We propose to contribute to cancer therapy by improving cytokinetic methods and applying them to understand the growth kinetics of cancer cells from man and experimental animals in the context of cancer therapy with cell cycle specific agents. In particular, we are continuing development of: 1) our procedure for simultaneously measuring the extent of incorporation of nonradioactive DNA precursor(s) like bromodeoxyuridine, and total cellular DNA content in a rapid, quantitative and simple method for cytokinetic analysis of cell populations in the midst of therapy; 2) monoclonal antibodies against iododeoxyuridine incorporated into DNA to provide additional markers of DNA synthesis, against ara-C incorporated into DNA for flow cytometric detection of ara-C sterilized cells and against ara-Cmetabolites for improved quantification of intracellular levels of these metabolites, and 3) analytical cytokinetic procedures applicable to therapeutically perturbed populations. We will apply our battery of cytokinetic procedures to analysis of the KHT tumor in C3H mice and the slow growing human NHIK 1922 tumor in nude mice before and during multidose therapy with cytosine arabinoside (ara-C). We will: 1) measure the metabolic and cytokinetic phenomena associated with ara-C to develop a quantitative basis for adjusting cytokinetic-based schedules to compensate for changes in dose level. 2) Characterize the cytokinetic properties of tumors throughout a multidose course of ara-C to estimate how well they can be extrapolated to immeasurably small tumor residuals and 3) combine on data on mid-therapy cyktokinetic properties of the NHIK 1922 tumor with similar data on the intestinal and bone marrow cells in the host mouse to determine if therapeutic advantages based on pretreatment cytokinetic differences between tumor and normal tissues remain during therapy and can be effectively exploited.
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