Novel drug combinations for the eradication of Ph+/BCR-ABL+ haemopoietic stem cells in chronic myeloid leukaemia

Copland, Mhairi (2007) Novel drug combinations for the eradication of Ph+/BCR-ABL+ haemopoietic stem cells in chronic myeloid leukaemia. PhD thesis, University of Glasgow.

Abstract

INTRODUCTION: Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder of the haemopoietic stem cell (HSC). It results from acquisition of the Philadelphia (Ph) chromosome and expression of the oncogenic fusion protein BCR-ABL. Imatinib mesylate (IM) is a tyrosine kinase inhibitor (TKI) which competitively inhibits ATP binding to BCR-ABL, resulting in inhibition of downstream signal transduction pathways. Despite inducing a complete cytogenetic response in the majority of CML patients in chronic phase (CP), nearly all patients treated with IM have detectable disease at the molecular level by quantitative RT-PCR and, therefore, are unlikely to be cured. It has been demonstrated that this molecular persistence results from a population of quiescent CML stem cells which are not effectively targeted by IM. In addition, a minority of CML patients harbour BCR-ABL kinase domain mutations, rendering them IM-resistant. We set out to investigate different therapeutic strategies for targeting the quiescent CML stem cell population in vitro. These strategies were treating with continuous or interrupted IM in combination with recombinant human granulocyte-colony stimulating factor (rHu-G-CSF), comparing the efficacy of IM with the novel, dual SRC/BCR-ABL TKI, dasatinib, and combining either IM or dasatinib with the cytotoxic farnesyltransferase inhibitor (FTI), BMS-214662.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Pharmacology, Oncology
• Subjects: Q Science > QR Microbiology
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: Holyoake, Prof. Tessa
• Date of Award: 2007
• Depositing User: Enlighten Team
• Unique ID: glathesis:2007-70962
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 08 May 2019 09:21
• Last Modified: 21 May 2021 13:38
• URI: https://theses.gla.ac.uk/id/eprint/70962