Investigation of Cytarabine Resistance: Targeting the Cell Cycle Checkpoints and Strategies for Overcoming Resistance of Acute Myeloid Leukemia to Cytarabine

Persistent Link:
http://hdl.handle.net/10150/221241
Title:
Investigation of Cytarabine Resistance: Targeting the Cell Cycle Checkpoints and Strategies for Overcoming Resistance of Acute Myeloid Leukemia to Cytarabine
Author:
Buechel, Megan
Affiliation:
The University of Arizona College of Medicine - Phoenix
Issue Date:
30-Apr-2012
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the College of Medicine - Phoenix, 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.
Collection Information:
This item is part of the College of Medicine - Phoenix Scholarly Projects 2012 collection. For more information, contact the Phoenix Biomedical Campus Library at pbc-library@email.arizona.edu.
Publisher:
The University of Arizona.
Abstract:
Patients diagnosed with Acute myeloid leukemia (AML) often become resistant to standard chemotherapeutic regimens. Cytarabine, a nucleoside analog, is the standard of care therapy for AML treatment. We hypothesized that by using an siRNA platform to inhibit 572 kinases in combination with Ara-C (cytarabine) in two AML cell lines (THP-1 and TF-1) we would be able to identify potential therapeutic targets to improve sensitivity to Ara-C (cytarabine). Our siRNA screen identified CHK1 as the most potent sensitizer to Ara-C. However, other kinases involved in DNA repair and checkpoint activation also improved sensitivity of cells to Ara-C. Checkpoints are present at the G1/S transition, within S phase and at the G2/M transition. Within the G2/M checkpoint, CHK1 functions to halt the transition to mitosis when DNA damage is detected. Additional siRNA screening of proteins that function in the G2/M checkpoint identified WEE1 as a potent sensitizer as well. It is hypothesized that abrogation of the G2/M checkpoint prevents repair pathways from repairing genotoxic damage caused by chemotherapeutics. Therefore, a literature review of the checkpoint targeting and rational therapeutic targets for future treatments was conducted. Both WEE1 and CHK1 are currently 4 being targeted in order to enhance activity of various genotoxic chemotherapeutics in many different cancers and present rational targets for further investigated in combination with Ara-C in AML.
Keywords:
Leukemia
MeSH Subjects:
Leukemia; Cytarabine; Leukemia, Myeloid, Acute
Description:
A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.
Mentor:
Tibes, Raoul, MD, PhD

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleInvestigation of Cytarabine Resistance: Targeting the Cell Cycle Checkpoints and Strategies for Overcoming Resistance of Acute Myeloid Leukemia to Cytarabineen_US
dc.contributor.authorBuechel, Meganen_US
dc.contributor.departmentThe University of Arizona College of Medicine - Phoenixen_US
dc.date.issued2012-04-30-
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the College of Medicine - Phoenix, 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.collectioninformationThis item is part of the College of Medicine - Phoenix Scholarly Projects 2012 collection. For more information, contact the Phoenix Biomedical Campus Library at pbc-library@email.arizona.edu.en_US
dc.publisherThe University of Arizona.en_US
dc.description.abstractPatients diagnosed with Acute myeloid leukemia (AML) often become resistant to standard chemotherapeutic regimens. Cytarabine, a nucleoside analog, is the standard of care therapy for AML treatment. We hypothesized that by using an siRNA platform to inhibit 572 kinases in combination with Ara-C (cytarabine) in two AML cell lines (THP-1 and TF-1) we would be able to identify potential therapeutic targets to improve sensitivity to Ara-C (cytarabine). Our siRNA screen identified CHK1 as the most potent sensitizer to Ara-C. However, other kinases involved in DNA repair and checkpoint activation also improved sensitivity of cells to Ara-C. Checkpoints are present at the G1/S transition, within S phase and at the G2/M transition. Within the G2/M checkpoint, CHK1 functions to halt the transition to mitosis when DNA damage is detected. Additional siRNA screening of proteins that function in the G2/M checkpoint identified WEE1 as a potent sensitizer as well. It is hypothesized that abrogation of the G2/M checkpoint prevents repair pathways from repairing genotoxic damage caused by chemotherapeutics. Therefore, a literature review of the checkpoint targeting and rational therapeutic targets for future treatments was conducted. Both WEE1 and CHK1 are currently 4 being targeted in order to enhance activity of various genotoxic chemotherapeutics in many different cancers and present rational targets for further investigated in combination with Ara-C in AML.en_US
dc.typeThesisen_US
dc.subjectLeukemiaen_US
dc.subject.meshLeukemiaen_US
dc.subject.meshCytarabineen_US
dc.subject.meshLeukemia, Myeloid, Acuteen_US
dc.descriptionA Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.en_US
dc.contributor.mentorTibes, Raoul, MD, PhDen_US
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