Large Bowel Tumors Research Articles

Inhibitory effect of the non-steroidal anti-inflammatory drug, indomethacin on the naturally occurring carcinogen, 1-hydroxyanthraquinone in male ACI/N rats

The effect of the non-steroidal anti-inflammatory drug indomethacin on 1-hydroxyanthraquinone (1-HA)-induced carcinogenesis was investigated in male ACI/N rats. Animals were fed the diet containing 1.5% 1-HA and simultaneously given indomethacin solution (16 p.p.m.) as drinking water for 48 weeks. The incidences of large bowel neoplasms (adenomas and adenocarcinomas) and forestomach (papillomas) in rats given 1-HA and indomethacin (large intestinal tumors: 0/14, 0%; forestomach tumors: 2/14, 14%) were significantly lower than those in rats given 1-HA alone (large intestinal tumors: 12/27, 44%; forestomach tumors: 14/27, 52%) (P = 0.002 and P = 0.01 respectively). Liver cell adenomas were developed in a rat given 1-HA and no liver tumors in rats treated with 1-HA and indomethacin. Altered liver cell foci were present in rats given 1-HA alone (18/27, 67%) and those given 1-HA and indomethacin (8/14, 57%), but no significant difference in the incidence between the two groups was found. Untreated animals and rats given indomethacin alone had no neoplasms in the large bowel, forestomach and liver. Thus, the non-steroidal anti-inflammatory drug indomethacin significantly inhibited carcinogenesis induced by the naturally occurring carcinogen, 1-HA.

Transforming growth factor beta: a promotor of late connective tissue injury following radiotherapy?

Transforming growth factor beta (TGF-beta) is a peptide which has a fundamental role in controlling proliferation of many cell types. Its main effect upon connective tissues in vivo is to stimulate growth. It can result in endothelial cell proliferation but tends to inhibit epithelial cell growth. Damage to the connective tissues and the vasculature are the principal findings in late radiotherapy damage. Following the initial cellular depletion after radiotherapy, an abnormal proliferation of these tissues occurs, which does not respond to normal feedback mechanisms. Immunocytochemical staining for TGF-beta has been performed upon six patients who had received pre-operative radiotherapy and three patients who had surgery alone for large bowel tumours. Transforming growth factor beta was found in relation to the pathological changes of late radiation damage in the non-tumour-bearing tissues of four out of six previously irradiated patients, but in none of the non-irradiated patients. This paper proposes that TGF-beta activity may modulate late post-radiation changes.

Colony‐forming Ability in vitro and Clonology of Colorectal Cancer

One hundred and twenty-three specimens (83 primary and 40 metastatic) of colorectal cancers from 102 patients were subjected to the human tumor clonogenic assay (HTCA) to determine the clonogenicities of tumor specimens stratified by the degree of histological differentiation and of tumor progression. No statistically significant differences in the clonogenicity were observed among the tumors with different histological differentiation. Viable malignant cells were abundant in the primary tumor specimens with submucosal (sm) and muscular layer (pm) invasion, and decreased significantly in number per gram of wet specimen as the tumors progressed (P less than 0.05). Clonogenicity was also higher in "sm" and "pm" primary tumor specimens, and decreased as the tumors advanced (P less than 0.05). These findings suggest that, at the onset or in the relatively early phase of the tumor progression, tumors are medullary and have a large fraction of clonogenic cells, and that they then develop more stroma while losing the clonogenic cell fraction by tumor progression. HTCA appears to be still valuable for analysis of the changes in biological properties over time in large bowel tumors.

Evidence for the existence of different types of large bowel tumor: Suggestions from the clinical data of a population‐based registry

