Modification of normal tissue response to radiotherapy and chemotherapy

This paper describes some of the mechanisms for modification of tissue response to radio- and chemotherapy. Attention is focused on the balance between radioprotection by thiol compounds such as WR-2721 and sensitization by oxygen or oxygen mimetic sensitizers such as misonidazole. Thiol protectors act, at least in part, by redox competition with oxygen for repair or fixation of the initial radiation lesion. The extent of radioprotection achieved is therefore critically dependent on the oxygen concentration at the time of irradiation. Maximum protection is usually achieved at intermediate oxygen concentrations with little or no protection in hypoxia. Many studies report lower protection in fractionated irradiation schedules than for single doses. Data are shown to demonstrate that this is often because toxicity limits the drug doses which can be used with fractionated schedules, and not because of a reduction of radioprotection at small X ray doses. Methods for manipulating the endogenous thiol levels are discussed in relation to their influence on normal tissue response to both radiation and chemotherapy. Other methods for preferentially increasing tumor chemo- or radio-sensitivity, such as inhibition of repair of potentially lethal damage or alterations in tumor oxygenation or blood flow are briefly discussed.