Exploiting Oxidative Stress and Signaling in Chemotherapy of Resistant Neoplasms |
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Authors: | N. F. Schor V. E. Kagan Ye Liang Ch. Yan Yu. Tyurina V. Tyurin K. D. Nylander |
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Affiliation: | Department of Pediatrics, University of Pittsburgh, Pittsburgh, USA. nfschor@pitt.edu |
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Abstract: | 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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Keywords: | oxidative stress chemotherapeutic agents apoptosis neural crest tumor cells |
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