The role of integrins as a determinant of drug response and resistance

Persistent Link:
http://hdl.handle.net/10150/289110
Title:
The role of integrins as a determinant of drug response and resistance
Author:
Damiano, Jason Sinclair
Issue Date:
2000
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Drug resistance continues to be one of the major obstacles to the successful treatment of hematopoietic cancers. Historically, most of the research being done in this area has been focused on reversing mechanisms of resistance which are known to be acquired by the tumor cell in vitro. Fewer studies have attempted to determine what intrinsic mechanisms allow these cells to resist the apoptosis inducing effects of cytotoxic drugs in an in vivo setting. It is now known that a tumor cell's interactions with its microenvironment can have a major influence on whether it lives or dies. The research presented in this dissertation shows that tumor cell interactions with the extracellular matrix component fibronectin influence cell survival following cytotoxic drug exposure, a phenomenon which has been termed Cell Adhesion Mediated Drug Resistance (CAM-DR). In the 8226 myeloma cell line, p130Cas is activated by Src following fibronectin (FN) adhesion, but this signaling pathway did not have an immediate effect on drug response. Similarly, members of the MAPK family, including ERK1/2 and p38, were found to be inactivated by FN adhesion but not to play a short-term role in suppressing drug induced apoptosis. Furthermore, experiments utilizing the K562 CML cell line demonstrated that cytoprotective signaling by the integrins is independent of AKT and BCR/ABL-associated signaling. By allowing the malignant cell to avoid cytotoxic drug induced apoptosis, the integrins may play a significant role in the generation of tumors which are refractory to chemotherapy. Pharmacological agents targeted at these adhesion molecules or at downstream signaling partners have the potential to potentiate the actions of anti-tumor agents and improve clinical responses.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Health Sciences, Pharmacology.; Health Sciences, Oncology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacology and Toxicology
Degree Grantor:
University of Arizona
Advisor:
Dalton, William S.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleThe role of integrins as a determinant of drug response and resistanceen_US
dc.creatorDamiano, Jason Sinclairen_US
dc.contributor.authorDamiano, Jason Sinclairen_US
dc.date.issued2000en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractDrug resistance continues to be one of the major obstacles to the successful treatment of hematopoietic cancers. Historically, most of the research being done in this area has been focused on reversing mechanisms of resistance which are known to be acquired by the tumor cell in vitro. Fewer studies have attempted to determine what intrinsic mechanisms allow these cells to resist the apoptosis inducing effects of cytotoxic drugs in an in vivo setting. It is now known that a tumor cell's interactions with its microenvironment can have a major influence on whether it lives or dies. The research presented in this dissertation shows that tumor cell interactions with the extracellular matrix component fibronectin influence cell survival following cytotoxic drug exposure, a phenomenon which has been termed Cell Adhesion Mediated Drug Resistance (CAM-DR). In the 8226 myeloma cell line, p130Cas is activated by Src following fibronectin (FN) adhesion, but this signaling pathway did not have an immediate effect on drug response. Similarly, members of the MAPK family, including ERK1/2 and p38, were found to be inactivated by FN adhesion but not to play a short-term role in suppressing drug induced apoptosis. Furthermore, experiments utilizing the K562 CML cell line demonstrated that cytoprotective signaling by the integrins is independent of AKT and BCR/ABL-associated signaling. By allowing the malignant cell to avoid cytotoxic drug induced apoptosis, the integrins may play a significant role in the generation of tumors which are refractory to chemotherapy. Pharmacological agents targeted at these adhesion molecules or at downstream signaling partners have the potential to potentiate the actions of anti-tumor agents and improve clinical responses.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHealth Sciences, Pharmacology.en_US
dc.subjectHealth Sciences, Oncology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacology and Toxicologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorDalton, William S.en_US
dc.identifier.proquest9965899en_US
dc.identifier.bibrecord.b40482054en_US
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