Relative resistance of tumor cells to radiation therapy and chemotherapy is the major factor which limits our ability to cure cancer with current therapeutic modalities. There are many potential genetic and biologic factors which could contribute to this tumor cell resistance and a better understanding of these factors would represent a significant advance towards developing improved therapeutic strategies to treat tumors. Preliminary data is presented which demonstrates that exposure of immortalized or tumor cells to certain growth factors results in significant resistance to ionizing irradiation. It is suggested that activation of such growth factor pathways, by either genetic mutations activating growth factor pathways or direct exposure to the appropriate growth factors, would be a major contributor to tumor resistance in vivo. The mechanism of this growth factor-mediated enhanced survival after cytotoxic stress remains unclear. Data in the literature demonstrates that growth factor manipulation can alter the generation of intracellular reactive oxygen species (ROI s). In addition, oxidative stress appears to also be an important regulator of the apoptosis process. The preliminary data, in conjunction with these observations in the literature, lead to the hypothesis that growth factors modulate cellular survival after cytotoxic stress by modulation of intracellular redox parameters. A model is presented suggesting that growth factor stimulation leads to an initial rapid rise in intracellular hydrogen peroxide and a subsequent induction of cellular defenses against oxidative stress which allows the cell to survive and proliferate in the continued presence of growth factor. This enhancement of cellular anti-oxidant defenses by the growth factor would also result in enhanced cell survival after irradiation or chemotherapy. In contrast, irradiation in the absence of this growth factor-stimulated anti-oxidant pathway, would lead to increased radiosensitivity. Experiments are proposed to test this hypothesis utilizing well- characterized growth factor-dependent systems. Alterations in a variety of intracellular redox parameters associated with growth factor manipulations will be assessed. Second, alterations in growth factor modulation of radiosensitivity by manipulation of these redox parameters with chemicals and genetic manipulations will be investigated. Finally, the mechanism(s) by which growth factors modulate these redox parameters will be investigated. Insights gained from these studies have the potential to provide novel targets for enhancing the sensitivity of tumor cells to radiation therapy or chemotherapy.
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