The clinical findings of a population-based colorectal tumor registry have been analyzed to determine elements of supporting or not supporting the existence of different types of large bowel cancer. Age-specific incidence rate of the 409 registered patients rose sharply with increasing age in all segments of the large bowel; however, regarding left colon and rectum, the male: female ratio showed a marked male preponderance, more evident in the more advanced age groups. Histopathology, studied in 87% of patients, revealed adenocarcinoma as the most frequent feature; however, adenocarcinoma with concomitant adenoma (i.e., presumably arising in adenoma) was observed in 14.3% of cancers of the left colon, in 17.7% of rectal tumors, but in only 5.7% of neoplasms of the proximal colon (P less than 0.05 and P less than 0.01, respectively, vs. left colon and rectum). Some histological features (carcinoid and mucinous carcinoma) were observed in right-side tumors only. Analysis of the familial occurrence of cancer showed that a significantly larger proportion of patients with neoplasms located in proximal colonic segments had three or more first-degree relatives affected by (or deceased from) cancer of all sites. Similarly, colorectal tumors among relatives were more frequent in patients with right-side cancer. The location of the 793 polyps observed during 3 years of registration showed that more than 70% of adenomas were located beyond the splenic flexure, overlapping the distribution of cancers. In conclusion, the differences of sex ratio at different colonic subsites, the higher fraction of adenocarcinomas with adenomas in cancer of the more distal tracts of the large bowel, and the more marked familial occurrence of colorectal cancer in patients with right-side neoplasms tend to support the view that cancer of the proximal colon, cancer of the distal colon, and cancer of the rectum may actually be three different types of tumors.

Does Adjuvant Therapy Work in Colon Cancer?

Colorectal carcinoma is second only to lung cancer as a cause of death from cancer in the United States. Although the majority of patients found to have a large-bowel tumor successfully undergo a removal of all gross tumor, 40 to 50 percent are found at the time of surgery to have invasion of the tumor through the serosa (Stage B2) or spread to regional lymph nodes (Stage C). The prognosis after such "complete" resection is closely related to surgical stage. The prognosis for each stage appears to have improved somewhat in recent years, most likely because of more . . .

Carcinogenicity of naturally occurring 1-hydroxyanthraquinone in rats: induction of large bowel, liver and stomach neoplasms

The carcinogenic potential of 1-hydroxyanthraquinone (HA), a naturally occurring compound, was examined. A total of 60 male ACI/N rats, 1.5 months old at the commencement were divided into two groups. Group 1 (30 rats) were fed the diet containing HA at a concentration of 1% throughout the experiment (480 days). Group 2 (30 rats) served as the control given a basal diet alone. Twenty-five of 29 effective animals in group 1 developed adenomas or adenocarcinomas in the cecum or upper portion of the colon, the mean number of large bowel tumors/tumor bearing rat being 2.3. In addition to these intestinal tumors, liver neoplasms (neoplastic nodules and hepatocellular carcinomas) were observed in 12 rats and benign stomach tumors were obtained in five animals; no rats of group 2 demonstrating development of any of these tumor types. The incidences of the large bowel, liver and stomach neoplasms in group 1 were all significant as compared with group 2 (P less than 2 x 10(-13), P less than 5 x 10(-5) and P less than 3 x 10(-2) respectively) clearly indicating that HA is carcinogenic in rats.

Diagnosis of large bowel tumours by colonic sonography

To investigate whether the retrograde instillation of fluid into the colon would improve the diagnostic value of ultrasonography in assessing neoplastic diseases of the large intestine 220 patients were examined by colonic sonography before colonoscopy. Polyps larger than 7 mm diameter could be identified in 91% of cases, whereas polyps smaller than 7 mm could not always be visualised. The sensitivity of the technique in the detection of colonic carcinomas was 94% and the specificity was 100%. The results suggest that colonic sonography is an effective diagnostic procedure that may find application as a screening procedure for neoplastic diseases of the colon.

The essential fatty acid requirement for azoxymethane-induced intestinal carcinogenesis in rats.

The essential fatty acid requirement for the development of intestinal carcinogenesis was determined and compared to the overall essential fatty acid status of the animals as measured by the triene/tetraene ratio in the plasma, liver and colon. To induce tumors, male Sprague-Dawley rats were given two weekly injections (20 mg/kg body wt) of azoxymethane. Two weeks after the last injection, the rats were divided into groups of 25 and given one of six diets containing various levels of essential fatty acids (as linoleate). The diets contained 5% total fat and were prepared by mixing safflower oil (high essential fatty acids, beef fat (low essential fatty acids), and medium chain triglyceride oil (no essential fatty acids). One group of rats was fed a 20% beef fat diet. The range of essential fatty acids was from less than 0.03% to 1.28% (w/w). Twenty-six weeks after the first azoxymethane injection, the animals were killed and intestinal tumor incidence and multiplicity were determined. Samples of plasma, liver and colon were also taken for measurement of the triene/tetraene ratio by gas chromatography. Large bowel tumor incidence showed a dependence on the essential fatty acid content of the diet. The results were as follows: (percent essential fatty acids: percent tumor incidence) Group A (1.28: 72.4), Group B (0.60: 73.3), Group C (0.11: 55.2), Group D (0.08: 39.3), Group E (less than 0.03: 37.9) and Group F, which was fed 20% beef fat, (0.34: 88.5).(ABSTRACT TRUNCATED AT 250 WORDS)

