-diet before or after AOM injection. The ACF-reducing effect of 0.2% CHA diet was evident (P < or = 0.05) only after AOM injection. Intervention with the CHA-diet 4 weeks after AOM injection demonstrated that the diet eliminated and/or remodelled a large proportion (50%) of ACF which had developed within 4 weeks and inhibited the growth of those ACF that persisted. This effect was also associated with higher (P < or = 0.05) mitotic activity in the colon. Discontinuing the treatment of rats with the CHA-diet resulted in a rapid increase in the number of ACF in their colons, establishing that the growth inhibitory effect of the CHA-diet on ACF was reversible. In conclusion, it was demonstrated that the CHA-diet modulated the number of ACF by inhibiting their development and growth and by eliminating or remodelling a selected population of ACF.

Animals↗