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.
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