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E E Deschner

Publications and source records attributed to E E Deschner.

At least 37 records · Page 2Linked to original sources
PubMed1986

Lipid peroxidation in liver and colon of methylazoxymethanol treated rats.

Weanling male Sprague-Dawley rats were injected via the tail vein with methylazoxymethanol (MAM) acetate at a dose of 70 mg/kg body weight. Measurements of lipid peroxidation were carried out on mitochondrial and microsomal fractions of liver and colonic mucosa at various intervals over the first 24 h following delivery of the carcinogen. Significantly increased levels of peroxidation were observed 3-6 h after treatment in microsomal and mitochondrial fractions of both these tissues. A return to control levels was seen by the end of the first day. These results are discussed in relation to the role of lipid peroxidation in carcinogenesis and the proposed mechanism of tumor prevention by selenium.

Animals↗
PubMed1985

Hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). I. Clinical description of resource.

Hereditary nonpolyposis colorectal cancer (HNPCC) is comprised of the following: the cancer family syndrome (CFS), or Lynch syndrome II, which shows early-onset proximal colonic cancer predominance and other associated extracolonic adenocarcinomas, particularly endometrial carcinoma; and hereditary site-specific colon cancer (HSSCC), or Lynch syndrome I, which shows all of the same characteristics, except for extracolonic cancer. Nine families with CFS and two with HSSCC provided the resource that was tested for biomarkers (see companion article). All families were meticulously evaluated for genealogy and cancer verification. Biologic specimens were obtained during field visits to areas of closest geographic proximity to the families. Cancer education and recommendations for surveillance/management were provided to patients and their physicians. Additionally, 40 families (about 3000 individuals) with either CFS or HSSCC have been ascertained. Syndrome cancers were restricted to direct-line relatives as opposed to nonbloodline relatives, arguing against involvement of environmental factors. One documented clinical feature was a predilection for proximal versus distal colonic cancer in both CFS and HSSCC kindreds. This has important clinical significance in that it clarifies the need for instituting effective surveillance earlier to detect the predominantly proximal colonic cancers.

Adolescent↗
PubMed1985

Hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). II. Biomarker studies.

Nine families with the cancer family syndrome (CFS), or Lynch syndrome II, and two with hereditary site-specific colonic cancer (HSSCC), or Lynch syndrome I, were investigated for the following potential biomarkers of genotype status: in vitro tetraploidy of dermal fibroblast monolayer cultures; tritiated thymidine uptake (3HdThd) labeling of colonic mucosa; cytogenetics of peripheral blood mononuclear leukocytes; quantitative serum immunoglobulin determinations; methionine dependence in dermal fibroblasts in tissue culture; segregation analysis; and the study of gene linkage with respect to 25 landmark serum and blood group markers. Positive lod scores of 3.19 for linkage of the Jk (Kidd blood group) with CFS were obtained. Both in vitro tetraploidy and 3HdThd uptake in the distal colonic mucosal crypt compartments were positively associated with cancer risk status in CFS and HSSCC kindreds. There was a high incidence of polymorphisms of centromeric heterochromatin, including complete inversion. These findings are of particular clinical and genetic significance because HNPCC lacks premonitory signs of cancer risk. If confirmed, they could conceivably enable definition of genotype as early as birth in members of HNPCC kindreds, thereby enabling psychologic preparation and intensive cancer education for improved compliance in surveillance/management programs. These studies also provide new clues about the chromosome(s) bearing the presumed cancer gene(s). For example, CFS gene(s) may possibly be located on chromosome 2, where Jk is located. These biomarkers merit intensive study in additional HNPCC kindreds for a more complete assessment of their sensitivity and specificity. Additionally, essential aspects of previous reports involving biologic samples from these and/or similar subject kindreds are included to permit a comprehensive presentation of the combined findings of this consortium to date.

Colon↗
PubMed1985

Acute effects of dietary cholic acid and methylazoxymethanol acetate on colon epithelial cell proliferation; metabolism of bile salts and neutral sterols in conventional and germfree SD rats.

