The general goal of this proposal is to quantify chronic damage, ie late effects, in normal tissues after treatment with radiation and chemotherapeutic drugs, drugs alone or radiation alone and to provide some understanding of the pathogenesis of such damage in these tissues. We suggest that all late effects do not share a common pathogenesis but that there are two types of late effects, """"""""consequential"""""""" resulting from killing and subsequent depletion of the parenchymal cells of the tissue and """"""""primary"""""""" which appears in the absence of parenchymal cell depletion and results from killing and depletion of vascular and/or stromal elements. It has been suggested that the effects of chemotherapeutic agents on normal tissues-differ from radiation in that drugs spare the fibroconnective tissue stroma. If this is true, they would not induce any primary late effects and any late effect observed after treatment with both agents would be due to the radiation. Conversely drugs that were toxic to parenchymal cells would exacerbate consequential late effects. The approach in these studies will be to determine the incidence of both consequential and primary bowel obstruction (a late effect) in mouse colon after treatment with radiation alone, drugs alone, or radiation and drugs. Two classes of drugs will be used, those that independently kill crypt cells, ie, 5FU, bleomycin, and cis-platinum, and two that have no measurable effects on crypt survival, ie cyclophosphamide and methyl CCNU at maximum tolerated doses. We will also determine the effect of an elemental diet (Vivonex) on consequential and primary obstruction induced by radiation and bleomycin or radiation and cyclophosphamide . The data from the above studies will be compared with the incidences of both types of obstruction after radiation alone when the acute toxicity (colon crypt survival) after the drug and radiation are matched with that of radiation alone. The potential importance of these studies to clinical practice is that the conceptual framework of late effects outlined in this proposal may provide a rational basis for combining radiotherapy and chemotherapy based on dose limiting toxicities in normal tissues.
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