The overall objective of this research program is to determine the importance of various tumor cell subpopulations in predicting a tumor's response to single and combined modality therapies. Cell subpopulations will be derived from solid KHT, RIF-1 or EMT6/Ro tumors using centrifugal elutriation. Experiments are proposed to determine the proportion and cell cycle location of quiescent (Q) cells and to measure growth imbalance in these solid tumor models using acridine orange (AO) staining and flow cytometric (FCM) analysis. The location, with respect to cell cycle phase and proliferation state, of oxygen-deficient (hypoxic) tumor cells will be characterized using radiation cell survival curve analysis, combinations of centrifugal elutriation plus viable cell sorting (Hoechst 33342) and the identification of hypoxic cells through the use of labelled hypoxic cell sensitizers. In situ sensitivity differences of various tumor cell subpopulations (including hypoxic and quiescent cells) will also be determined. It is further an objective to assess which subpopulations are most affected by radiation, sensitizers and selected chemotherapeutic agents. Possible interactions of sensitizers, drugs and radiation in terms of their effects on the total tumor as well as specific subpopulations will be evaluated. These studies should allow the development of mechanisms of interactions for the different combined modality treatments. Experiments aimed at determining the response of tumors and their subpopulations to different fractionated dose regimen also will be performed. In particular the effects of fractionated therapies on cell cycle redistribution and quiescent cell recruitment will be measured. These investigations should produce information which will improve the understanding of the role played by various cell subpopulations in determining the overall response of tumors to therapy and which may guide the efforts for the most effective use of combinations of radiation, chemotherapeutic agents and sensitizers.
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