The acute effects of cholic acid ingestion on methylazoxymethanol acetate [(MAM) CAS: 592-62-1]-treated conventional and germfree rats were investigated. Male SD rats were divided into 4 treatment groups. The first group received control chow; the second group, control chow plus 0.5% cholic acid; the third group, control chow plus MAM; and the fourth group, control chow plus 0.5% cholic acid plus MAM. Fecal bile acids, cholesterol, cholesteral degradation products, and neutral sterols, as well as labeling indices and numbers of epithelial cells per crypt column, were measured after 6 weeks of treatment. The administration of MAM to germfree groups diminished both fecal bulk and the amount of fecal water. MAM did not affect the fecal bile acid composition. Analysis of the fecal bile acids in conventional rats fed cholic acid demonstrated that half of the bile acids were in a form of deoxycholic acid. In the germfree groups fed cholic acid, 90% of the bile acids appeared unaltered in the feces. Neither in the germfree nor in the conventional groups was an effect seen of MAM on the output of fecal neutral sterols. The addition of cholic acid to the food decreased the output of neutral sterols both in the conventional (P less than .001) and in the germfree (P less than .02) animals. The germfree animals showed a reduced amount of neutral steroid excretion (P less than .01) when compared to the findings for the conventional groups. MAM had no influence on the fecal cholesterol or coprostanol output. The consumption of 0.5% cholic acid decreased the total output of cholesterol (P less than .05). The excretion of coprostanol was significantly diminished in the conventional rats fed cholic acid (P less than .001). No difference in labeling indices was observed between conventional and germfree rats, whether treated with cholic acid, MAM, or cholic acid plus MAM. However, all germfree groups showed less epithelial cells per crypt column (P less than .001) than did conventional animals.

Animals↗
PubMed1985

Gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine: role of gastrectomy and duodenal reflux.

The effect of gastrectomy and duodenal reflux on gastric carcinogenesis was studied because gastrectomized patients may be considered at "high risk" for the development of gastric stump cancer. Wistar rats received N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) (83 mg/liter) ad libitum in the drinking water for either four, eight, or twelve weeks. A control group received tap water. After MNNG administration animals were antrectomized. Antrectomy was not performed in a control group. Bowel continuity was restored either with a Billroth II (BIL) or with a ROUX en Y (ROUX) procedure. Duodenogastric reflux is possible after the BIL but not after the ROUX procedure. Eight months after the beginning of the experiment the stomachs of the animals were studied. In both operated and unoperated animals, the number of cancers observed was significantly related to the duration of MNNG administration. Animals receiving MNNG plus the BIL procedure had a significantly higher number of anastomotic cancers than the ROUX animals, indicating that duodenogastric reflux played a promotional role in gastric carcinogenesis. Three BIL gastrectomized rats not receiving the carcinogen had an adenocarcinoma on the anastomotic line further emphasizing the risk attached to the duodeno-gastric reflux.

Animals↗
PubMed1984

Detection of in vitro tetraploidy in heritable colon cancer syndromes. Confirmation by three different assays.

The incidence of in vitro tetraploidy during logarithmic growth in dermal fibroblast monolayer cultures from normals without a family cancer history and affected with heritable colon cancer syndromes, familial polyposis coli (FPC) and the Gardner syndrome (GS) was assayed by (1) examination of metaphase preparations for percentage of tetraploids (4N nuclei); (2) determination of [3H]thymidine incorporation (average cpm/cell); and (3) measurement by flow cytophotometry of the percentage of cells with greater than 4C DNA content. For each monolayer culture assayed, if cell density was standardized, concurrence was observed between the first two assays and with the third assay when done. In cultures of individuals with a low level of in vitro tetraploidy (37 normals without a family cancer history, 9 FPC, and 1 GS patient) incidence of this parameter, as measured by all three assays, was not significantly influenced by variation in cell density. However, in cultures with increased in vitro tetraploidy (17 FPC and 6 GS patients) all three assays revealed an inverse relationship between the incidence of tetraploidy and cell density, i.e., tetraploidy increased with decreasing cell density. Only at cell densities below 4.0 X 10(3) cells/cm2 growth area was increased tetraploidy consistently observed by any of the three assays. Above this density its incidence was indistinguishable in all cultures. The use of these three independent assays (two of which are automated) for the determination of tetraploidy in duplicate subcultures from the same dermal monolayer culture should allow reliable detection of this in vitro expression of some cancer-related genes in extensive human kindreds.

Cells, Cultured↗
PubMed1984

The antitumoral activity of 4'-deoxydoxorubicin compared to doxorubicin and 5-fluorouracil on methylazoxymethanol acetate-induced colon tumors in CF1 mice.

