Our overall goal is to identify those parameters of cellular kinetics which are important in determining the response of tissues to combined treatment with chemotherapy and X-irradiation. Initially we will evaluate the changes in cell kinetic parameters which follow treatment of two established C3H mouse mammary tumor lines (Slow and S102F) and two normal tissues (duodenal mucosa and bone marrow) with one of two chemotherapeutic agents (adriamycin and bleomycin). We will also evaluate the effects of single dose X-irradiation in these tissues. The kinetic changes which follow treatment with one of the chemotherapeutic agents will be mathematically modeled, and the predictions will be made regarding the outcome of combined treatment when various intervals between the chemotherapy and X-irradiation are used. These predictions will be experimentally confirmed using systems which assay for survival of clonogenic cells from each tissue of interest. The methods to be used will include the microcolony crypt survival assay (duodenum), spleen colony forming unit assay (bone marrow) and the lung colony assay (tumor lines). These results will be used to further predict an optimal schedule to maximize tumor cure while minimizing normal tissue effects. These schedules will then be tested experimentally by determining the effects on tumor growth delay and local tumor control (TCD50/120) and on animal survival (LD50/6 (gut death) and LD50/30 (bone marrow death)). Modifications of our modeling will be made to account for differences in predicted response and experimentally determined response.
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