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Mechanisms of chemotherapeutic resistance in glioma
Descriptive
TypeOfResource
Text
TitleInfo
(ID = T-1)
Title
Mechanisms of chemotherapeutic resistance in glioma
SubTitle
mathematical modeling and gene expression profiling
Identifier
ETD_2583
Identifier
(type = hdl)
http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000053568
Language
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eng
Genre
(authority = marcgt)
theses
Subject
(ID = SBJ-1);
(authority = RUETD)
Topic
Biomedical Engineering
Subject
(ID = SBJ-2);
(authority = ETD-LCSH)
Topic
Gliomas--Chemotherapy
Subject
(ID = SBJ-3);
(authority = ETD-LCSH)
Topic
Drugs--Side effects
Subject
(ID = SBJ-4);
(authority = ETD-LCSH)
Topic
Gene expression
Abstract
(type = abstract)
Gliomas 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.
PhysicalDescription
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electronic resource
Extent
ix, 129 p. : ill.
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application/pdf
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Note
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Ph.D.
Note
Includes abstract
Note
Vita
Note
(type = bibliography)
Includes bibliographical references
Note
(type = statement of responsibility)
by Salaheldin S. Hamed
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Hamed
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Salaheldin
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author
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Salaheldin Hamed
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Roth
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Charles M
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chair
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Advisory Committee
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Charles M Roth
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(type = family)
Shreiber
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(type = given)
David I
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internal member
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Advisory Committee
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David I Shreiber
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NamePart
(type = family)
Cai
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(type = given)
Li
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internal member
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Advisory Committee
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Li Cai
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NamePart
(type = family)
Banerjee
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(type = given)
Debabrata
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outside member
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Advisory Committee
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Debabrata Banerjee
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NamePart
Rutgers University
Role
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degree grantor
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Graduate School - New Brunswick
Role
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school
OriginInfo
DateCreated
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2010
DateOther
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2010
Place
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xx
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TitleInfo
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Rutgers University Electronic Theses and Dissertations
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ETD
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Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
(type = local)
rucore19991600001
Identifier
(type = doi)
doi:10.7282/T3M61K96
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
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The author owns the copyright to this work.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
RightsHolder
(ID = PRH-1);
(type = personal)
Name
FamilyName
Hamed
GivenName
Salaheldin
Role
Copyright Holder
RightsEvent
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Type
Permission or license
DateTime
2010-04-13 14:33:17
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Name
Salaheldin Hamed
Affiliation
Rutgers University. Graduate School - New Brunswick
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Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
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Type
Embargo
DateTime
2010-05-31
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 30th, 2012.
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ETD
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application/pdf
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application/x-tar
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8069120
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