John Potter, PhD - US grants

The awarding of a Clinical Cancer Education Grant in 1978 to the Vincent T. Lombardi Cancer Research Center played a critical role in the initiation of important new cancer educational programs in Georgetown Medical School. These programs could not have come into being without that grant support. This current grant request seeks renewal of this support to continue programs which have established their merits. They are innovative and multidisciplinary and are not achievable in the traditional medical school curriculum. These programs will be expanded and improved. To this time, our efforts have been confined primarily to the Medical School. Now they are being expanded to include the Schools of Dentistry and Nursing. Increased emphasis is being placed on programs in cancer prevention. New programs include the development of a coordinated vertical matrix in cancer education employing the faculty and resources of the three health professional schools. The Cancer Librarian Program will be improved by the utilization of new computer technology. The Student Assistantship Program, which has been extraordinarily popular, will be increased in size and will recruit dental and nursing students, as well as offering new opportunities in such areas as nutrition and epidemiology. A new program is being developed for continuing education of practitioners in the three health professions using multidisciplinary conferences. Another new venture is the development of Preceptorships. In this effort, practicing professionals in medicine, dentistry and nursing will come to the Vincent T. Lombardi Cancer Research Center for a "hands-on" learning experience under the direct supervision of a faculty tutor. Finally, a new program in the epidemiology, prevention and early detection of breast cancer will be offered. Improvements will be made in program evaluation by the identification of a professional in this field.

Many biologic functions are dictated by the primary structure of proteins. Our ability to understand these functions has been limited by our ability to understand these structures. Over the past few years, methods have been developed which allow the application of protein sequence analysis to a variety of major biologic questions. The nature and sites of protein polymorphism, of chemical modification and of substrate binding give insights into the way in which molecules function. A number of NIH-supported projects on the Georgetown University campus are examining the structure-function relationship for proteins involved in immune response, proteins involved in chromatin/DNA interaction and proteins alterated during chemotherapy. These studies include the biochemistry of: (1) Human histocompatibility antigens encoded by the HLS-D region. (2) Poly (ADP-ribose) polymerase as it relates to chromatin structure and function. (3) Cobra venon factor as it relates to the human complement component C3b. (4) DNA endonucleases. (5) Intracellular proteins as modified by nitrosourea, an antitumor drug. Each of these studies requires the use of a protein sequencer. This proposal constitutes a request by members of Georgetown University to purchase this sequencer. This sequencer will be an important tool in defining protein primary structure so that an understanding of protein function can be obtained.

The Lombardi Cancer Center is engaged in multidisciplinary programs in basic and clinical research. A salient feature of Lombardi activity is the involvement of basic and clinical scientists on the same research team. Major interdisciplinary research programs in medical, gynecologic, surgical, pediatric, and radiation oncology are in operation. In addition, we are conducting collaborative research programs in virology, immunology, cellular and molecular biology, and monoclonal antibody studies. The Center has established clinical and basic shared core services to insure that the required resources for effective programs of research are available. Cancer control efforts are an important aspect of the Lombardi Center's activities. A strong educational program is present for medical students, graduate students, house officers, and practicing physicians.

This study proposes to use a community-based intervention program to modify eating behavior according to recommendations for reducing dietary-related cancer risks. Two similar rural Minnesota communities (with specified population, media, grocery-store, health and extension service characteristics), one serving as an education site, the other as reference, will be compared. Existing community-based strategies, procedures, and materials will be adapted to encompass diet and cancer risk recommendations, and consist of a) a grocery-store intervention using product-labeling, taste-testing, incentive programs, and print and visual education materials; b) an eight-week intensive home-based education program; c) a 12-month maintenance program; d) a mass media information program throughout; e) involvement of the Minnesota Extension Service and Minnesota Department of Health and trained volunteers under their supervision; and f) involvement of grocery store managerial and regular staff. Themes, focus, and message strategies will be established through a social marketing planning process using a community survey, and focus group interviews. Intervention effectiveness will be evaluated using comparisons both between the education and reference communities, and within the education community to establish whether different program "doses" are associated with corresponding differences in effects. Dietary knowledge, attitudes, and behavior will be used as outcome measures and will be compared at baseline, at mid-intervention, and at post- intervention. In addition, the study design permits measurements of effects due to self-selection. Finally, a cost-effectiveness evaluation is a crucial part of this proposal to evaluate the feasibility of broad dissemination.

This proposal requests equipment that will expand the on-line data storage capabilities of existing computer hardware. Thirteen PHS grants and contracts within the Division of Epidemiology, School of Public Health, University of Minnesota will share this resource. The ability of these thirteen projects to process and analyze data will be seriously impaired without this addition of an intelligent on-line data storage system.