The clonal origin of experimental large bowel tumours.

Induction de tumeurs chez la souris presentant un deficit en G6PD sur le mode homozygote, et sur le mode heterozygote (mosaique). Determination du phenotype enzymatique de chaque tumeur par histochimie

Site distribution of carcinoma of the large intestine. Retrospective study of 600 cases.

The site distribution of large-bowel adenocarcinomas was studied in a retrospective study compromising 600 patients. These patients were divided into two groups according to the year of their operation; group A included patients operated upon between 1978 and 1982, and group B patients were operated upon between 1983 and 1987. Comparing these two five-year periods, a statistically significant increase in the incidence of right colon tumors was noted (P less than 0.05). There was no difference in the distribution pattern of the carcinomas according to sex or age between the two groups (P less than 0.1). The shift to the right of large-bowel neoplasms may indicate the need for an alteration of the diagnostic procedures concerning this disease, with more emphasis given to total colonoscopy and or double-contrast barium enema.

Large bowel tumors and diamine oxidase (DAO) activity in patients: a new approach for risk group identification.

In the intestinal mucosa, diamine oxidase (DAO) seems to be involved in a feed-back regulation mechanism for the termination of proliferation. Therefore, we studied the DAO activity in large bowel tumors and in the non-affected mucosa of these patients in comparison with patients having a normal large mucosa. The DAO activity in the tumor tissue itself was diminished by 85% as compared to the surrounding mucosa. Comparing the colonic mucosa of normal and tumor bearing individuals, the DAO activity in cancer patients was diminished by 22%, while it was elevated by 64% in patients with polyps (biphasic response of the DAO activity). Histologically proven hyperproliferative mucosal alterations were indicated by a reduced DAO activity with 75% sensitivity and 42% specificity. It remains open whether this limited specificity may indicate a more sensitive reaction of the DAO activity to proliferative mucosal alterations than the histological examinations.

Lack of peptide YY immunoreactivity in adenomatous colonic polyps: Evidence in favor of an adenoma-carcinoma sequence

The aim of endoscopic polypectomy is to prevent colorectal cancer, as it is assumed that most, if not all, large bowel cancers are derived from adenomatous polyps. While it is now recognized that colonic endocrine cells, like other mucosal epithelial cells, have an endodermal origin, they are relatively sparse components of large bowel tumors. Peptide YY (PYY) is the most abundant endocrine regulatory peptide localized to the distal bowel. Endocrine cells, like the other cells of the mucosal epithelia, are derived from a common stem cell in the base of the crypts. The presence of endocrine peptides may thus be viewed as a marker for cellular differentiation in the gut. PYY was therefore measured in colonic carcinomas and adenomatous polyps, as its absence would be evidence in favor of genetic alterations in epithelial stem cell maturation. PYY concentrations in extracts of surgically removed colonic carcinomas ( n = 22) from all regions were very low compared with those of adjacent normal bowel. Similarly, PYY concentrations in extracts of polyps ( n = 39) obtained during endoscopic polypectomy were also very low when compared with those of adjacent normal mucosa. These varied between 1 and 11% of the normal epithelial content, depending upon the region. Low PYY levels appeared to reflect the malignant potential of these lesions: highest in tubular polyps, lower in villous polyps, and lowest in carcinomas. The very low concentrations of PYY in adenomatous polyps, like those of colonic cancer, are consistent with epithelial dysplasia and the incomplete formation of mucosal endocrine cells. These findings support the hypothesis of an adenoma to carcinoma sequence in colonic cancer.

