We propose using a multicellular in vitro tumor analogue to model, experimental and theoretically, all stages of the following radiation therapy scenario: as a solid, poorly vascularized tumor develops, the percentage of proliferating cells decreases; necrotic regions surrounded by hypoxic cells appear; the hypoxic cells are reoxygenated; and finally repopulation of the tumor occurs. The tumor analogue will be the sandwich system, a two-dimensional, diffusion limited, organized multicellular system which develops a necrotic region, has many properties in common with the spheroid system but has important differences which make it a useful complement to the spheroid system in investigating tumor growth and radiation response. The first part of the experimental work will model tumor development. It will single out oxygen and glucose, measuring their coupled consumption and concentration profiles, their effect in the cell growth fraction at different spatial locations, their joint influence on the development of necrosis, and the development of hypoxic regions. The second part of the experiment will model tumor radiation response. We propose using the sandwich system in a variety of standard radiation survival experiments, emphasizing experiments which characterize the hypoxic fraction and its spatial location. We also propose non-standard radiation experiments designed to analyze reoxygenation and repopulation in situ. The effect of a radiosensitizer, misonidazole, in reducing repopulation by sensitizing the hypoxic region will be investigated. In the theoretical work we will use a new model that extends current """"""""one substance"""""""" oxygen or glucose models by including interactions between these substance. Computer numerical integration of coupled non-linear integral equation will be used to calculate concentration profiles, investigate the influence of diffusion-limited concentration on the cell kinetic properties, characterize conditions for the development of necrosis, describe metabolic and cell kinetic modifications of cellular radiation response (particularly in the hypoxic region), and analyze the processes underlying reoxygenation and repopulation.
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