Susan R. Doctrow, Ph.D.

Faculty and Fellows

doctrowSusan R. Doctrow, Ph.D.
Research Associate Professor

College/Undergraduate Education: University of Rochester, B.A. Biology, 1978

Graduate School PhD Program: Brandeis University, Ph.D. Biochemistry, 1985
Thesis:  Identification of possible adenosine receptors in vascular smooth muscle (lab of Dr. John M. Lowenstein)

Post-doctoral Fellowships/ Other Training: Postdoctoral fellowship, Children’s Hospital Boston (lab of Dr. Judah Folkman) 1984 – 87; American Cancer Society fellowship (1984-86)

Special Interests

RESEARCH:

  • Development and evaluation of synthetic “mito-protective” superoxide dismutase/catalase (SOD/cat) mimetics.
  • SOD/cat mimetics as potential mitigators of radiation injury and combined injury, for example, in a radiological terrorism scenario.
  • Broader interest in the role of oxidative stress in neurodegenerative and other pathological processes, using SOD/cat mimetics as biologically active “probes”.

Over a number of years, beginning at the small biotechnology company Eukarion, we have developed and studied synthetic “mito-protective” superoxide dismutase/catalase (SOD/cat) mimetics as potential therapeutic agents for pathologies in which reactive oxygen species (ROS) and reactive nitrogen species (RNS) are implicated.  We focus on two classes of compounds:  (1) Salen manganese complexes that catalytically scavenge ROS and RNS and protect tissues in many experimental models for injury, disease, and degeneration.  Examples of these compounds include the “classic” mimetics EUK-8 and EUK-134, the more lipophilic analog EUK-189, and the more biologically-stable cyclic analog EUK-207.  All are active in vivo when administered by injection and infusion and, in some cases, topically. (2) Low molecular weight porphyrin manganese complexes, for example EUK-451, with oral bioavailability and anti-apoptotic activity.

Recently, we’ve had a particular interest in SOD/cat mimetics as potential mitigators of non-hematological radiation injury.  Our lab conducts this work as part of a BioShield funded, NIAID administered multi-institution “Center for Medical Countermeasures Against Radiation (CMCR)”.  Our CMCR studies novel agents for their ability to mitigate delayed injury to kidney, lung, CNS, and GI system in scenarios relevant to radiological terrorism.  Delayed injury to these organ systems is expected to occur weeks, months or years after radiation exposure in survivors of the initial exposure.  Such tissue damage is hypothesized to result from chronic oxidative stress through such mechanisms as “proinflammatory” cascades and/or mitochondrial dysfunction.  Mitigating effects of SOD/cat mimetics support this hypothesis, and our ongoing research is aimed at elucidating this further.  With Dr. John Moulder’s laboratory (Medical College of WI, MCW), we’ve found that EUK-207, initiated weeks after radiation, mitigates chronic renal injury induced by total body irradiation in rats.  Other collaborating CMCR laboratories observe substantial radiation mitigating effects of EUK-207 in the lung and brain.  More complex scenarios involve “combined injury”, for example radiation and trauma.  With collaborators in the labs of Dr Zela Lazarova (MCW) and Dr. Moulder, we’ve found that systemic EUK-207 given 48 hrs after radiation, improves both skin inflammation and wound healing, including angiogenesis, in a rat combined injury (radiation/wounding) model.  Such data suggest that SOD/cat mimetics mitigate injury, at least in part, at the level of the microvascular endothelial cell.  To further support this concept, we’ve found with Dr. Susan Braunhut’s laboratory (UMass Lowell) that both our classes of SOD/cat mimetics, given after radiation, decrease apoptosis in capillary endothelial cell cultures.

More broadly, we have had a longstanding interest in the role of oxidative stress in neurodegenerative and other disease models, based on the effectiveness, including “structure-activity relationships”, of SOD/cat mimetics.  One key target for these compounds is the mitochondrion, an organelle whose dysfunction is strongly implicated in certain neurodegenerative and other chronic disorders.  Mice lacking the mitochondrial form of SOD (sod2-/- mice) suffer severe, lethal pathologies due to mitochondrial oxidative injury.  With Dr. Simon Melov’s laboratory (Buck Institute), we’ve found that salen Mn complexes, especially the more lipophilic EUK-189, protect the brain and peripheral organs, extending lifespan about 3-fold.  Of all agents, synthetic and natural products, that have been tested so far, EUK-189 continues to be the most “mito-protective” agent in this model.  Another likely mechanism of intervention by these SOD/cat mimetics is through suppression of ROS-associated transcriptional pathways.  For example, they suppress activation of NF kappa B and AP-1 while protecting tissues such as the brain and liver in certain in vivo injury models.  Such effects have implications not only in disease and injury, but also in age-associated degeneration.  Several years ago, work with Dr. Gordon Lithgow’s lab (Buck Institute) showed that EUK-8 and EUK-134 increased lifespan of c elegans, wild type as well as a strain with a mitochondrial dysfunction (mev-1).  More recently, studies with Dr. Michel Baudry’s lab (USC) showed that in aged mice, chronically infused EUK-189 or EUK-207 improved cognitive function in behavioral models, while suppressing numerous biochemical indicators of oxidative stress in the brain.  We continue to explore, with our key collaborators, how modulation of mitochondrial function and certain ROS- and RNS-dependent signaling pathways can mediate the effects of SOD/cat mimetics in complex models for injury, aging, and disease.  Microvascular endothelial cells and neurons are particular target cells of interest.