Familial fragile 8q22 involved as a cancer breakpoint in cells of a large bowel tumor

A familial fragile 8q22 and an interferon-induced fragile 16q22 were found in two sisters. Eight years previously, both sisters developed an endometrial adenocarcinoma and now one of them presented with an adenocarcinoma of the colon. An 8q22 deletion was found in all the cells of the colonic tumor and seemed to be the primary initiating change. Other nonrandom and possibly promoting aberrations were also present, among others, a 16q22 deletion. The possibility exists that a familial fragile 8q22 may predispose to cancer and a fragile 16q22 may have promoting capacities.

Large bowel tumor promotion by diamine oxidase inhibition: animal model and clinical aspects.

In the intestinal mucosa, diamine oxidase probably is involved in a feedback regulation mechanism for the termination of proliferation. This was proven by a considerable promotion of large bowel tumors induced by diamine oxidase inhibition in a rat model. Carcinogenesis was accompanied by characteristic alterations in mucosal diamine oxidase activity. In large bowel cancer patients similar changes in intestinal diamine oxidase activity had been observed as in the animal model. Events entailing a reduction of diamine oxidase activity are suspicious for large bowel cancer promotion under experimental and clinical conditions.

The effects of chronic ethanol administration on polyamine content during dimethylhydrazine-induced colorectal carcinogenesis in the rat.

Chronic ethanol (EtOH) consumption has been implicated as a co-carcinogen, selectively promoting rectal tumor formation. We studied the effects of EtOH consumption on tumor formation and polyamine content (putrescine, spermidine and spermine) in proximal and distal colon and rectum of Sprague-Dawley rats treated with the procarcinogen 1,2-dimethylhydrazine (DMH). Sixty-four adult male rats were pair fed nutritionally complete liquid diets with 36% of calories supplied as EtOH or isocaloric carbohydrates. Both groups received 4 weeks of the liquid diet followed by 4 weeks of standard laboratory chow during which 50% of the rats in each group received DMH (30 mg/kg) or vehicle s.c. weekly. This cycle was repeated four times (32 weeks). Animals were sacrificed at the end of each 8 week cycle and normal appearing and available tumor bearing tissue from proximal and distal colon and rectum was obtained for polyamine content and histology. Five animals, unexposed to DMH or EtOH served as baseline controls. There were no consistent regional differences in putrescine, spermidine or spermine of baseline controls. A progressive decrease in tissue putrescine was seen in all three regions of the control group and was significant at 24 and 32 weeks versus baseline controls. In all three regions, chronic EtOH consumption prevented the decrease in tissue putrescine. Spermidine content was also significantly increased in the distal colon of EtOH-treated animals compared to baseline values. Consistent changes in spermine content were seen in any treatment group or region. A significant increase in putrescine content of normal appearing and tumor-bearing tissue of DMH treated animals at 32 weeks was noted. Chronic EtOH administration did not augment rectal or colonic polyamine content in DMH-treated animals. Likewise, chronic EtOH consumption did not alter the number, size or distribution of large bowel tumors of DMH treated animals.

Incidence and familial occurrence of colorectal cancer and polyps in a health-care district of northern Italy.

The first year of registration of colorectal tumors in a predominantly urban population (263,546 inhabitants) of northern Italy gave us the opportunity to investigate: (a) the incidence (crude, age-specific, age-standardized) of both colorectal cancer and polyps and their localization; (b) the familial occurrence of these neoplasms; and (c) if the data could fit into the "Adenoma-Carcinoma Sequence." Crude incidence of cancer was 52.8 new cases/100,000 in 1984, with 53.4 cases in men and 52.2 cases in women. The corresponding figures for polyps were 59.6 new cases, with 83.4 in men and 37.3 cases in women. The incidence increased with age for both cancer and polyps, although the latter were more frequent until patients were in their sixties and the peak of incidence of polyps anticipated that of cancer by a 5 year period. Both cancer and polyps had a similar distribution in the large bowel, more than 60% being located in the left distal portion. There were 72 cases of colorectal cancer among the first-degree relatives of the registered patients compared with 16 in the controls (RR = 4.26, chi 2 = 27.2 p less than 0.001). An increased frequency of cases of colorectal cancer in the families was found in both the cancer group and the polyp group. In conclusion, the observed incidence of large bowel tumors was similar to that of other well-developed countries. The earlier rise and peak of age-specific incidence of polyps as compared to cancer, the similar distribution of benign and malignant neoplasms in the various intestinal tracts, and the similar familial aggregation observed both in the cancer and in the polyp groups further support the "polyp-cancer sequence" and provide us with a promising strategy for the prevention of colorectal malignancies.

