Enzymatic mechanisms of resistance to alkylating agents in tumor cells and normal tissues.

The presence in tumor cells and in normal cells of enzymes which metabolize and inactive alkylating agents appears to play a major role in determining the effectiveness of alkylating agents against human tumors and the toxicities of these agents to normal tissues. The enzyme aldehyde dehydrogenase appears to protect bone marrow and the gastrointestinal tract against toxicity from cyclophosphamide and other closely related oxazophosphorine agents. The presence of this enzyme in bone marrow stem cells facilitates the elimination of tumor cells from bone marrow suspensions, with preservation of the ability of the marrow suspension to reconstitute normal hematopoiesis in a patient. A variety of mouse and human tumors has been shown to be resistant to cyclophosphamide on the basis of an elevated aldehyde dehydrogenase content. The clinical significance of this type of resistance is currently being explored. Increased levels of glutathione-S-transferase have been shown to be associated with cellular resistance to a variety of alkylating agents. We have identified and characterized the conjugates of nitrogen mustards with glutathione. The formation of these conjugates is catalyzed by glutathione-S-transferase. The further study and characterization of these specific reactions should contribute to the understanding and quantitation of this type of alkylating agent resistance.