Kathleen M. Nauss

Rodent models for carcinoma of the colon

ConclusionRodent models for colon cancer have contributed information on many aspects of the disease that may be applicable to prevention and treatment. Data of major importance on factors that retard or enhance tumorigenesis are now within reach. There are several basic research needs in the further development of animal models. Major questions, such as the controversies over the role of dietary fat and fiber, will be resolved only if investigators use comparable, consistent regimens and protocols, report full results, and use comparable endpoint and statistical analyses. If the deceptively simple controversies in the animal models can be resolved, we shall have powerful tools for further investigation of carcinogenesis in the intestine.

Functional Characteristics of Lymphocytes Isolated From the Rat Large Intestine: Response to T-Cell Mitogens and Natural Killer Cell Activity

Using successive ethylenediaminetetraacetic acid and collagenase treatments, two fractions of mucosal lymphocytes have been isolated from the rat large intestine that differ in morphologic and functional characteristics. Intraepithelial lymphocytes consisted largely of granular lymphocytes (91 +/- 6%) that did not respond to stimulation with phytohemagglutinin or concanavalin A, but had natural killer cytotoxic activity against the YAC-1 cell line. The natural killer cytotoxicity of the intraepithelial lymphocytes was specifically reduced by the addition of increasing numbers of unlabeled homologous tumor cells but not by unlabeled thymocytes. The sensitivity of different target cell lines to lysis by intraepithelial lymphocytes was the same as splenocytes from the same rat strain. Lymphocytes from the lamina propria contained 21 +/- 4% granular cells with the remainder being typical small lymphocytes. The lamina propria fraction responded well to stimulation with concanavalin A, phytohemagglutinin, and pokeweek mitogen, and also had natural killer activity against YAC-1 cells.

Effects of Dietary Folate, Vitamin B12 and Methionine/Choline Deficiency on Immune Function

Numerous epidemiological studies have confirmed that a relationship exists between nutritional status and resistance to infection. More recently attention has been focused on the more difficult question of the role of individual nutrients in the proper development and maintenance of the immune system. These parameters are more difficult to assess in human populations because the severe nutritional diseases usually seen (kwashiorkor and marasmus) represent an advanced state where the contribution of a single nutrient cannot be assessed.

Depressed transformation response by splenic lymphocytes from vitamin A-deficient rats

Abstract Concanaval in A (Con A)-stimulated lymphocytes isolated from the spleen of vitamin A-deficient rats showed decreased [ 3 H]thymidine incorporation compared to pair-fed and ad libitum-fed controls. This decrease was evident over a range of Con A concentrations (1–7 μg/ml), and the mitogen concentration which elicited maximum response was the same (2 μg/ml) for all three dietary groups. A three-day in vivo repletion with retinyl acetate led to recovery of normal or greater than normal [ 3 H]thymidine incorporation at all concentrations of Con A. At time intervals when DNA synthesis was significantly increased by Con A (48, 72 and 96 hours after stimulation) the [ 3 H]thymidine incorporation by vitamin A-deficient lymphocytes was always lower than that of pair-fed and ad libitum-fed controls. Decreased splenocyte blastogenesis was also demonstrated for the B-cell mitogen E. coli lipopolysaccharide, which was not completely accounted for by reduced numbers of B-cells in the spleen of vitamin A-deficient rats.

Effect of dietary selenium levels on methylbenzylnitrosamine-induced esophageal cancer in rats

Male Sprague-Dawley rats fed selenium deficient diets received either 0 ppm, 0.15 ppm or 4.0 ppm selenium in the drinking water. Animals were treated with methylbenzylnitrosamine (MBN). Dietary selenium deficiency had no effect on MBN-induced esophageal carcinogenesis. Animals treated with 4 ppm selenium in the drinking water during the initiation and post-initiation period had the same number of tumors as the group which received 0.15 ppm selenium for the entire experimental period. The incidence and frequency of carcinomas was lowest in the group which was supplemented with extra selenium (4.0 ppm) during the period of carcinogen administration and highest in the group which received 4.0 ppm selenium during the post-initiation period.

Effect of colon tumor development and dietary fat on the immune system of rats treated with DMH.

