Squamous cell bronchogenic carcinomas continue to be chemically induced at preselected endobronchial sites in dogs. These preparations allow serial testing during the evolution (transitional continuum) of lung cancers like those which occur in humans. Material from patients and a hamster model will be utilized in adjunctive fashion.
We aim to: 1) Make the existing cancer models more cost effective; 2) Delineate relationships between polyploidy and stages of respiratory epithelial carcinogenesis; 3) Develop methods for in vivo preparation and propagation of pre-neoplastic and cancer cells; 4) Determine the role of DNA methylation during lung carcinogenesis; 5) Explore factors of genetic control upon pulmonary carcinogenesis. Toward cost effectiveness we shall use endobronchial sustained release implants (SRI) of carcinogens and heterotopical autogenous segmental tracheo-bronchial transplants treated with carcinogen. Using image analysis and FACS separation techniques, we shall study ploidy serially during carcinogenesis and work toward improved cell culture methodology. Transfer of tumor cells to nude mice shall be used for cancer cell propagation; importantly adjunctive, in vivo autogenous tracheal segment grafts treated with carcinogen shall be used to propagate autogenous bronchial cancer cells. Pre-neoplastic cell populations shall be harvested from autologous tracheo-bronchial grafts and endobronchial sites undergoing bronchial carcinogenesis. Lung cancer specimens from humans, dogs, and hamsters shall be used to test the hypothesis that undermethylation is a key factor in bronchial carcinogenesis. The effect of the methylation inhibitor 5-azacytidine upon the continuum of bronchiocarcinogenesis will be tested in dogs and hamsters. Using karyotyping in correlation with assessment of total DNA and DNA methylation measurements, the biologic and genetic differences between more and less carcinogen susceptible hosts will be explored. This project involves collaboration between surgeons, cytogeneticists and molecular biologists seeking better to understand lung cancer. It utilized specimens from three species - man, dog, hamsters and proposed specifically to use the canine model for studies not possible with humans or hamsters.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA026529-06
Application #
3167347
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1978-11-01
Project End
1987-12-31
Budget Start
1985-04-01
Budget End
1986-12-31
Support Year
6
Fiscal Year
1985
Total Cost
Indirect Cost
Name
City of Hope National Medical Center
Department
Type
DUNS #
City
Duarte
State
CA
Country
United States
Zip Code
91010
Ten Have-Opbroek, A A; Benfield, J R; Hammond, W G et al. (1994) In favour of an oncofoetal concept of bronchogenic carcinoma development. Histol Histopathol 9:375-84
TenHave-Opbroek, A A; Hammond, W G; Benfield, J R et al. (1993) Expression of alveolar type II cell markers in acinar adenocarcinomas and adenoid cystic carcinomas arising from segmental bronchi. A study in a heterotopic bronchogenic carcinoma model in dogs. Am J Pathol 142:1251-64
Benfield, J R; Hammond, W G (1992) Bronchial and pulmonary carcinogenesis at focal sites in dogs and hamsters. Cancer Res 52:2687s-2693s
Hammond, W G; Benfield, J R; Teplitz, R L (1991) Metastatic behaviour of canine lung carcinoma in autochthonous and xenotransplant hosts. Clin Exp Metastasis 9:567-77
Hammond, W G; Teplitz, R L; Benfield, J R (1991) Variable regression of experimental bronchial preneoplasia during carcinogenesis. J Thorac Cardiovasc Surg 101:800-6
Hammond, W G; Benfield, J R; Teplitz, R L (1991) Metastases from fresh human non-small cell lung cancers propagated in nude mice. Cancer Lett 61:53-60
Ten Have-Opbroek, A A; Hammond, W G; Benfield, J R (1990) Bronchiolo-alveolar regions in adenocarcinoma arising from canine segmental bronchus. Cancer Lett 55:177-82
Hammond, W G; Yellin, A; Gabriel, A et al. (1990) Quantitative DNA alterations during 5-azacytidine-induced differential modulation of benzo(a)pyrene carcinogenesis in hamster bronchi. Cancer Commun 2:135-44
Hammond, W G; Yellin, A; Gabriel, A et al. (1990) Effects of 5-azacytidine in Syrian golden hamsters: toxicity, tumorigenicity, and differential modulation of bronchial carcinogenesis. Exp Mol Pathol 53:34-51
Benfield, J R; Wain, J C; Derrick, M et al. (1988) Biochemical and cytogenetic studies of human lung cancers. J Thorac Cardiovasc Surg 96:840-8

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