The suitability of carcinogen-induced colon tumors in mice for chemotherapy investigations and the potential antitumoral activity of a new anthracycline, 4'-deoxydoxorubicin (4' deoDX ) were evaluated. The latter was compared with 5-fluorouracil (5-FU) and doxorubicin (DX) either alone or in combination. CF1 mice were given 10 weekly subcutaneous injections of methylazoxymethyl acetate (MAM) and killed between 16 and 39 weeks after delivery of the first carcinogen treatment. The number and size of macroscopic tumors was observed; only 6% of mice showed no tumor development (19 of 327). Statistically significant reduction of tumor size occurred at a tolerated dose of 5-FU given as six intravenous injections (46 mg/kg) (P less than 0.05). With 4' deoDX a significant decrease in tumor number was observed using four weekly injections of 2.7 mg/kg (P less than 0.05) or six weekly injections of 5 mg/kg (P less than 0.05). Given in combination, 4' deoDX (3.3 mg/kg) and 5-FU (23 mg/kg) demonstrated a statistically significant reduction of the tumor number as compared with the untreated controls (P less than 0.025). Moreover, this reduction was greater than the observed response with any dose levels of the single compound thus demonstrating a potentiation of activity. These results indicate that MAM-induced colonic tumors are an appropriate model for the assessment of chemotherapeutic drugs. Moreover, 4' deoDX showed antitumoral activity comparable with 5-FU indicating this new anthracycline may be a useful candidate either alone or combined with 5-FU for clinical trials against colon cancer.

Animals↗
PubMed1984

Differential susceptibility of inbred mouse strains forecast by acute colonic proliferative response to methylazoxymethanol.

The proliferative response of colonic epithelial cells to methylazoxymethanol (MAM) was followed in 1,2-dimethylhydrazine (DMH)-sensitive SWR/J, moderately resistant C57BL/6J, and resistant AKR/J strains. Untreated AKR mice had a significantly lower labeling index (L1) a shorter proliferative compartment (PC), and a smaller percentage of DNA synthesizing cells in the middle third of the crypts than did the SWR strain. SWR had the highest Ll, the widest PC, and the largest percentage of DNA synthesizing cells in the middle third of the crypts. C57BL/6 mice had characteristics that lay between the sensitive and resistant strains. Pooled data from 1 week after the fifth and sixth injections and 12 weeks after the first MAM injection revealed that extension of the PC had occurred in all strains, but it was only the DMH-sensitive SWR strain that showed extension of the PC to the upper third of the crypt, the greatest shift of proliferating cells to the middle and upper third of crypts, and the greatest increase in Ll. The AKR strain demonstrated these proliferative alterations least, and the C57BL/6 strain fell between them. This differential response to MAM among the strains mimicked that previously reported by us when DMH was investigated. The similarity in response of the colonic epithelial cells of each strain to either a direct-acting (MAM) or indirect-acting carcinogen (DMH) would support the concept that susceptability to this family of carcinogens is directly related to the genetically controlled indigenous proliferative characteristics of the colon.

1,2-Dimethylhydrazine↗
PubMed1984

Degraded carrageenan-induced colitis in CF1 mice. A clinical, histopathological and kinetic analysis.

Delivery of 10% carrageen (degraded carrageenan, Glaxo, France) for 10 days in the drinking water to CF1 mice induced bloody diarrhea, pericryptal inflammation, and marked dilatation of the cecum and ascending colon. Histologically, the mucosa was characterized by distorted crypt architecture, inflammatory infiltration of the lamina propria, and ulceration, conditions which were more pronounced in the proximal colon but were also present in the distal colon. Treatment with hydrocortisone and levamisole reduced the severity of all phases of the reaction. Alterations in colonic epithelial cell proliferation corresponded with the clinical and histopathological findings. Labeling indices (LI) significantly increased over control values in both proximal (12.9 +/- 4.9 vs. 7.6 +/- 2.9) and distal colon (13.9 +/- 5.2 vs. 7.2 +/- 2.4), effectively doubling the number of proliferating cells per crypt column in both areas. However, DNA-synthesizing cells extended further upward along the cryptal wall of the proximal colon reflecting greater mucosal damage. Only in the proximal colon did the proliferative compartment (PC) extend to the upper third of the glands, normally not a proliferative zone. Hydrocortisone and levamisole administered concurrently with 10% carrageen were less effective in protecting the proximal colon since LI and numbers of labeled cells per crypt column were consistently lower in the distal colon. Moreover, hydrocortisone alone significantly depressed DNA synthesis only in the distal colon. All distal colonic crypts were not equally protected by administration of hydrocortisone since some continued to express large numbers of proliferating cells and an extended PC, well characterized preneoplastic defects in regulatory control of colonic epithelial cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Carcinogenic effects of intracolonic benzo[a]pyrene in beta-naphthoflavone-induced mice.

