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Molecular Pharmacology

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Research ArticleArticle

Urinary Metabolites of the Antitumor Agent Cyclophosphamide

ROBERT F. STRUCK, MARION C. KIRK, L. B. MELLETT, SALAH EL DAREER and DONALD L. HILL
Molecular Pharmacology September 1971, 7 (5) 519-529;
ROBERT F. STRUCK
Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35205
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MARION C. KIRK
Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35205
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L. B. MELLETT
Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35205
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SALAH EL DAREER
Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35205
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DONALD L. HILL
Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35205
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Abstract

2-Carboxyethyl N, N-bis(2-chloroethyl)phosphorodiamidate and 4-ketocyclophosphamide (2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorin-4-one 2-oxide) have been isolated and identified as urinary metabolites of dogs treated with the anticancer agent cyclophosphamide (2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide). 2-Carboxyethyl N, N-bis(2-chloroethyl)phosphorodiamidate is the major urinary metabolite, whereas 4-ketocyclophosphamide is a minor metabolite and represents the first known product of cyclophosphamide which retains the ring structure. Another urinary metabolite yields β-hydroxypropionamide on hydrolysis, a further indication that the primary oxidative step in the metabolism of cyclophosphamide occurs on carbon 4 of the ring. Neither of the two isolated metabolites is highly cytotoxic to human epidermoid cancer cells in vitro or to Leukemia L1210 cells in vivo. Neither compound is on a pathway leading to an active form of the drug.

ACKNOWLEDGMENTS We are very grateful to Miss D. Adamson and Mrs. M. H. Vail for performing the cytotoxicity studies with cloned cells. Dr. L. Wilkoff and Dr. F. Schabel of the Chemotherapy Department of Southern Research Institute determined the cytotoxicity tests in swirl cultures, with monolayers of cells, and with mice implanted with tumor cells. Human urine was obtained from patients at M. D. Anderson Hospital, Houston, through the courtesy of Dr. James Luce. Mr. T. C. Herren and Mr. H. E. Finch assayed samples for radioactivity. The microanalytical and spectral determinations were performed by Dr. W. C. Coburn, Jr., and associates. Some of the analyses were performed by Galbraith Laboratories, Knoxville, Tenn. We are indebted to Dr. N. Brock for a recent gift of a sample of synthetic 4-ketocyclophosphamide, and to Dr. A. Takamizawa for a sample of synthetic 2-carboxyethyl N,N-bis(2-chloroethyl)phosphorodiamidate.

  • Copyright ©, 1971, by Academic Press, Inc.

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Molecular Pharmacology
Vol. 7, Issue 5
1 Sep 1971
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Research ArticleArticle

Urinary Metabolites of the Antitumor Agent Cyclophosphamide

ROBERT F. STRUCK, MARION C. KIRK, L. B. MELLETT, SALAH EL DAREER and DONALD L. HILL
Molecular Pharmacology September 1, 1971, 7 (5) 519-529;

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Research ArticleArticle

Urinary Metabolites of the Antitumor Agent Cyclophosphamide

ROBERT F. STRUCK, MARION C. KIRK, L. B. MELLETT, SALAH EL DAREER and DONALD L. HILL
Molecular Pharmacology September 1, 1971, 7 (5) 519-529;
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