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Boiso, Samuel
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Publications (3 of 3) Show all publications
Skoglund, K., Boiso, S., Jönsson, J.-I., Vikingsson, S., Carlsson, B. & Green, H. (2014). Single-nucleotide polymorphisms of ABCG2 increase the efficacy of tyrosine kinase inhibitors in the K562 chronic myeloid leukemia cell line. Pharmacogenetics & Genomics, 24(1), 52-61
Open this publication in new window or tab >>Single-nucleotide polymorphisms of ABCG2 increase the efficacy of tyrosine kinase inhibitors in the K562 chronic myeloid leukemia cell line
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2014 (English)In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 24, no 1, p. 52-61Article in journal (Refereed) Published
Abstract [en]

ObjectiveThe tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia are substrates for the efflux transport protein ATP-binding cassette subfamily G member 2 (ABCG2). Variations in ABCG2 activity might influence pharmacokinetics and therapeutic outcome of TKIs. The role of ABCG2 single-nucleotide polymorphisms (SNPs) in TKI treatment is not clear and functional in-vitro studies are lacking. The aim of this study was to investigate the consequences of ABCG2 SNPs for transport and efficacy of TKIs [imatinib, N-desmethyl imatinib (CGP74588), dasatinib, nilotinib, and bosutinib].Materials and methodsABCG2 SNPs 34Ggreater thanA, 421Cgreater thanA, 623Tgreater thanC, 886Ggreater thanC, 1574Tgreater thanG, and 1582Ggreater thanA were constructed from ABCG2 wild-type cDNA and transduced to K562 cells by retroviral gene transfer. Variant ABCG2 expression in cell membranes was evaluated and the effects of ABCG2 SNPs on transport and efficacy of TKIs were measured as the ability of ABCG2 variants to protect against TKI cytotoxicity.ResultsWild-type ABCG2 had a protective effect against the cytotoxicity of all investigated compounds except bosutinib. It was found that ABCG2 expression provided better protection against CGP74588 than its parent compound, imatinib. ABCG2 421Cgreater thanA, 623Tgreater thanC, 886Ggreater thanC, and 1574Tgreater thanG reduced cell membrane expression of ABCG2 and the protective effect of ABCG2 against imatinib, CGP74588, dasatinib, and nilotinib cytotoxicity.ConclusionThese findings show that the ABCG2 SNPs 421Cgreater thanA, 623Tgreater thanC, 886Ggreater thanC, and 1574Tgreater thanG increase the efficacy of investigated TKIs, indicating a reduced transport function that might influence TKI pharmacokinetics in vivo. Furthermore, the active imatinib metabolite CGP74588 is influenced by ABCG2 expression to a greater extent than the parent compound.

Place, publisher, year, edition, pages
Lippincott, Williams andamp; Wilkins, 2014
Keywords
ABCG2; CGP74588; chronic myeloid leukemia; imatinib; N-desmethyl imatinib; pharmacogenetics; single-nucleotide polymorphism; tyrosine kinase inhibitor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-103285 (URN)10.1097/FPC.0000000000000022 (DOI)000328629800007 ()
Available from: 2014-01-17 Created: 2014-01-16 Last updated: 2017-12-06
Boiso, S., Zackrisson, A. L., Jakobsen Falk, I., Karlsson, L., Carlsson, B., Tillmar, A., . . . Green, H. (2013). ABCB1 gene polymorphisms are associated with suicide in forensic autopsies. Pharmacogenetics & Genomics, 23(9), 463-469
Open this publication in new window or tab >>ABCB1 gene polymorphisms are associated with suicide in forensic autopsies
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2013 (English)In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 23, no 9, p. 463-469Article in journal (Refereed) Published
Abstract [en]

Background Polymorphisms in ABCB1 have the ability to affect both the function and the expression of the transporter protein P-glycoprotein and may lead to an altered response for many drugs including some antidepressants and antipsychotics.Objective The aim of this study was to examine the impact of the ABCB1 polymorphisms 1199Gandgt;A, 1236Candgt;T, 2677Gandgt;T/A, and 3435Candgt;T in deaths by suicide.Patients and methods A total of 998 consecutive Swedish forensic autopsies performed in 2008 in individuals 18 years of age or older, where femoral blood was available and a toxicological screening had been performed, were investigated. Genotypes were assessed with pyrosequencing and information on the cause and manner of each death was obtained from the forensic pathology and toxicology databases.Results There was a significantly higher frequency of the T allele at positions 1236, 2677, and 3435 among the suicide cases compared with the nonsuicide cases.Conclusion Our result from forensic cases suggests that ABCB1 polymorphisms are associated with an increased risk for completed suicides. The biological mechanisms involved and the clinical implications for these findings are largely unknown and need to be examined further.

Place, publisher, year, edition, pages
Lippincott, Williams and Wilkins, 2013
Keywords
ABCB1, autopsy, forensic material, genotype, postmortem, sex, suicide
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-97235 (URN)10.1097/FPC.0b013e328363a9bf (DOI)000323220200002 ()
Note

Funding Agencies|National Board of Forensic Medicine in Sweden||Swedish Research Council||Swedish Cancer Society||

Available from: 2013-09-06 Created: 2013-09-05 Last updated: 2017-12-06
Skoglund, K., Moreno, S. B., Baytar, M., Jönsson, J.-I. & Gréen, H. (2013). ABCB1 haplotypes do not influence transport or efficacy of tyrosine kinase inhibitors in vitro. Pharmacogenomics and Personalized Medicine, 6, 63-72
Open this publication in new window or tab >>ABCB1 haplotypes do not influence transport or efficacy of tyrosine kinase inhibitors in vitro
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2013 (English)In: Pharmacogenomics and Personalized Medicine, ISSN 1178-7066, Vol. 6, p. 63-72Article in journal (Refereed) Published
Abstract [en]

Single-nucleotide polymorphisms (SNPs) in the gene coding for the efflux-transport protein ABCB1 (P-glycoprotein) are commonly inherited as haplotypes. ABCB1 SNPs and haplotypes have been suggested to influence the pharmacokinetics and therapeutic outcome of the tyrosine kinase inhibitor (TKI) imatinib, used for treatment of chronic myeloid leukemia (CML). However, no consensus has yet been reached with respect to the significance of variant ABCB1 in CML treatment. Functional studies of variant ABCB1 transport of imatinib as well as other TKIs might aid the interpretation of results from in vivo association studies, but are currently lacking. The aim of this study was to investigate the consequences of ABCB1 variant haplotypes for transport and efficacy of TKIs (imatinib, its major metabolite N-desmethyl imatinib [CGP74588], dasatinib, nilotinib, and bosutinib) in CML cells. Variant haplotypes - including the 61A>G, 1199G>A, 1236C>T, 1795G>A, 2677G>T/A, and 3435T>C SNPs - were constructed in ABCB1 complementary DNA and transduced to K562 cells using retroviral gene transfer. The ability of variant cells to express ABCB1 protein and protect against TKI cytotoxicity was investigated. It was found that dasatinib and the imatinib metabolite CGP74588 are effectively transported by ABCB1, while imatinib, nilotinib, and bosutinib are comparatively weaker ABCB1 substrates. None of the investigated haplotypes altered the protective effect of ABCB1 expression against TKI cytotoxicity. These findings imply that the ABCB1 haplotypes investigated here are not likely to influence TKI pharmacokinetics or therapeutic efficacy in vivo.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-97421 (URN)10.2147/PGPM.S45522 (DOI)24019750 (PubMedID)
Available from: 2013-09-12 Created: 2013-09-12 Last updated: 2017-12-06Bibliographically approved
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