Various carcinogenic agents are known to cause tumors in specific cells of certain organs and not elsewhere. Part of this specificity can be attributed to the pharmacodynamics of the system. But recent studies on oncogenes indicate that specific types of human and animal tumors exhibit patterns of change not previously suspected. These include specific deletions; characteristic chromosomal translocations and rearrangements; base substitution point mutations at specific positions in an oncogene; gene amplification, etc. These results suggest that the specific kinds of DNA changes that a particular carcinogen induces may also play a role in the kinds of tumors that develop. As part of an ongoing program to determine the mechanisms involved in the multi-stepped carcinogenesis process, we propose to use recombinant DNA techniques to examine the specific kinds of changes induced by selected carcinogens at the molecular level. These will include (1) homologous genetic recombination, (2) gene amplification, (3) genetic deletions or rearrangements, and (4) """"""""point mutations"""""""" determined by DNA sequencing. The cells to be used are mammalian cells, including normally repairing and repair-deficient human cells. The genetic targets for the research include the human HPRT gene, as well as shuttle vectors carrying defined, selectable markers, replicating in the cells as plasmids or stably integrated into the chromosome. The carcinogenic agents to be studied are UV radiation, ionizing radiation and a representative aromatic amine, polycyclic aromatic hydrocarbon, simple alkylating agents and intercalating agents. The ultimate objective of these studies is to provide us with the information on what types of DNA lesions lead to which types of DNA changes in mammalian cells. Thus, it provides a kind of Rosetta stone which will allow one to determine whether particular types of DNA changes in tumor cells are consistent with the exposure to specific agents and it will allow one to rationally define in tumor or transformation studies the role of the carcinogenic agent chosen.
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