The overall goal of the proposed CPRU is the development of strategies for the prevention of colorectal cancer. To accomplish that goal, a multi- disciplinary groups of scientists is collaborating on a group of projects using shared resources. The studies revolve around understanding better the factors which increase risk of development of adenomatous polyps and the undertaking of a feasibility study on the prevention of recurrence of these lesions. There are 4 specific projects: a) a case-control study of the role of familial and environmental factors in the occurrence of adenomatous polyps; b) a study to establish the feasibility of major dietary intervention (specifically increasing vegetable and fruit intake) in the recurrence of polyps; c) studies seeking to improve self-report dietary methods for etiologic and intervention studies; d) feeding studies to dietary methods for etiologic and intervention studies; d) feeding studies to test objective markers of diet exposure, specifically exposure to vegetables and fruit; There are 5 core support units: Dietary; Laboratory; Clinical; Statistical and DAta management; and Survey. The program is integrated at a number of levels - thematic, organizational, data-sharing, resource-sharing, and intended future cross-disciplinary studies. It is based on the extensive prior experience of the collaborators in the relevant areas, relates strongly to other existing research and emphasizes combined and complementary skills in the intellectual effort. The program is a collaborative arrangement among the personnel, and using the resources, of 3 divisions of the School of Public Health, 2 departments of the Medical School, and 1 department of the School of Agriculture of the University of Minnesota.

Promising, but as yet inconclusive evidence has been accumulating to indicate that dietary calcium in sufficient quantity, may be a protective factor against colorectal cancer--particularly for those consuming typical high fat Western-style diets. Evidence now also exists to support colonic epithelial cell proliferation as indicated by tritiated thymidine [3H]dTh - labeling of the cells as a biomarker or potential precursor lesion for colonic polyps and colonic cancer. These cells which can be obtained for study by simple non-prep rectal biopsies reflect risk for neoplasia that has occurred higher in the colon. Furthermore, evidence now also exists that this hyperproliferation in the colonic mucosa can be reversed by administration of calcium supplementation and the risk of colonic cancer thereby reduced. To date three uncontrolled trials on the effect of calcium on colonic epithelial cell proliferation in humans have been conducted. All three have shown important reductions. However, to date no randomized controlled trials or trials utilizing different dosages have been reported. Furthermore, there has been no serial or long term follow-up of the effect of calcium on colonic epithelial cell proliferation to determine how quickly a full benefit is achieved or whether or not an adaptive process may occur which would lessen the effect over time. Also, at this point, little is known regarding the possible natural fluctuation of colonic epithelial cell proliferation in high risk humans with previous colonic adenomatous polyps. This proposed randomized double-blind placebo-controlled clinical trial would address these gaps by having a control group (which performs a dual function of also being a high risk natural history group), having two different calcium supplementation level groups and by following up each group with rectal biopsies at three different times. This study therefore will provide needed data on the relationship between calcium and colonic epithelial cell proliferation, adenomatous polyps and colonic cancer. This study will also provide a basis for further studies of the value of colonic epithelial cell proliferation as a biomarker of subsequent development of colonic polyps and colonic cancer and for other dietary interventions on this marker including the evaluation of dietary interactions such as those of calcium with fat, vitamin D3, and fiber.

The investigators are currently undertaking two NCI-funded case-control studies of colon cancer (2400 cases and 24 control) and adenomatous polyps of the large bowel (600 cases and 1800 controls), investigating the role of diet, physical activity, reproduction, and family history. The two studies were designed to answer similar questions using similar instruments. It is increasingly clear that, in addition to the environmental factors, genetic susceptibility is important in the etiology of these disorders. Since the original submission of CA48998, much progress has been made in Utah and elsewhere in identifying genes associated with colon cancer. The FAP gene is located on 5q21 and the search for it has now been narrowed to a small region, less than 400 kilobases. It is expected that this gene (whether or not it is the recently identified MCC gene) will be cloned and sequenced before the completion of data collection, allowing genotyping of the case-control study subjects. Further, it is appropriate to consider at least one other marker for restriction fragment length polymorphism (RFLP) analysis, namely fast-acetylator genotype, for which there is evidence, albeit inconsistent, of an association with colon cancer. Three polymorphisms have now been identified. Southern Blot analysis allows direct determination of acetylator-genotype. Other candidate markers will be identified over the next few years. The specific aims of this proposal are: 1. To collect blood from participants in the 2 population-based studies of colon cancer (R01 CA48998) and adenomatous polyps (P01 CA50305; 2. To analyze DNA from all participants to explore the role of acetylator status and the FAP gene in the etiology of colon neoplasia; and 3. To explore the evidence for confounding and interaction between the genotypes and diet, particularly intake of meat, fat, protein, but also of total calories, calcium, micronutrients, and fiber, and physical activity, reproduction, and family history, in the etiology of colon neoplasia. 4. To store white blood cells and DNA for future analysis of specific genes as they become available from the work at Utah or elsewhere. The combined environment/diet/gene dataset will provide the first and perhaps the most comprehensive opportunity to determine the way in which genes and environment interact in the etiology of colon cancer and its precursor lesion.

