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Mechanisms of chemotherapeutic resistance in glioma
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Hamed, Salaheldin. Mechanisms of chemotherapeutic resistance in glioma. Retrieved from https://doi.org/doi:10.7282/T3M61K96

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TitleMechanisms of chemotherapeutic resistance in glioma
NameHamed, Salaheldin (author); Roth, Charles M (chair); Shreiber, David I (internal member); Cai, Li (internal member); Banerjee, Debabrata (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2010
Other Date2010 (degree)
SubjectBiomedical Engineering, Gliomas--Chemotherapy, Drugs--Side effects, Gene expression
Extentix, 129 p. : ill.
DescriptionGliomas are refractory to chemotherapy because of acquired resistance, which is associated with changes in important cellular processes, such as cell cycle kinetics and cell death. The mechanistic relationship between resistance markers and failure of chemotherapy remains to be elucidated. To that end, identification of biological systems and their interactions is of great promise. We characterized the pharmacological response of glioma cell lines to chemotherapeutic drugs, carmustine and etoposide. We developed a cell cycle structured mathematical model that reproduces the dynamics of dose response of cells to the two chemotherapeutic agents based on two parameters relating to cell cycle arrest and cell death. We have shown that the model can provide a quantitative distinction between the influence of these two processes on tumor cells simply from pharmacological dose response curves, from which mechanism is not obtained using traditional analyses. The model suggests that carmustine elicits its effect via cell death, while etoposide primarily induces cell cycle arrest. We have also applied this methodology to track acquisition resistance to chemotherapy. We have generated a panel of glioma cell lines resistant to carmustine by incremental stepwise exposure to sublethal doses of the drug. To characterize molecular events underlying response of resistant and parent cell lines to carmustine, we performed gene expression profiling using micaroarrays followed by functional network analysis. We found that NFκB activation is implicated in the response to carmustine, and resistant cells exhibit increased survival mediated by inflammatory responses. In addition, resistant cells induce genes promoting cell cycle arrest and repress genes implicated in cell cycle phase transitions and proliferation. In agreement with gene expression results, we found that resistant cells exhibit decreased cell death and rapid and efficient arrest. We have characterized the DNA repair capacity, which is known to modulate cell cycle arrest and apoptosis. Our results provide insights into molecular pathways involved in resistance to carmustine in vitro. If they prove to hold for gliomas in human patients, these results can point the way towards improved therapeutic regimens that act upon NFκB mediated cell survival module in concert with cell cycle checkpoint abrogators.
NotePh.D.
NoteIncludes abstract
NoteVita
NoteIncludes bibliographical references
Noteby Salaheldin S. Hamed
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3M61K96
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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