The proposed studies will, using normal tissue systems in the mouse, allow evaluation of the in vivo and in vitro binding capabilities of nuclear sites (especially the nucleohistones) for agents capable of causing DNA damage. Both nuclear binding data, and data for agent-induced changes in cell survival, proliferation and multiplicity, will be correlated against the capability of the agent to induce a delayed proliferative defect in normal tissue. We have previously reported such delayed proliferative defects for a number of agents, and have hypothesized that the defect resides within the non-proliferating compartment originally exposed to the agents. Specifically, the studies proposed in this program will determine the appropriateness of the hypotehsis that: """"""""The proliferative defect seen within stem cell populations exposed to DNA interactive chemotherapeutic agents, environmental compounds, and inductrial chemicals is latent in nature and manifest only when such cells are recruited into cycle. Upon recruitment, sequestered intranuclear concentrations of the drug in question are released by several species of nucleohistones and immediately cause DNA damage and reproductive death of the cell"""""""". The ultimate goal of the proposed studies is to understand more fully the basic nature of the interactions between living cells and noxious agents in their environment; thereby delayed aspects of chemical toxicities may be understood and ameliorated by either biologic or biochemical intervention.
