Squamous cell bronchogenic carcinomas have been induced by sustained-release implants (SRI) of chemical carcinogens placed endobronchially in outbred Syrian Golden Hamsters. A family of lung cancer models has been produced, best with benzo(a)pyrene and methylcholanthrene. A developmental continuum of epidermoid cancer like that thought to occur in humans is now reproducible in hamsters. Using our lung cancer models in inbred hamsters, we aim to: 1) continue to study the epithelial polyploidy which we have found to be a regular feature of the neoplastic transitional continuum; 2) study chromosomal abnormalities in hamster lung cancers; 3) assess the extent, role, and sites of DNA hypomethylation in chemical carcinogen-induced lung cancer; 4) seek inter-relationships between polyploidy and DNA hypomethylation; 5) explore factors of genetic control in hamster pulmonary carcinogenesis; 6) develop models of adenocarcinoma and small cell undifferentiated cancers; 7) develop standard model systems which will be useful for evaluation of radiotherapeutic and chemotherapeutic modalities. The SRI method, previously successful in causing epidermoid cancers endobronchially, will be used for induction of focal carcinogenesis in the lung periphery. We shall study the pathogenesis of adenocarcinomas and small cell cancers. With cytologic and cytogenetic techniques and image analysis, we shall study ploidy serially during carcinogenesis. The methylation inhibitor 5-azacytidine will be used to aid our assessments of DNA methylation in hamster lung cancer. Using karyotyping in correlation with measurements of total cellular DNA and DNA methylation, genetic factors related to the biologic differences between more and less carcinogen-susceptible hosts will be explored. Adjunctive to cell culture methods for karyotype preparation, transfer of tumor to syngeneic hamster and to athymic nude mice shall be used for cancer cell propagation. Syngeneic tumor transplantation by quantitated single-cell suspensions injected at multiple sites will provide models whose tumor growth rates are suitable for quantitative evaluations of the efficacy of therapy for lung cancer. This project involves collaboration between surgeons, pathologists, cytogeneticists, and molecular biologists seeking better to understand lung cancer by utilizing the hamster model for studies not possible with humans.
