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Influence of variant ABCG2 on tyrosine kinase inhibitor transport and efficacy in the K562 chronic myeloid leukemia cell line
Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.ORCID-id: 0000-0001-5765-2964
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Objective: The tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia are substrates for the efflux transport protein 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). Methods: ABCG2 SNPs 34G>A, 421C>A, 623T>C, 886G>C, 1574T>G and 1582G>A were constructed from ABCG2 wild type cDNA and transduced to K562 cells by retroviral gene transfer. The ability of variant cells to express ABCG2 in the cell membrane and protect against TKI cytotoxicity was investigated. Results: Wild type ABCG2 had a protective effect against the cytotoxicity of all investigated compounds except bosutinib. It was found that ABCG2 expression provided a better protection against CGP74588 than its parent compound, imatinib. ABCG2 421C>A, 623T>C, 886G>C and 1574T>G reduced cell membrane expression of ABCG2 and the protective effect of ABCG2 against imatinib, CGP74588, dasatinib and nilotinib cytotoxicity. The most prominent effect was found for the 623T>C SNP which resulted in undetectable ABCG2 expression and low protection against TKI cytotoxicity. Conclusion: These findings show that the ABCG2 SNPs 421C>A, 623T>C, 886G>C and 1574T>G impair ABCG2 transport function and might influence TKI pharmacokinetics in vivo. Furthermore, the active imatinib metabolite CGP74588 is to a greater extent than the parent compound transported by ABCG2.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:liu:diva-97423OAI: oai:DiVA.org:liu-97423DiVA, id: diva2:647701
Tillgänglig från: 2013-09-12 Skapad: 2013-09-12 Senast uppdaterad: 2014-04-22Bibliografiskt granskad
Ingår i avhandling
1. Influence of CYP3A enzymes and ABC transporters on the activity of tyrosine kinase inhibitors in chronic myeloid leukemia
Öppna denna publikation i ny flik eller fönster >>Influence of CYP3A enzymes and ABC transporters on the activity of tyrosine kinase inhibitors in chronic myeloid leukemia
2013 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The introduction of imatinib, a tyrosine kinase inhibitor (TKI), in the treatment of chronic myeloid leukemia (CML) was a major break-through and the first drug that was successfully designed to target the specific mechanism of a malignant disease. Imatinib still remains as the standard treatment of newly diagnosed CML patients although a second generation of TKIs has also been approved for first-line CML treatment.

Most patients achieve a good therapeutic effect with imatinib, but some patients are resistant to the drug and are at greater risk of disease progression. In order to further improve CML treatment, a better understanding of the underlying reasons for variable responses to imatinib and the second generation TKIs is important.

A number of potential determinants of imatinib response have been suggested, including interindividual variability in pharmacokinetics. Variations in drug metabolism and cellular transport might contribute to the large variations observed in imatinib plasma concentrations and might, therefore, affect the amount of drug that reaches target CML cells. Imatinib is primarily metabolized by the CYP3A hepatic enzymes that are known to be highly variable in activity between different individuals. Imatinib is also a substrate of the ABCB1 and ABCG2 efflux pumps that potentially regulate the elimination of imatinib from the plasma. The ABCB1 and ABCG2 genes are polymorphic and contain single nucleotide polymorphisms (SNPs) that might influence the transport capacity of these proteins. The primary aim of the present thesis was to investigate the influence of CYP3A metabolic activity and cellular transport mediated by genetic variants of ABCB1 and ABCG2 on the response to imatinib and the second generation TKIs used for CML therapy.

In vivo CYP3A activity and plasma concentrations of imatinib and its pharmacologically active metabolite CGP74588 were analyzed in CML patients treated with imatinib. CYP3A phenotypes were correlated to plasma concentrations and imatinib outcome 12 months after initiation of treatment. The influence of ABC transport on TKI efficacy was evaluated in vitro by the transduction of genetic variants of ABCB1 and ABCG2 into the CML cell line K562. Functionality of the transport proteins was evaluated by measuring protein expression levels on the cell surface, the intracellular accumulation of TKIs, and the ability of ABCB1 and ABCG2 variants to protect cells from TKI cytotoxicity.

We found that CYP3A metabolic activity does not influence the drug plasma concentrations or the therapeutic outcome of imatinib in CML patients. These findings indicate that even though imatinib is primarily metabolized by CYP3A this metabolic activity is not the rate-limiting step in imatinib elimination. CYP3A activity, therefore, is not a suitable predictive marker of imatinib outcome. The in vitro studies revealed that the ABCB1 variants investigated here do not alter the transport of imatinib, CGP74588, dasatinib, or nilotinib. In contrast, the ABCG2 SNPs 421C>A, 623T>C, 886G>C, and 1574T>G significantly impaired the cellular efflux of imatinib, CGP74588, dasatinib, and nilotinib and could possibly influence transport of these TKIs in vivo. It was also found that CGP74588 is by far a better substrate than imatinib for both ABCB1 and ABCG2, and this might have implications in patients with high levels of CYP3A activity. In conclusion, our studies show that ABCG2 SNPs might be important for prediction of imatinib outcome in vivo. On the other hand, CYP3A activity and the ABCB1 SNPs investigated in this study are not likely to be useful as predictors of imatinib outcome.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2013. s. 77
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1370
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-97427 (URN)978-91-7519-576-6 (ISBN)
Disputation
2013-10-25, Nils-Holgersalen, Campus US, Linköpings universitet, Linköping, 09:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2013-09-12 Skapad: 2013-09-12 Senast uppdaterad: 2019-12-08Bibliografiskt granskad

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Skoglund, KarinMoreno, Samuel BoisoJönsson, Jan-IngvarVikingsson, SvanteCarlsson, BjörnGréen, Henrik

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Avdelningen för läkemedelsforskningHälsouniversitetetAvdelningen för radiologiska vetenskaperCentrum för medicinsk bildvetenskap och visualisering, CMIVAvdelningen för mikrobiologi och molekylär medicinKlinisk farmakologi
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