Selected Publications:

  1. Rosenthal, R.A., Huffman, K., Fisette, L., Damphousse, C.A., Callaway, W., Malfroy, B., and Doctrow, S.R. Orally available Mn porphyrins with superoxide dismutase and catalase activities.  Journal of Biological Inorganic Chemistry (online July, 2009).
  2. Vorotnikova, E., Rosenthal, R.A., Tries, M., Doctrow, S.R., and Braunhut, S.J.  Novel synthetic SOD/catalase mimetics can mitigate capillary endothelial cell apoptosis caused by ionizing radiation. (manuscript submitted).
  3. Brazier, M.W., Doctrow, S.R., Masters, C.L., and Collins, S.J.  A manganese superoxide dismutase/catalase mimetic extends survival in a mouse model of human prion disease.  2008.  Free Radicals in Biology and Medicine 45:185-192
  4. Clausen, A., Doctrow, S.R. and Baudry, M. Prevention of cognitive deficits and brain oxidative stress with superoxide dismutase/catalase mimetics in aged mice. 2008.  Neurobiology of Aging, (online June, 2008)
  5. Srinivasan, V., Doctrow, S., Singh, V.K., and Whitnall, M.H.  EUK-189, a Synthetic Superoxide Dismutase/Catalase Mimetic, Enhances Survival in Mice Exposed to Gamma radiation.  2008. Immunopharmacology and Immunotoxicology 30: 271-290.
  6. Peng J., Peng L., Stevenson F.F., Doctrow S.R., Andersen J.K. Iron and paraquat as synergistic environmental risk factors in sporadic Parkinson’s disease accelerate age-related neurodegeneration. 2007.  Journal of Neuroscience 27: 6914-22.
  7. Doctrow, S.R. (corresponding), Baudry, M., Huffman, K., Malfroy, B., and Melov, S.  Salen-manganese complexes:  multifunctional catalytic antioxidants protective in models for neurodegenerative diseases of aging in Medicinal Inorganic Chemistry (J. Sessler, S. R. Doctrow, T. McMurry, and S. Lippard, eds)  American Chemical Society Symposium Series 903, ACS and Oxford University Press, 2005, pp. 319-347.
  8. Peng, J., Stevenson, F.F., Doctrow, S.R. and Andersen, J.K.  Superoxide dismutase/catalase mimetics are neuroprotective against selective paraquat-mediated dopaminergic neuron death in the substantia nigra.  Implications for Parkinson Disease.  2005.  Journal of Biological Chemistry, 280: 29194-98.
  9. Melov, S. Wolf, N., Strozyk, D., Doctrow, S.R. and Bush, A.I..  Mice transgenic for Alzheimer’s disease beta-amyloid develop lens cataracts that are rescued by antioxidant treatment. 2005. Free Radicals in Biology and Medicine 38: 258-61.
  10. Zhang , H.J., Doctrow, S.R., Xu, L., Oberley, L.W., Beecher, B., Morrison, J., Oberley, T.D., and Kregel, K.C. Redox modulation of the liver with chronic antioxidant enzyme  mimetic treatment prevents age-related oxidative damage  associated with environmental stress. 2004.  FASEB Journal 18: 1547-49.
  11. Friedman, J.S., Lopez, M.F., Fleming, M.D., Rivera, A., Martin, F., Welsh, M., Boyd, A., Doctrow, S.R., and Burakoff, S. SOD2  Deficiency  Anemia:    Protein  oxidation  and  altered  protein  expression reveal targets of damage, stress response and anti-oxidant  responsiveness. 2004.  Blood, 104:2565-73.
  12. Browne, S.E., Roberts, L.J. II, Dennery, P.A., Doctrow, S.R., Beal, M.F., Barlow, C., and Levine, R.L.  Treatment with a catalytic antioxidant corrects the neurobehavioral defect in ataxia-telangiectasia mice.  2004.  Free Radicals in Biology and Medicine  36: 938-42
  13. Hinerfeld, D., Train, M.D., Weinberger, R.P., Cochran, B., Doctrow, S.R., Harry, J., and Melov, S.  Endogenous mitochondrial oxidative stress – neurodegeneration, proteomic analysis, specific respiratory chain defects, and efficacious antioxidant therapy in superoxide dismutase 2 null mice. 2004.   Journal of  Neurochemistry  88:657-67
