Susan M. Ludeman, Ph.D.
Ph.D. in Organic Chemistry, The Catholic University of America, Washington, D.C.
Courses Taught at ACPHS
Organic Chemistry I
Methods in Spectroscopy
Research in my lab is based on the application of synthetic and physical organic chemistry to studies of drug design, metabolism and delivery. Projects and interests include the following:
- Alkylating Agents as Anticancer Drugs. My lab group has a long history of investigating the chemistry as well as biochemical and clinical pharmacology of alkylating agents, in particular cyclophosphamide (CP) and its structural isomer, ifosfamide (IF). CP was first introduced into clinical usage in the 1950's and remains one of the most widely used alkylating agents. CP and IF are prodrugs that must be oxidized by hepatic P450, thereby leading to metabolites which cross-link DNA. Competing with this activation are secondary oxidations that produce metabolites with dose-limiting neurotoxicity and possible connections to therapy-induced leukemia.
One focus of our current research is a determination of the mechanisms that influence the repair of the DNA alkylations and crosslinks induced by metabolites of CP and IF. This work is in collaboration with Dr. Paul Miller, Professor, School of Public Health, The Johns Hopkins Medical Institutions. Other efforts address our hypothesis that genetic variants are responsible for the human variation in the extent of CP and IF pharmacokinetics. An understanding of the genotype(s) responsible for the extent and path of metabolism could have significant implications for the use of these agents. Identifications could be made, before treatment, of patients for whom the normal dose of CP or IF would be inadequate or toxic. Related to this project is our study of ‘metabolic switching,’ i.e., use of kintic isotope effects to favor one metabolic pathway over another. These latter projects are in collaboration with Dr. M. Eileen Dolan, Professor and Director of the Pharmacokinetics and Pharmacogenomics Laboratory, School of Medicine, University of Chicago.
- Improved Drug Delivery. The effects of aging and neurodegenerative diseases such as Alzheimer's and Parkinson's have been shown to be linked to lowered concentrations of antioxidants, especially glutathione, in the brain. Due to its poor uptake by the brain, direct administration of glutathione is not an effective treatment for neurodegeneration. The hypothesis of this work is that precursors (prodrugs) of glutathione which are more readily transported across the blood brain barrier could be used to elevate brain glutathione levels. Furthermore, the use of 13C-labeled prodrugs, in conjunction with magnetic resonance imaging (MRI), could provide a non-invasive method for monitoring in vivo uptake, distribution and conversion to glutathione. This work is being done in collaboration with Dr. Michael Gamcsik, Professor in Biomedical Engineering, joint appointment in the Department of Biomedical Engineering, NC State University and the University of North Carolina at Chapel Hill. The specific aim of my contribution to this work is the synthesis of 13C-labeled prodrugs of glutathione.
- Neuroblastoma and Pheochromocytoma. Neuroblastoma is the most common, extra-cranial, solid tumor found in childhood. Of the children who present with high risk metastatic disease, approximately 50% suffer relapse after treatment and those with high risk Stage 3 or 4 tumors have 5-year survival rates of just 25-30%. Radioiodinated meta-iodobenzylguanidine (MIBG) is an in vivo imaging agent developed for use in detecting NB. The preferential uptake of MIBG by NB is a result of active transport by the norepinephrine transporter (NET), a protein which is expressed in 85-90% of primary and metastatic NB tumors. The main focus of this project is to investigate targeted drug delivery to NB cells by exploiting the selective NET affinity of MIBG. Preliminary work already has identified a promising MIBG analog which not only demonstrates NET-dependant uptake but also depletes the intracellular, chemoprotectant glutathione. The analog significantly enhances the cytotoxicity of melphalan, a glutathione-sensitive, front-line chemotherapeutic against neuroblastoma.
Pheochromocytoma (PHEO) is another neuroendocrine tumor; while relatively rare, the incidence of PHEO is reportedly on the rise, perhaps due to improvements in detection. Like neuroblastoma, PHEO is characterized by high expression of the norepinephrine transporter (NET) and highly efficient (up to 95%) uptake of MIBG by both primary and metatstatic tumors. As with NB, a decrease, in vitro, of cellular and mitochondrial glutathione levels in PHEO cells is linked to a loss of mitochondrial function and cell viability. Our design of building upon MIBG selectivity and targeting cellular resistance mechanisms provides a novel treatment possibility for PHEO.
Boyd, V.L.; Robbins, J.D.; Egan, W.; Ludeman, S.M. "31P Nuclear Magnetic Resonance Spectroscopic Observation of the Intracellular Transformations of Oncostatic Cyclophosphamide Metabolites." J. Med. Chem. 1986 29, 1206-1210.
Habib, A.D.; Boal, J.A.; Hilton, J.; Nguyen, T.; Chang, Y.H.; Ludeman, S.M. "The Effect of Stereochemistry on the Oxidative Metabolism of the Cyclophosphamide Metabolite Aldophosphamide." Biochem. Pharmacol. 1995, 50, 429-433.
Springer, J.B.; Colvin, M.E.; Colvin, O.M.; Ludeman, S.M. “Isophosphoramide Mustard and Its Mechanism of Bisalkylation.” J. Org. Chem. 1998, 63, 7218-7222.
Ludeman, S.M. “From Chemical Warfare Agent to Anticancer Drug: The Chemistry of Phosphoramide Mustard.” In Biomedical Chemistry/Applying Chemical Principles to the Understanding and Treatment of Disease, Torrence, P.F. (ed.), John Wiley & Sons, Inc., NY, 2000, pp 163-187.
Ludeman, S.M.; Gamcsik, M.P. “Mechanisms of Resistance Against Cyclophosphamide and Ifosfamide: Can They Be Overcome Without Sacrificing Selectivity?” In Clinically Relevant Resistance to Anticancer Agents (Cancer Treatment and Research) Andersson, B.S. and Murray, D. (eds.), Kluwer Publishers, Inc., Norwell, MA, 2002, pp 177-197. [Cancer Treat. Res. 2002, 112, 177-197]
Hansen, R.J.; Ludeman, S.M.; Pegg, A.E.; Dolan, M.E. “Role of MGMT in Protecting against Cyclophosphamide and Ifosfamide.” DNA Repair 2007, 6, 1145-1154.
Pinto N, Ludeman SM, Dolan ME. Pharmacogenetic Studies Related to Cyclophosphamide-Based Therapy. Pharmacogenomics 2009, 10(12), 1897-1903.
Gamcsik, M.P.; Clark, M.D.; Ludeman, S.M.; Springer, J.B.; D'Alessandro, M.A.: Simpson, N.E.; Pourdeyhimi, R.; Johnson, C.B.; Teeter, S.D.; Blackband, S.J.; Thelwall, P.E. “Non-invasive Monitoring of L-2-Oxothiazolidine-4-carboxylate Metabolism in the Rat Brain by In vivo 13C Magnetic Resonance Spectroscopy.” Neurochem. Res. 2011, 36, 443-451.
Amoyaw, P.N.A.; Springer, J.B.; Gamcsik, M.P.; Mutesi, R.L.; D’Alessandro, M.A.; Dempsey, C.R.; Ludeman, S.M. “Synthesis of 13C-Labelled Derivatives of Cysteine for Magnetic Resonance Imaging Studies of Drug Uptake and Conversion to Glutathione in Rat Brain.” J. Label. Compd. Radiopharm. 2011, 54, 607-612.