The long term objectives of this program is to investigate in mouse and man the characteristics of tumor physiology which will determine the effectiveness of 'bioreductive radiation therapy' (defined as the combination of fractionated irradiation with multiple doses of a hypoxic cytotoxin), and to ascertain to what extent this therapy can be improved by manipulations of the tumor physiology. Adding to radiation therapy a drug that selectively kills hypoxic cells is potentially applicable to all solid tumors containing hypoxic cells, irrespective of whether these hypoxic cells limit the efficacy of standard radiation fractionation. Theoretically, the presence of hypoxic cells should render the tumors considerable more susceptible to radiation therapy than if all of the tumor cells were well oxygenated, provided the hypoxic cytotoxin can be given repeatedly, preferably with each radiation dose. In other words, the presence of hypoxic cells in solid tumors can be an advantage in cancer treatment by radiotherapy. One of the most hypoxic- selective bioreductive drugs known to date, the benzotriazine di-N-oxide, SR 4233, is about to enter clinical trails and will be used with as many radiation doses as possible in a typical radiotherapy regimen. However, the extent to which this therapy can exploit hypoxic cells in radiotherapy depends on key assumptions of the physiology of tumors. A major goal of this application is to test these assumptions in a selection of transplanted murine tumors and human tumor xenografts. In these tumors, the kinetics both of rehypoxiation following a single dose of SR 4233 and of reoxygenation following a single X-ray dose will be measured and compared. The extent to which the kinetics of these two processes are similar will provide important evidence on the underlying mechanism of these two processes. Since the efficacy of bioreductive radiation therapy should depend on the level of tumor hypoxia, various methods to measure tumor hypoxia and to follow it during therapy will be employed. These will include radiobiological assays. 14C-misonidazole binding and oxygen tension measurements using a computerized polarographic electrode. In addition to the work with animal tumors, oxygen tension measurements in human tumors before and during therapy will be monitored using the same polarographic oxygen electrode system (pO2 histography) used with the mouse tumors. The possibility of increasing the efficacy of bioreductive therapy by manipulating the tumor physiology to increase tumor hypoxia will also be investigated. These manipulations will include reducing inspired O2 levels to 10% and 15%, using the agent BW12C which increased oxygen bonding to hemoglobin and using the cytokine interleukin 1. These manipulations have been chosen as likely to produce some--not necessarily a large--increase in the hypoxia of human tumors when given repeatedly following irradiation.
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