  14. Liu, R., Liu, I.Y., Bi, X., Thompson, R.F., Doctrow, S.R. Malfroy, B., and Baudry, M.  Reversal of age-related learning deficits and brain oxidative stress in mice with superoxide dismutase/catalase mimetics.  2003.  Proceedings of the National Academy of Sciences (USA) 100:8526-31
  15. Doctrow, S.R. (corresponding), Huffman, K., Marcus, C.B., Tocco, G., Malfroy, E., Adinolfi, C.A., Kruk, H., Baker, K., Lazarowych, N., Mascarenhas, J., and Malfroy, B.  Salen manganese complexes as catalytic scavengers of hydrogen peroxide and cytoprotective agents:  structure-activity relationship studies. 2002.  Journal of Medicinal Chemistry 45: 4549-4558.
  16. Melov, S., Doctrow, S.R., Schneider, J.A., Haberson, J., Patel, M., Coskun, P.E., Huffman, K. Wallace, D.C., and Malfroy, B. Lifespan extension and rescue of neurodegeneration in superoxide dismutase 2 nullizygous mice treated with superoxide dismutase/catalase mimetics.  2001.  Journal of Neuroscience 21:  8348-8353.
  17. Jung, C., Rong, Y., Doctrow, S., Baudry, M., Malfroy, B., and Xu, Z. Synthetic superoxide dismutase/catalase mimetics reduce oxidative stress and prolong survival in a mouse amyotrophic lateral sclerosis model.  2001.  Neuroscience Letters 304: 157-160.
  18. Pong, K., Doctrow, S.R., Huffman, K., Adinolfi, C.A., and Baudry, M.  Attenuation of staurosporine-induced apoptosis, oxidative stress, and mitochondrial dysfunction by EUK-134, a superoxide dismutase and catalase mimetic, in cultured cortical neurons. 2001.  Experimental Neurology 171:84-97.
  19. Melov, S., Ravenscroft, J., Malik, S., Gill, M.S., Walker, D.W., Clayton, P.E., Wallace, D.C., Malfroy, B., Doctrow, S.R., and Lithgow, G.  Extension of Caenorhabditis elegans lifespan with synthetic superoxide dismutase/catalase mimetics. 2000. Science 289:1567-1569.
  20. Rong, Y., Doctrow, S.R., Tocco, G., and Baudry, M.  EUK-134, a synthetic superoxide dismutase and catalase mimetic, prevents oxidative stress and attenuates kainate-induced neuropathology.  1999.  Proceedings of the National Academy of Sciences (USA)  96:9897-9902.
  21. Baker, K., Bucay Marcus, C., Huffman, K., Kruk, H., Malfroy, B., and Doctrow, S.R. Synthetic combined superoxide dismutase/catalase mimics are protective as a delayed treatment in a rat stroke model:  a key role for reactive oxygen species in ischemic brain injury.  1998.  Journal of Pharmacology and Experimental Therapeutics 284:215-221.
  22. Gonzalez, P.K., Zhuang, J., Doctrow, S.R., Malfroy, B., Benson, P.F., Menconi, M.J., and Fink, M.P.  EUK-8, a synthetic superoxide dismutase and catalase mimetic, ameliorates acute lung injury in endotoxemic swine.  1995.  Journal of Pharmacology and Experimental Therapeutics  275: 798-806

Recent pertinent meeting abstracts:

  • Doctrow, S.R., Fish, B., Huffman, K., Rosenthal, R., and Moulder, J. Synthetic SOD/catalase mimetics to mitigate radiation-induced kidney injury.  Abstract and poster presentation at Radiation Research Society 54th annual meeting, September, 2008, Boston, MA.
  • Rosenthal, RA, Vorotnikova, E, Huffman, KD, Tries, M, Fisette, LW, Damphousse, CA, Callaway, WB, Malfroy, B, Braunhut, SJ, and Doctrow,  SR.   Salen Mn complexes and orally available Mn porphyrin compounds are SOD/catalase mimetics which protect cultured cells from oxidative stress  and radiation injury.  Abstract and poster presentation at Radiation Research Society 54th annual meeting: September, 2008, Boston, MA.
  • SOD/Catalase Mimetics to Mitigate Delayed Radiation Injury, (invited speaker/abstract, Susan R. Doctrow) symposium entitled Novel Mitigators Against Radiation-Induced Normal Tissue Damage, 55th Annual Meeting of the Radiation Research Society, Savannah, GA., October, 2009

Selected Reprints:

Primary teaching affiliate
of BU School of Medicine