In our work we have contributed to the definition of the nature and properties of cyclophosphamide metabolites and have devised quantitative techniques to measure these compounds. We have examined the cellular pharmacology of the active metabolites in murine L1210 cells, defined two mechanisms of cellular resistance in L1210 cells and helped establish the probable basis for bone marrow stem cell resistance to cyclophosphamide. We propose to continue the study of cyclophosphamide metabolites, to characterize their cellular pharmacology and to make comparative studies in human and murine tumor cells. The value of these studies lies in the definition of optimum dose scheduling of cyclophosphamide and the examination of potential modulation of cyclophosphamide therapy by other agents. We also plan to extend our work on resistance to finding and characterizing other mechanisms of resistance in human tumor. This work is essential to devising approaches to circumvent resistance and has the potential for establishing rapid biochemical techniques for detecting resistance in human tissue samples. We plan to explore the nature of DNA alterations produced by alkylating metabolites of cyclophosphamide and the biological consequence of these alterations. For these studies we will use DNA sequencing and nuclease digestion. Finally, we plan to develop new analytical techniques to study the clinical pharmacology of activated metabolites using methods which can be readily adapted to other laboratories so that pharmacologic measurements will be readily available for use in clinical studies. While the primary focus of this proposal is the study of cyclophosphamide, many of the techniques will be applicable to the study of other alkylating agents, and comparative studies will be performed as they seem appropriate.

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National Cancer Institute (NCI)
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Experimental Therapeutics Subcommittee 2 (ET)
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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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