Chronic myelogenous leukaemia (CML) is a malignant clonal disorder that results in
the uncontrolled production of white blood cells. This disease is a result of a
reciprocal translocation of the long arms of chromosome 9 and 22 resulting in a
shortened chromosome 22, harbouring the BCR-ABL fusion gene, known as the
Philadelphia chromosome. The BCR-ABL oncogene encodes for a constitutively
activated tyrosine kinase that interferes with normal cell differentiation and apoptosis.
CML can be effectively treated with tyrosine kinase inhibitors, such as imatinib
mesylate (GleevecĂ). However, some CML patients experience adverse drugs
reactions (ADRs) to imatinib and cannot be treated at the recommended dose. There
is a concern that lowering the dose of imatinib to reduce the side effects can result in
the development of resistant cancer cells, and thus a cessation in treatment is rather
recommended. Imatinib is metabolized by the cytochrome P450 enzyme, CYP3A4.
However, if the ADRs were a result of decreased metabolic effect of CYP3A4, it
would be possible to reduce the dose of imatinib without effecting efficacy.
It is hypothesised that single nucleotide polymorphisms (SNPs) can alter the catalytic
activity of the CYP3A4 enzyme. Thus a decrease in metabolic rate can result in
ADRs due an increased exposure to the drug. Therefore, the aim of this study was to
determine whether SNPs in the CYP3A4 gene are associated with ADRs from
imatinib treatment. In this study, the DNA sequence of the CYP3A4 gene from 25
CML patients treated with imatinib were compared to a reference DNA sequence
obtained from Genbank. The SNPs identified during this study was statistically
analysed, and their association with the presence of ADRs was determined using the
online statistics package, SNPator.
A total of six SNPs were detected, I193I, T15871G, CYP3A4*1G, C23187T, I369V
and G73239A. Of these, I369V and G73239A are novel and not described previously
in literature. It was found that I369V resulted in an amino acid change, involving a
substitution of isoleucine with valine. The remaining SNPs identified in this study
were located in intron regions, with the exception of I193I which is a synonymous
SNP. There is little information available on the frequency of SNPs located in introns, since
these SNPs are generally regarded to have no impact on the expression or activity of
a protein. However, in this study an SNP located in intron 10 was significantly
associated with the presence ADRs. Current hypothesises suggest that intron SNPs
could affect the expression levels of a protein by influencing the splicing efficiency of
mRNA and subsequently translation efficacy. Future research needs to elaborate on
the role of CYP3A4*1G on CYP3A4 expression as well as on the prevalence of other
alleles identified in this study in South African populations.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ufs/oai:etd.uovs.ac.za:etd-02152010-151334 |
| Date | 15 February 2010 |
| Creators | Lamprecht, G A |
| Contributors | Prof CD Viljoen |
| Publisher | University of the Free State |
| Source Sets | South African National ETD Portal |
| Language | en-uk |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.uovs.ac.za//theses/available/etd-02152010-151334/restricted/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University Free State or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.0025 seconds