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(Use extra pages as needed) 1. Prinupol Invesvlgator (give tit!e and degrees): Ph.D. Shirley L. Kauffman, bi.D. 2. Ins'irutlan 8 cddress: . State University of New York Downstate Medical Center 450 Clarkson Avenue Brooklyn, New York 11203 l. Shorr title of study: Oncogenes in Chemical Carcinogenesis. 5. Proposed starting dote: July 1, 1983 6. c:t?mn1ed time to complete: 3 years description of :pecific research aims: Transforming genes have recently been identified in cells derived from a variety of human, as well as mouse and chicken tumors (1-14). The direct study of human tumors is difficult due to the rapid degradation of nucleic acids which occurs when tumors are deprived of their blood supply during surgery or after removal. Thus, most of the information regarding oncogenes in tumors has been obtained from analyses,of cell lines established in vitro, a derivative approach which, although useful, has some disadvantages. One of these is the inability to determine the number or sequence of oncogenes activated in the primary tumors, since the cell lines represent a small sample, perhaps a single clone, derived from the original tumor. To facilitate the study of the interaction between tissue, carcinogens, and oncogenes during the tumor pathogenesis, a method of studying in vivo tumor development is desirable. We propose using the mouse lung adenoma system in which multiple lung tumons are induced by transplacental exposure to ENU to study oncogene activation. ~ Using this system, we propose an investigation which centers around four questions relating to oncogenes and chemical carcinogenesis: 1. Are activated transforming genes present in the DNAs of chemically-induced lung adenomas and in malignant cell lines derived from them? 2. Are transforming genes expressed during normal lung tissue differentiation? 3. Does exposure to carcinogen during the period of greatest susceptibility to tumor induction correlate with a specific pattern of transforming gene activation during embryogenesis? ' 4. Does ENU interact with oncogene DNA to effect a change in expression of that DNA? - a Brief statement of working hypothesis: There is increasing evidence that oncogenes are activated=during malignant trans= formation, and one specific oncogene (Ki-ras) has been identified in a human cell line derived from an undifferentiated lung carcinoma (1). The mechanism by which this activation occurs is as yet unknown. The finding that oncogenes are expressed during embryogenesis has led to the proposal that they play a role in regulating tissue proliferation and/or differentiation. Our working hypothesis is that oncogene expression during embryogenesis and cell differentiation is a normal phenomenon which may result in cellular transformation if this expression is perturbed as a result of exposure to carcinogen 50248422