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REVIEW: Exploiting Oxidative Stress and Signaling in Chemotherapy of Resistant Neoplasms

N. F. Schor1,2,3,5*, V. E. Kagan3,4, Ye Liang1,5, Ch. Yan5, Yu. Tyurina4, V. Tyurin4, and K. D. Nylander5

Departments of Pediatrics1, Neurology2, Pharmacology3, and Environmental and Occupational Toxicology4, University of Pittsburgh, Pittsburgh, USA

5Pediatric Center for Neuroscience, Children's Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA; fax: 412-692-6165; E-mail: nfschor@pitt.edu

* To whom correspondence should be addressed.

Received April 30, 2003
Neural crest tumors of childhood are particularly resistant to apoptosis induction by chemotherapeutic agents. Mechanisms of resistance include altered glutathione handling that accompanies up-regulation of Bcl-2 and its relatives. We have designed and tested in preclinical model systems approaches to this problem. These approaches include adjunctive use of oxygen radical-generating neurotransmitter analogs taken up by these neural crest tumor cells with scavenging (i.e., “rescue”) agents that are selective for normal neural crest and the use of reduction-dependent prodrugs of apoptosis-inducing agents. Promising prototypes for these conceptual approaches include, respectively, adjunctive use of the oxygen radical generator, 6-hydroxydopamine, with the normal cell-selective antioxidant, Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), and use of the reduction-dependent chemotherapeutic prodrug neocarzinostatin.
KEY WORDS: oxidative stress, chemotherapeutic agents, apoptosis, neural crest tumor cells