The objective of the proposed research is to improve the chemotherapy of malignant diseases through a better understanding of the pharmacology and mode of action on two of the more clinically effective antitumor agents, cyclophosphamide and bis-chloroethylnitrosourea (BCNU). The study of these agents is complex since evidence suggests that the antitumor effects of both agents are mediated not by the parent compounds, but by metabolites or decomposition products. In the present project, we propose to identify metabolites and decomposition products of cyclophosphamide and BCNU in vitro, in experimental animals, and in patients receiving the agents. The primary methodology for identification will be gas chromatography and mass spectrometry, supplemented with conventional chromatographic techniques. The identified compounds will be tested for toxicity and antitumor effect in animals. The reaction of the active moieties with biological molecules will be studied and the functional significance of these reactions ascertained. BIBLIOGRAPHIC REFERENCES: Colvin, M., Brundrett, R. B. Kan, M-N. N., Jardine, I. and Fenselau, C. Alkylating Properties of Phosphoramide Mustard. Cancer Res. 36: 1121-1126, 1976. Colvin, M., Brundrett, R. B., Cowens, J. W., Jardine, I. and Ludlum, D. B. A Chemical Basis for the Antitumour Activity of Chloroethylnitrosoureas. Biochem. Pharm. 25: 695-699, 1976.