Absence of large bowel tumors in rats injected with 1,2-dimethylhydrazine and fed high dietary cellulose.

The effect of very high concentrations of dietary cellulose against the development of colon tumors was investigated in 20 rats injected with conventional doses of 1,2-dimethylhydrazine. Ten of these rats were fed a regular (5%) concentration of cellulose and 10 were fed a very high (15%) concentration of cellulose. Rats fed regular cellulose developed a total of 16 tumors, nine in the small bowel and seven in the large bowel. In this group colonic tumors were large and invasive; 75% were carcinomas. Rats fed very high concentrations of cellulose had only four tumors, noninvasive and localized to the small intestine. Large bowels of rats fed high cellulose were completely devoid of neoplasms. This study suggests that very high concentrations of cellulose may suppress the development of large bowel tumors in rats. This could have significant implications concerning dietary protection against colon carcinogenesis.

Eosinophils of human colonic mucosa: C3b and Fcγ receptor expression and phagocytic capabilities

Because little is known about eosinophils of the human intestine, we measured their C3b and Fcγ receptor expression and phagocytic activity in mucosal suspensions from colon resections for large bowel neoplasms. Enzymatically dissociated suspensions were enriched for eosinophils by countercurrent centrifugation. C3b and Fcγ receptors were measured by immunofluorescent assays with flow cytometry. Phagocytosis of Escherichia coli ON2 was determined by an in vitro microscopic method. Suspensions of normal tissue from neoplasm resections yielded 1.8 × 10 6 eosinophils/g mucosa, and these cells were more numerous than either macrophages or neutrophils. Fivefold enrichment was achieved by countercurrent centrifugation, and 75% of these cells expressed C3b receptors and 90% expressed Fcγ receptors. Sixty-seven percent of mucosal eosinophils were phagocytic for E. coli ON2 and ingested a mean of 4.7 bacteria per cell. Eosinophils accounted for more overall phagocytic activity than either neutrophils or macrophages.

Antitumor effects of inhibitors of arachidonic acid cascade on experimentally induced intestinal tumors.

The antitumor action of inhibitors of cyclooxygenase (indomethacin) and lipoxygenase activity (nordihydroguaiaretic acid) of arachidonic acid cascade was investigated in the chemically induced large bowel tumors in Sprague-Dawley rats. Indomethacin treatment completely prevented the carcinogenic effect of methylazoxymethanol. Thus, no tumors were found in the 14 rat test group, compared with 13 of 14 tumor-bearing rats in the untreated control group. Although nordihydroguaiaretic acid treatment does not abolish prostaglandin synthesis, it does reduce the effect of the carcinogen and tumors were found in only five of 14 treated rats. From this study it can be postulated that not only is reduction in prostaglandin formation responsible for the inhibition of tumor growth, but also leukotrienes may play some role.

Effects of differing concentrations of sodium butyrate on 1,2-dimethylhydrazine-induced rat intestinal neoplasia

The incidence, distribution, size, and histopathology of small and large bowel tumors induced by parenteral administration of 1,2-dimethylhydrazine were examined in rats given 1% or 2% sodium butyrate dissolved in drinking water. Although previous in vitro reports on colon cancer cell lines have suggested that sodium butyrate might have a role to play as a chemotherapeutic “differentiating agent,” the results of this in vivo study indicate that sodium butyrate treatment enhanced the development of colonic neoplasia and was associated with increased fecal butyric acid concentrations. In contrast, no changes were seen in the incidence of small bowel tumors, luminal butyric acid concentrations, mucosal morphology, or brush-border enzyme activities (i.e., sucrase, alkaline phosphatase). This study suggests that dietary butyrate has an important, possibly indirect, regulatory role in carcinogenesis associated with an experimental animal model of colonic neoplasia.