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Title: Factors affecting the response to tyrosine kinase inhibitors in chronic myeloid leukaemia
Author: Francis, Sebastian
ISNI:       0000 0004 6058 1548
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2015
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Chronic myeloid leukaemia (CML) is a clonal stem cell disorder characterised by the Philadelphia chromosome. The treatment and outcomes of CML patients have improved with the introduction of tyrosine kinase inhibitors (TKI). Imatinib is associated with complete cytogenetic response (CCR) rate of 71% at 12 months, as documented by large phase 3 clinical trials. I carried out a large population study in the Merseyside, Cheshire and North Wales area, which showed a maximal CCR rate of 65% over 5 years of observation. This suggests there is a higher rate of imatinib failure in a general unselected CML population compared to large clinical studies which have strict exclusion criteria. My population study also confirmed that second generation TKIs can produce high CCR rates in imatinib intolerant/resistant patients. There are a number of mechanisms of imatinib resistance. The hOCT1 transporter has been shown to be an important predictor of response to imatinib treatment. However, it has been suggested there are other drug transporters involved in imatinib transport which may have prognostic significance. This thesis examined the role of SLCO1A2, OCTN1 and OCTN2 in the transport of TKIs. Transfected cell lines expressing high levels of the respective drug transporter were made using the AMAXA nucleofection process. The cell lines with the highest gene expression, as quantified by TaqMan PCR, were then selected and used in radioactive uptake experiments. Imatinib was confirmed to be a substrate for SLCO1A2. However, the mRNA expressions levels of SLCO1A2 did not have any prognostic correlation to outcome. A review of patient co-medication also showed inhibitors of SLCO1A2 had no effect on CCR and major molecular response (MMR) rates in imatinib treated patients. OCTN1 and OCTN2 did not transport imatinib. Nilotinib and dasatinib are not substrates for SLCO1A2, OCTN1 or OCTN2. Drug drug interactions have also been implicated in drug resistance. Imatinib and metformin are actively transported by hOCT1. It was postulated that varying concentrations of metformin could potentially affect the uptake of imatinib by competitive inhibition. A metformin concentration of 768µM was required reduce imatinib uptake by 50%. However, this concentration is much higher than therapeutic metformin levels, therefore these drugs do not interact at therapeutic concentrations. This thesis shows imatinib is an effective treatment in CML but the CCR rate is lower than in published phase 3 trials. SLCO1A2 transports imatinib but RNA levels have no prognostic significance. Imatinib and metformin do not interact at normal therapeutic concentrations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RB Pathology ; RM Therapeutics. Pharmacology