The effects and mechanisms which involve thiol-depleting reagents and electron-affinic radiosensitizers acting on irradiated mammalian cells in culture will be studied both independently and interactively. This will be done with the view to determining how such reagents and sensitizers, manipulated in combination, might improve the radiation therapy of cancer. It has been demonstrated that hypoxic cells exist in and limit the local control of animal tumors treated under some fractionated regimens. Clinical evidence suggests that a similar situation obtains for at least some tumors of the head, neck and pelvis treated by conventional fractionated techniques. Much of the attention to date in dealing with hypoxic cells has been focussed on seeking substitutes for oxygen in view of its limited tumor penetrability set by cell metabolism. Electron-affinic compounds are now available which preferentially sensitize hypoxic cells but clinical success to date has been restrained, chiefly by toxicity problems. From mechanistic considerations of the oft-quoted chemical competition model offered to explain sensitizing action, means other than oxygen substitution may yield promise, namely, by using reagents to eliminate or bind those thiols which may play an important role in affording protection to the hypoxic cells in the first place. The actions and roles of thiols in cell radiosensitization are not well understood; evidence is available indicating that the above model is an incomplete and inadequate description of sensitizing action. Interest in thiols has been heightened recently both from clinical evidence on patients suffering from 5-oxoprolinuria and by the availability of interesting new thiol-depleting reagents, e.g., buthionine sulfoximine. In this project we plan to characterize those actions of thiol-depleting reagents acting on NPSH and/or protein-associated thiols which are relevant to radiosensitization of hypoxic cells and to DNA damage repair processes. Our well-established capabilities with ultra-high dose rate irradiation will be exploited to examine the time scale of thiol action where important and where appropriate. Combinations of thiol reagents and electron-affinic compounds will be sought which offer maximum preferential hypoxic cell radiosensitization with minimum toxicity.
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