Resistance to chemotherapy severely limits the success of treatment for cancer. It has been increasingly recognized that many cancers are globally resistant to chemotherapeutic agents because of their overexpression of Bcl-2 or related antiapoptotic proteins. In the past three years, funded by our present R01, we have begun to develop a chemotherapeutic approach that takes advantage of the enhanced capacity for glutathione turnover seen in cells that overexpress Bcl-2. Using chemotherapeutic agents that require reductive activation by glutathione, we have demonstrated potentiation, rather than abrogation of apoptosis in cancer cells that overexpress Bcl-2. Our recent studies suggest that potentiation by Bcl-2 of apoptosis induced by reduction-dependent chemotherapeutic agents is not universal, but rather, requires both that Bcl-2 alter glutathione turnover and the cells express caspase 3. The present proposal is aimed at determining the mechanistic relationship between Bcl-2-mediated enhancement of glutathione turnover and cleavage of Bcl-2 by caspase 3. In addition, it is aimed at the development of a panel of predictive tests to identify those Bcl-2-overexpressing tumors that will demonstrate potentiation of apoptosis in response to reduction-dependent chemotherapeutic agent treatment. Ultimately, this predictive panel will help to identify those patients whose chemoresistant tumors are likely to be particularly sensitive to enediyne treatment. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA074289-05A2
Application #
6617253
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
1998-05-01
Project End
2007-04-30
Budget Start
2003-05-06
Budget End
2004-04-30
Support Year
5
Fiscal Year
2003
Total Cost
$271,952
Indirect Cost
Name
Children's Hosp Pittsburgh/Upmc Health Sys
Department
Type
DUNS #
044304145
City
Pittsburgh
State
PA
Country
United States
Zip Code
15224
Schor, Nina F (2018) A Life at the Interface: The 2017 Hower Award Lecture. Pediatr Neurol 80:3-7
Ratner, Nancy; Brodeur, Garrett M; Dale, Russell C et al. (2016) The ""neuro"" of neuroblastoma: Neuroblastoma as a neurodevelopmental disorder. Ann Neurol 80:13-23
Hansen, Jeanne N; Lotta Jr, Louis T; Eberhardt, Allison et al. (2016) EYA1 expression and subcellular localization in neuroblastoma and its association with prognostic markers. J Cancer Res Ther (Manch) 4:11-18
Ganeshan, Veena R; Schor, Nina F (2014) p75 neurotrophin receptor and fenretinide-induced signaling in neuroblastoma. Cancer Chemother Pharmacol 73:271-9
Schor, Nina F (2013) Why our patients (and we) need basic science research. Neurology 80:2070-5
Ganeshan, Veena; Ashton, John; Schor, Nina F (2013) p75NTR: an enhancer of fenretinide toxicity in neuroblastoma. Cancer Chemother Pharmacol 71:777-87
Rogers, Danny A; Schor, Nina F (2013) Kidins220/ARMS is expressed in neuroblastoma tumors and stabilizes neurotrophic signaling in a human neuroblastoma cell line. Pediatr Res 74:517-24
Schor, Nina F (2013) Aiming at neuroblastoma and hitting other worthy targets. J Child Neurol 28:768-73
Ganeshan, Veena R; Schor, Nina F (2011) Pharmacologic management of high-risk neuroblastoma in children. Paediatr Drugs 13:245-55
Ingraham, Christopher A; Schor, Nina F (2009) Necdin and TrkA contribute to modulation by p75NTR of resistance to oxidant stress. Exp Cell Res 315:3532-42

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