Benzo[a]pyrene (BP) was administered intracolonically to ICR/Ha and C57Bl/6 female mice, 1 mg/mouse, once weekly for 14 weeks. Half of the mice received beta-naphthoflavone (beta-NF, a mixed-function oxygenase inducer) i.p. 24 h prior to the BP. No colonic neoplasms were found in any of the mice after 18 months. However, the BP treatment did cause a significant increase in numbers of primary lung tumors, forestomach papillomas, mammary carcinomas, and sarcomas in one or both strains, relative to controls, and the incidence of all of these except for the sarcomas was significantly reduced by treatment with beta-NF prior to BP. Overall, the beta-NF pretreatment reduced total incidence of neoplasms by about 30% in the ICR/Ha mice and by about 60% in the C57Bl/6 mice, and did not potentiate the action of the carcinogen in any organ.

Animals↗
PubMed1983

A morphologic and kinetic basis for the more invasive character of N-methyl-N'-nitro-N-nitrosoguanidine induced duodenal tumors following pyloroplasty.

Pyloroplasty increased the invasiveness of duodenal tumors in Wistar rats receiving N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 12 weeks (83 mg/l in drinking water) (Arch. Surg., 117, 768-771). To assess morphologic and kinetic alterations, analyses of tritiated thymidine (3HTdR) pulse-labeled fundic, antral and duodenal mucosa were carried out. The normal appearance of MNNG-treated antral and duodenal mucosa was characterized by the appearance of elongated hyperactive columns exhibiting elevated levels of DNA synthesis. Pyloroplasty in carcinogen-treated rats induced both a 3-fold enhancement in the number of these elongated columns and an elevation in the number of proliferating cells within them (P less than 0.001). In the MNNG and pyloroplasty treated duodenal mucosa 26% of columns contained over 130 cells/column rather than an average of 100 cells in normal appearing MNNG-treated mucosa. DNA synthesis was increased by 23% within these hyperactive glands (11.3 proliferative cells/column vs. 9.4/column in normal appearing mucosa). Pyloroplasty creates both an increase of gastric bile reflux and an increase of the gastric evacuation rate, conditions which influence cell proliferation. Such alterations in antro-pyloro-duodenal physiology contribute to the increased cellular activity observed, promote malignant transformation and foster the expression of invasiveness.

Animals↗
PubMed1983

Tissue concentrations and proliferative effects of massive doses of ascorbic acid in the mouse.

The effect of ascorbic acid supplementation on CF1 mice fed ascorbic acid for approximately six months at dose levels of 1%, 5%, and 10% of diet was investigated by analysis of tissue ascorbic acid concentration in the liver, kidney, stomach, small intestine, and large bowel. The effect on epithelial cell proliferation was also examined in the small and large bowel but only at the 5% level. In the control animals, ascorbic acid concentration was lowest in the liver (0.406 +/- 0.07 mg/g) and highest in the small bowel (0.754 +/- 0.16 mg/g). Dietary intake of 5% and 10% ascorbic acid significantly elevated levels in the liver (0.741 +/- 0.13; p less than 0.05), and all doses of ascorbic acid significantly raised tissue concentrations in the kidney and colon. No difference was observed in the percentage of DNA-synthesizing cells in the jejunum of controls or animals fed 5% ascorbic acid at 1 or 24 hours after 3HTdR injection. However, at 1 hour a significantly decreased level of proliferation was observed in the distal colon of ascorbic-acid-treated mice compared with controls (labeling index [L.I.] = 7.3 +/- 0.28 vs. 10.1 +/- 1.15; p less than 0.05), and an even greater suppression of DNA synthesis was achieved by 24 hours (L.I. = 11.4 +/- 1.06 vs. 18.6 +/- 1.61; p less than 0.01). None of the doses of ascorbic acid employed was toxic to the experimental mice.

Animals↗
PubMed1983

Proliferative defects in ulcerative colitis patients.

