NUCLEAR DETERMINANTS OF THERAPEUTIC RESPONSE

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The overall objective of the proposed research program is to test the hypothesis that measurable nuclear components are involved in the response- (s) of mammalian cells to therapeutic agents (ionizing radiation, hyper- thermia,,chemotherapeutic drugs, etc.). A condition sufficient to substan- tiate this hypothesis is that nuclei contain one or more measurable determinants of response to a given therapeutic modality. If this condi- tion is true, then it would follow that such measurable determinants would be candidates for potential clinically relevant predictive assays for therapeutic response. Therefore, we are proposing a series of research projects to investigate the relationships between specific nuclear (and related cytoplasmic) components and given cellular effects of certain therapeutic agents. These include nuclear determinants related to cell killing and/or damage repair following exposure to ionizing radiation or hyperthermia and determinants of cell proliferation and cell-cycle progres- sion. Emphasis is placed on ionizing radiation and hyperthermia because these modalities are used clinically and are not membrane limited. Cell proliferation is included logically because hyperthermia, ionizing radia- tion and certain chemotherapeutic agents induce cell-cycle perturbations that result in unbalanced growth, which in turn can affect the response to further treatment. In Project 1, a specific nuclear matrix protein will be studied in terms of its role in anchoring DNA loops and in radiosensitivit- y, which will provide insight into the mechanism(s) of repair and fixation of radiation damage. In Project 2, the interrelationship between the nuclear matrix and the cytoskeleton will be investigated in terms of cellular radiosensitivity. Work proposed in Project 3 will be to study the relationship between the nucleus and cytoplasm affecting the expression of lethal damage after hyperthermia. In contrast to Project 3, which will be done on tumor cells (in vitro and in vivo), Project 4 will investigate the effects of hyperthermia on a normal cell system, the macrophage system. Specifically, Project 4 will investigate the role of environmental factors in the responses of macrophages to hyperthermia. This system will allow us to find determinants for the induction of chronic thermotolerance. In Project 5, the relationship between cytoplasmic and nuclear proteins and perturbed cell-cycle transit will be studied. In this project we propose to find determinants of accelerated G1 transit resulting from unbalanced growth.