Abstract

Multinuclear Fourier-transform nuclear magnetic resonance spectroscopy will be used in conjunction with a perfusable gel matrix to study the intracellular chemistry of the cytoxan metabolites 4-hydroxy-cytoxan (4-hydroxycyclophosphamide) aldophosphamide, and phosphoramide mustard. The influence of metabolite structure and stereochemistry on the kinetics of cellular uptake, intracellular detoxification, and intracellular toxicogenation in normal versus neoplastic cells will be investigated using metabolite-analogs. These studies will probe those factors of cytoxan metabolism which are pertinent to its oncostatic selectivity. A series of novel lipophilic analogs of aldophosphamide will be synthesized and tested for their anticancer activity against brain tumors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037323-03
Application #
3175152
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1986-04-01
Project End
1990-12-31
Budget Start
1988-04-01
Budget End
1990-12-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Catholic University of America
Department
Type
Schools of Arts and Sciences
DUNS #
City
Washington
State
DC
Country
United States
Zip Code
20064

  Publications

Flowers, J L; Ludeman, S M; Gamcsik, M P et al. (2000) Evidence for a role of chloroethylaziridine in the cytotoxicity of cyclophosphamide. Cancer Chemother Pharmacol 45:335-44
Cai, Y; Wu, M H; Ludeman, S M et al. (1999) Role of O6-alkylguanine-DNA alkyltransferase in protecting against cyclophosphamide-induced toxicity and mutagenicity. Cancer Res 59:3059-63
Habib, A D; Boal, J H; Hilton, J et al. (1995) Effect of stereochemistry on the oxidative metabolism of the cyclophosphamide metabolite aldophosphamide. Biochem Pharmacol 50:429-33
Boal, J H; Ludeman, S M; Ho, C K et al. (1994) Direct detection of the intracellular formation of carboxyphosphamides using nuclear magnetic resonance spectroscopy. Arzneimittelforschung 44:84-93
Ludeman, S M; Ho, C K; Boal, J H et al. (1992) Carboxyphosphamide: NMR studies of its stability and cell membrane permeability. Drug Metab Dispos 20:337-8
Hales, B F; Ludeman, S M; Boyd, V L (1989) Embryotoxicity of phenyl ketone analogs of cyclophosphamide. Teratology 39:31-7
Boal, J H; Williamson, M; Boyd, V L et al. (1989) 31P NMR studies of the kinetics of bisalkylation by isophosphoramide mustard: comparisons with phosphoramide mustard. J Med Chem 32:1768-73
Boyd, V L; Summers, M F; Ludeman, S M et al. (1987) NMR spectroscopic studies of intermediary metabolites of cyclophosphamide. 2. Direct observation, characterization, and reactivity studies of iminocyclophosphamide and related species. J Med Chem 30:366-74