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

N. F. Schor^1,2,3,5*, V. E. Kagan^3,4, Ye Liang^1,5, 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

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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.

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KEY WORDS: oxidative stress, chemotherapeutic agents, apoptosis, neural crest tumor cells

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