Leslie L. Muldoon

Ph.D., University of Chicago, 1986

Assistant Professor, Department of Neurology

Joint Assistant Professor, Cell and Developmental Biology

Treatment of tumors or diseases affecting the central nervous system is impeded by the blood-brain barrier of the cerebral vascular endothelial cells, which blocks penetration of therapeutic agents from the blood to the brain. Preclinical studies in my laboratory are aimed at circumventing the blood-brain barrier to improve CNS therapy approaches in animal models. One of our projects is gene therapy in a feline model of a neurodegenerative lysosomal storage disorder (GM2-gangliosidosis, Sandhoff disease) which results from a defect in the HEXB gene. Global delivery of a viral vector expressing the normal HEXB or other therapeutic genes may decrease apoptosis of affected neurons or glial cells. Other projects are aimed at brain tumor therapy. For example, increasing delivery of toxic genes to tumor cells in the brain may improve gene therapy efficacy in a rat model of brain metastasis. Enhancing chemotherapy delivery can also increase toxic side effects, and we are investigating approaches to protect against hearing loss and bone marrow toxicity. Cell biology studies in my laboratory are directed toward increasing tumor cell cytotoxicity while protecting normal cells. Mechanisms to enhance chemotherapy toxicity include targeting drug delivery with tumor-specific antibodies, reducing levels of the endogenous free radical scavenger glutathione or blocking drug efflux via the multidrug resistance pathways. Raising antioxidant levels in normal cells with thiol agents may protect against chemotherapy toxicity and apoptosis.

?Muldoon LL, Walker-Rosenfeld SL, Hale C, Purcell SE, Bennett LC, Neuwelt EA. Rescue from enhanced alkylator-induced cell death with low molecular weight sulfur-containing chemoprotectants. J Pharmacol Exper Therapeutics 296/3:797-805, 2001.

?Muldoon LL, Pagel MA, Kroll RA, Brummet RE, Doolittle ND, Zuhowski EG, Egorin MJ, Neuwelt EA. Delayed administration of sodium thiosulfate in animal models reduces platinum ototoxicity without reduction of antitumor activity. Clin Can Res, 6:309-315, 2000.

?Muldoon, L.L., Kroll, R.A., Pagel, M.A., Roman-Goldstein, S., and Neuwelt, E.A. (1998) Delivery of Therapeutic Genes to Brain and Intracerebral Tumors. In: Gene Transfer and Therapy for Neurological Disorders. (EA Chiocca and XO Breakefield eds.) Humana Press. Totowa, New Jersey, pp. 295-312.

 To contact Dr. Muldoon directly: muldoonl@ohsu.edu