We examined the effect of dietary fat and colon tumorigenesis on the morphology and function of the rat mesenteric lymph node (MLN) and spleen at two stages of tumor development. Male Sprague-Dawley rats were fed semipurified diets of varying fat content (5% mixed fat, 24% beef fat, 24% corn oil, or 24% Crisco) and treated for five weeks with either the colon carcinogen 1,2-dimethylhydrazine (DMH) or the vehicle (saline). Animals consuming high-fat diets had an increased incidence of splenic follicular and germinal center hyperplasia. Carcinogen treatment had no significant effect on the histological morphology of the spleen. MLN morphology was not dramatically affected by either diet or DMH treatment. At this time period, the splenic lymphocyte transformation response induced by concanavalin A (Con A), phytohemagglutinin, or pokeweed mitogen was significantly depressed in the group fed 24% corn oil (vehicle-treated) and in the DMH-treated groups fed 5% fat compared with the vehicle-treated group fed 5% fat. In contrast, the MLN transformation response was elevated in the group fed 24% Crisco. DMH treatment did not significantly influence the MLN response. Four months after carcinogen or vehicle treatment, at the point of colon tumor development, no statistically significant differences were seen in the splenic or MLN blastogenic responses of DMH- or saline-treated animals. Splenic natural killer cell cytotoxic activity was also not significantly affected by dietary fat, carcinogen treatment, or tumor development.

Natural killer cell activity and autologous mixed lymphocyte response of splenic, mesenteric lymph node, and colonic lymphocytes during DMH-induced colon carcinogenesis in the rat

Twoin vitro models of immune surveillance were used to examine the immune status of the gut-associated lymphoid tissue, mesenteric lymph nodes, and spleen during the early stages of 1,2-dimethylhydrazine (DMN)-induced colon tumorigenesis. DMH-and vehicletreated Fischer rats were sacrificed at one of three time points; one week, two months, or five months after cessation of treatment. Colonic, lymph node, and splenic natural killer cell cytolytic activity toward YAC-1 tumor targets and T-cell response to autologous la-induced balstogenesis were measured at each time point. We found little change in natural killer cell activity or T-cell proliferation induced by autologous Ia gene products at these time periods.

Colon carcinogenesis in the marmoset

Speakers and discussants in the cancer subgroup presented salient features of colon cancer in Saquinus oedipus oedipus, and comparisons were made with the human disease and other animal models of colon carcinoma. Etiology: The marmoset is the only animal model for gastrointestinal carcinogenesis which is characterized by a high incidence of spontaneous colon tumors. Colon cancer in the two marmoset colonies about which we have the most information does not exist in the absence of colitis. However, there are animals of the S. oedipus species who have colitis and have not yet developed tumors. There was a general consensus that the basic question which must be resolved is the relationship between colitis and cancer in the marmoset model. This requires identifying the cause of colitis in these animals, using objective parameters to measure the severity of the disease, and bringing the disease under control so that its relationship to tumors can be evaluated and the clinical course can be manipulated. Nutritionists stressed the necessity of adopting defined standardized diets, and success in this area has been achieved with a limited number of animals (Dr. Knapke). Tumor Location: Large bowel neoplasms in human patients typically present on the left side of the colon or in the cecum. In patients with ulcerative colitis, tumors are present throughout the colon and predominate in the transverse section (Dr. McDermott). The location of chemically induced gastrointestinal tumors in rodents varies depending on the species, strain, carcinogen dose, and route of administration (Dr. Rogers and Dr. Ahnen). Dr.

DEPRESSED LYMPHOCYTE TRANSFORMATION IN A WHOLE BLOOD CULTURE SYSTEM AFTER ORAL GLUCOSE INGESTION

Abstract Twelve healthy volunteers (20 to 40 years old) were evaluated to determine the effect of oral glucose ingestion on in vitro lymphocyte transformation induced by phytohemagglutinin (PHA) and pokeweed mitogen (PWM). Whole blood transformation induced by PHA or PWM was depressed in all subjects from 0.5–1.0 h post-glucose ingestion. By 2.0 h, the mean transformation response had returned to near fasting levels. There was no significant difference in the mitogenic response of purified peripheral lymphocytes isolated from fasting and nonfasting samples. These findings suggest that utilization of whole blood lymphocyte cultures to assess immune function, should be restricted to fasting patients.