The investigators are currently undertaking two NCI-funded case-control studies of colon cancer (2400 cases and 24 control) and adenomatous polyps of the large bowel (600 cases and 1800 controls), investigating the role of diet, physical activity, reproduction, and family history. The two studies were designed to answer similar questions using similar instruments. It is increasingly clear that, in addition to the environmental factors, genetic susceptibility is important in the etiology of these disorders. Since the original submission of CA48998, much progress has been made in Utah and elsewhere in identifying genes associated with colon cancer. The FAP gene is located on 5q21 and the search for it has now been narrowed to a small region, less than 400 kilobases. It is expected that this gene (whether or not it is the recently identified MCC gene) will be cloned and sequenced before the completion of data collection, allowing genotyping of the case-control study subjects. Further, it is appropriate to consider at least one other marker for restriction fragment length polymorphism (RFLP) analysis, namely fast-acetylator genotype, for which there is evidence, albeit inconsistent, of an association with colon cancer. Three polymorphisms have now been identified. Southern Blot analysis allows direct determination of acetylator-genotype. Other candidate markers will be identified over the next few years. The specific aims of this proposal are: 1. To collect blood from participants in the 2 population-based studies of colon cancer (R01 CA48998) and adenomatous polyps (P01 CA50305; 2. To analyze DNA from all participants to explore the role of acetylator status and the FAP gene in the etiology of colon neoplasia; and 3. To explore the evidence for confounding and interaction between the genotypes and diet, particularly intake of meat, fat, protein, but also of total calories, calcium, micronutrients, and fiber, and physical activity, reproduction, and family history, in the etiology of colon neoplasia. 4. To store white blood cells and DNA for future analysis of specific genes as they become available from the work at Utah or elsewhere. The combined environment/diet/gene dataset will provide the first and perhaps the most comprehensive opportunity to determine the way in which genes and environment interact in the etiology of colon cancer and its precursor lesion.

A case-control study to examine the independent and combined effects of arylamine acetylator status and N-oxidation status, cigarette smoking, and high meat consumption on subsequent risk of pancreatic cancer is proposed. The proposal is based on the hypothesis that aromatic amines (AAs) are carcinogenic for the human pancreas; a view supported by our laboratory evidence. All cases of adenocarcinoma of the exocrine pancreas (N = 630) who are: 1) age 20 or above, 2) newly diagnosed during a three and one- half year period in the seven-county metropolitan area of Minneapolis/St. Paul, and 3) confirmed with a histological or clinical diagnosis of cancer through either pathology report, hospital based-tumor registry, or medical records, will be eligible for this study. Because of the relatively short survival time and the high percentage of clinically diagnosed cases, we will contract for the services of existing data managers within hospitals to assist in the early identification of the cases through physicians, pathology reports, initial discharge, and tumor registries. Controls will be frequency matched to the cases by sex and age (in 5-year age groups) and randomly selected from the same seven-county area as the cases. Controls aged 20 to 64 will be chosen by random digit dialing, and controls aged 65 and above will be selected from Health Care Financing Administration records. In-person interviews will be conducted and blood samples drawn by trained interviewer/phlebotomists at a time and location of the study subject's choice. Detailed information will be ascertained for each subject including: 1) arylamine acetylator and N-oxidation status; 2) complete cigarette smoking history; 3) dietary intake; 4) medical and family history; 5) occupational history; 6) complete allergy history; and 7) basic demographic information. Participants will be phenotyped with respect to acetylator and N-oxidation status by the examination of levels of caffeine metabolites in a urine specimen collected after ingestion of a 100 mg caffeine tablet. Blood samples will be used for genotypic determination of acetylator status and will be stored for future analyses. Statistical analyses will address the a priori hypotheses that: 1) high exposure to arylamines of smoking and dietary origin, rapid acetylator, and rapid N-oxidation status are independently associated with an increased risk of pancreatic cancer. The association between rapid acetylator status and pancreatic cancer will also be evaluated among smokers and heavy meat consumers.

Higher plant food intake is associated with lower cancer risk in humans. Bioactive constituents present in plant foods or derived from them in the human GI tract have specific effects on xenobiotic metabolism; however, evidence regarding mechanisms of cancer risk reduction in humans is almost totally lacking. To test the hypothesis that induction of Phase II enzyme systems through increased intakes of vegetables and fruits is a plausible mechanism for reduced cancer risk, we propose to examine the effects of diet on glutathione S-transferase isoenzyme activity in humans.