MECHANISMS OF CHEMOPOTENTIATION BY RADIOSENSITIZERS

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The radiation sensitizers misonidazole, SR2508 and RSU 1069 are presently being considered for use in clinical trials that attempt to take advantage of their ability to potentiate the activity of various chemotherapeutic agents. Many of these trials will attempt to add their ability to potentiate chemotherapeutic agents to their ability to sensitize hypoxic cells to ionizing radiation. The success of these clinical trials will depend on the answers to several questions. Must all these radiosensitizers be metabolized by hypoxic cells before chemopotentiation can be obtained? Should the chemotherapeutic agent be selected on the basis of some inherent ability to be potentiated or should it be selected because it is the most effective agent against a particular tumor type? If hypoxia is required for chemopotentiation, how long must the cells be hypoxic before the maximum chemopotentiation occurs? How rapidly is the ability to chemopotentiate lost upon reoxygenation of hypoxic cells? Is the time-dose relationship for chemopotentiation governed by a simple or complex time-dose function? While extrapolation from animal tumor experiments to the clinical situation is always tenuous, it is nevertheless preferable to extrapolation from tissue culture experiments where physiological and pharmacokinetic parameters are substantially different. If the above questions are to be addressed in an animal tumor system, the tumor must contain no detectable hypoxic cells. We propose to use our unique 9L rat brain tumor model to address these questions. Intracerebral (i.c.) and subcutaneous (s.c.) 9L tumors contain no detectable hypoxic cells. However, s.c. 9L tumors can be clamped to produce a state of hypoxia that is completely reversible upon removing the clamp. The clamp does not alter the subsequent pharmacokinetics of two nitrosoureas, BCNU and CCNU. 9L tumors will be treated with misonidazole, SR2508 or RSU 1069 and then either clamped or left unclamped. Subsequently, treating with the nitrosoureas BCNU, CCNU or chlorozotocin after removal of the clamp and measuring cell survival 24 hr later with an in vivo to in vitro assay will allow the first two questions to be answered. Clamping the radiosensitizer treated s.c. tumors for various periods of time before treating with the nitrosoureas and treating with the nitrosoureas at various times after unclamping the radiosensitizer treated s.c. tumors should provide the answers to the last three questions. Clearly, it is the unique characteristics of the 9L tumor model that make these experiments possible.