In this application we propose to continue our studies of the chemistry and pharmacology of cyclophosphamide and ifosfamide. The studies proposed focus on two critical aspects of the pharmacology of these agents, the definitive characterization of the DNA interstrand crosslinks produced by phosphoramide mustard and isophosphoramide mustard and the elucidation of the chemical and enzymatic determinants of the two P450 oxidations which determine the activation and inactivation of cyclophosphamide and ifosfamide. Our studies have demonstrated significant differences in the chemistry of phosphoramide mustard and isophophoramide mustard and in the interstrand crosslinks which will be produced by these molecules and their decomposition products. We have also recently discovered that acrolein produced from 4-hydroxycyclophosphamide gives O[6]-guanylate alkylation, probable crosslinking of DNA, and selects for resistance to BCNU by increased O[6]-alkyltransferase. We will explore the mechanisms of these reactions and determine if chloroacetaldehyde will produce similar effects. The repair of the demonstrated DNA crosslinks will be studied in our separately funded collaboration with Dr. Henry Friedman. We will also continue our studies of the P450 activation and dechlorethylation of cyclophosphamide and ifosfamide - determining the relative ratio of these reactions for different P450 enzymes, measuring deuterium isotope effects, defining the mechanism of the reactions, and examining the pharmacokinetic and antitumor properties of ifosfamide after altering the metabolism of ifosfamide by isotope and alkyl substitution induced kinetic switching of dechlorethylation to activation. We believe the results of these studies will have important implications for improving the clinical effectiveness of these important and unique antitumor agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA016783-26S1
Application #
6412326
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Rosenfeld, Bobby
Project Start
1977-09-30
Project End
2005-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
26
Fiscal Year
2001
Total Cost
$18,462
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Springer, James B; Colvin, O Michael; Ludeman, Susan M (2014) Labeled oxazaphosphorines for applications in mass spectrometry studies. 2. Synthesis of deuterium-labeled 2-dechloroethylcyclophosphamides and 2- and 3-dechloroethylifosfamides. J Labelled Comp Radiopharm 57:110-4
Pinto, N; Gamazon, E R; Antao, N et al. (2014) Integrating cell-based and clinical genome-wide studies to identify genetic variants contributing to treatment failure in neuroblastoma patients. Clin Pharmacol Ther 95:644-52
Gamcsik, Michael P; Clark, M Daniel; Ludeman, Susan M et al. (2011) Non-invasive monitoring of L-2-oxothiazolidine-4-carboxylate metabolism in the rat brain by in vivo 13C magnetic resonance spectroscopy. Neurochem Res 36:443-51
Hlavin, Erica M; Smeaton, Michael B; Noronha, Anne M et al. (2010) Cross-link structure affects replication-independent DNA interstrand cross-link repair in mammalian cells. Biochemistry 49:3977-88
Pinto, Navin; Ludeman, Susan M; Dolan, M Eileen (2009) Drug focus: Pharmacogenetic studies related to cyclophosphamide-based therapy. Pharmacogenomics 10:1897-903
Emmenegger, Urban; Shaked, Yuval; Man, Shan et al. (2007) Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice. Mol Cancer Ther 6:2280-9
Spasojevic, Ivan; Colvin, O Michael; Warshany, Keith R et al. (2006) New approach to the activation of anti-cancer pro-drugs by metalloporphyrin-based cytochrome P450 mimics in all-aqueous biologically relevant system. J Inorg Biochem 100:1897-902
Springer, James B; Chang, Young H; Koo, Kyo I et al. (2004) 1,3- vs 1,5-intramolecular alkylation reactions in isophosphoramide and phosphoramide mustards. Chem Res Toxicol 17:1217-26
Smith, Sonali M; Ludeman, Susan M; Wilson, Lynette R et al. (2003) Selective enhancement of ifosfamide-induced toxicity in Chinese hamster ovary cells. Cancer Chemother Pharmacol 52:291-302
Ludeman, Susan M; Gamcsik, Michael P (2002) Mechanisms of resistance against cyclophosphamide and ifosfamide: can they be overcome without sacrificing selectivity? Cancer Treat Res 112:177-97

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