The proliferative characteristics of epithelial cells in rectal biopsies from a group of 18 patients (ages 18-72) with ulcerative colitis spanning several months to over 20 years duration were examined, using an in vitro 3HTdR labeling technique. Although the labeling indices for patients with inflammatory bowel disease did not differ significantly from that of control (8.9 +/- 3.6 vs 7.7 +/- 3.9), the number of labeled cells/individual crypt column was higher among some crypts in ulcerative colitis patients. A normal proliferative pattern was demonstrated in crypts of 5/18 patients (27.8%) with DNA synthesis confined to the lower two-thirds of the crypt and the lower third the major zone of proliferation. Thirteen patients (72.2%) showed extension of the proliferative compartment to the surface of the glands, while retaining the lower third of the gland as the predominant proliferative zone (Stage I abnormality). Of these 13, seven had an additional abnormality, namely, a shift of the major zone of proliferation to the middle third of the crypt (Stage II abnormality), a pattern first reported in the colorectal mucosa of patients with a history of colon cancer. Precancerous lesions, including incompletely differentiated epithelium and lateral crypt budding, were recognized in all of these cases, suggesting that the Stage II abnormality is a proliferative parameter forecasting neoplastic transformation.

Adolescent↗
PubMed1983

Adenomas: preneoplastic events, growth and development in man and experimental systems.

Adenoma formation in the colon has been shown to be initiated by an alteration in the genetic make-up which controls the repopulation of the mucosa. This defect is recognized primarily by an upward displacement of the major zone of DNA synthesis within one or a few crypts. Progression to a microadenoma involves an elevation of cell proliferation within these glands and may be hastened by mucosal responses to environmental and dietary factors which enhance cell turnover. The high proliferative activity of epithelial cells within these select crypts allows the unmasking of the neoplastic genotype and the expansion of these cells with a proliferative advantage. Continued rapid cell proliferation within the adenoma either indigenous to the excrescence or fueled additionally by luminal conditions may contribute to the evolution of a malignant genotype, the establishment of a severely dysplastic clone and ultimately to the production of invasive colon cancer.

Adult↗
PubMed1983

Differential susceptibility of AKR, C57BL/6J, and CF1 mice to 1,2-dimethylhydrazine-induced colonic tumor formation predicted by proliferative characteristics of colonic epithelial cells.

The proliferative characteristics of the colonic mucosae of various mouse strains were examined to determine their value in forecasting the differential susceptibility of each to 1,2-dimethylhydrazine (DMH)-induced tumor formation. The control labeling index (LI) was highest (9.9 +/- 2.6) and the proliferative compartment (PC) widest in the DMH-sensitive CF1 strain, whereas the LI was lowest (7.3 +/- 1.3) (P greater than 0.01) and the PC shortest in the AKR resistant strain. The size of the PC and the LI for moderately resistant C57BL/6J mice lay between these values (8.5 +/- 1.1). Pooled data from 1 week after the fifth and sixth injections and 12 weeks after the first injection of six showed elevated LI in the distal colons of all DMH-treated mice. Distribution analyses of [3H]thymidine-labeled cells indicated extension of the PC (Stage II abnormality) in all strains with a shift of DNA-synthesizing cells from the major zone or lower third to the middle and upper thirds of the crypt (Stage II abnormality) occurring primarily in the CF1 strain. Cytotoxicity measurements at 6 hours and compensatory DNA synthesis at 3 and 4 days after DMH injection (20 mg/kg body wt) revealed similar relative response levels in CF1 and AKR mice, which suggested induction initially of like numbers of mutations. Indigenous conditions shown to influence the expression of colonic neoplasia are the level of DNA synthesis and the dimensions of the PC within the mucosa.

Animals↗
PubMed1982

A randomized trial of ascorbic acid in polyposis coli.

The possibility of pharmacological control of large bowel adenomas has been suggested by effectiveness of antioxidants in experimental tumor models and by the results of a limited clinical study using ascorbic acid. Over a two year period we tested this hypothesis in a randomized, double-blind study of 49 patients with polyposis coli. Of 36 patients who were evaluable at completion, 19 had received ascorbic acid, 3 g/day, and 17 had received a placebo. We found a reduction in polyp area in the ascorbic acid-treated group at nine months of follow-up (P less than 0.03) and trends toward reduction in both number and area of rectal polyps during the middle of the trial. A labeling study of rectal epithelium with tritiated thymidine also hinted at a treatment effect. Our data suggest that ascorbic acid temporarily influenced polyp growth or turnover. Although these results have no current therapeutic value, our findings support continued studies of chemoprevention in this and other high risk settings.

Adult↗