The objective of the proposed research is ultimately to improve the therapy of malignant disease with antitumor alkylating agents. We propose to accomplish this objective through a better understanding of the pharmacology of the drug cyclophosphamide, as well as other clinically useful alkylating agents. Our goals are: a) To design more effective and selective analogues of cyclophosphamide, based on an understanding of the chemistry and pharmacology of this drug; and b) To utilize cyclophosphamide or appropriate derivatives more rationally, based on a better understanding of the complex pharmacodynamics of this drug. To this end we propose: a) To continue our studies on the chemistry and metabolism of cyclophosphamide and its metabolites; b) To investigate the interaction of the metabolites with normal and tumor cells, including cytotoxicity, transport across the cell membrane, alkylation of DNA, crosslinking of DNA, and effects on cellular metabolism; and c) To expand our studies on the clinical pharmacokinetics of cyclophosphamide and metabolites. Similar studies will be carried out with other alkylating agents, such as L-phenylalanine mustard, to compare the properties of these alkylating agents with those of cyclophosphamide.
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