ABCB1 p.Glu255Val
| Predicted by SNAP2: | A: D (80%), C: D (80%), D: D (53%), F: D (85%), G: D (85%), H: D (85%), I: D (85%), K: D (91%), L: D (85%), M: D (85%), N: D (80%), P: D (91%), Q: D (75%), R: D (91%), S: D (85%), T: D (85%), V: D (85%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: D, C: D, D: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: N, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Influence of CYP3A5 and drug transporter polymorph... J Hum Genet. 2010 Nov;55(11):731-7. Epub 2010 Aug 19. Takahashi N, Miura M, Scott SA, Kagaya H, Kameoka Y, Tagawa H, Saitoh H, Fujishima N, Yoshioka T, Hirokawa M, Sawada K
Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia.
J Hum Genet. 2010 Nov;55(11):731-7. Epub 2010 Aug 19., [PMID:20720558]
Abstract [show]
Imatinib mesylate (IM) trough concentration varies among IM-treated chronic myeloid leukemia (CML) patients. Although IM pharmacokinetics is influenced by several enzymes and transporters, little is known about the role of pharmacogenetic variation in IM metabolism. In this study, associations between IM trough concentration, clinical response and 11 single-nucleotide polymorphisms in genes involved in IM pharmacokinetics (ABCB1, ABCC2, ABCG2 CYP3A5, SLC22A1 and SLCO1B3) were investigated among 67 Japanese chronic phase CML patients. IM trough concentration was significantly higher in patients with a major molecular response than in those without one (P=0.010). No significant correlations between IM trough concentration and age, weight, body mass index or biochemical data were observed. However, the dose-adjusted IM trough concentration was significantly higher in patients with ABCG2 421A than in those with 421C/C (P=0.015). By multivariate regression analysis, only ABCG2 421A was independently predictive of a higher dose-adjusted IM trough concentration (P=0.015). Moreover, previous studies have shown that the ABCG2 421C>A (p.Q141K) variant is prevalent among Japanese and Han Chinese individuals and less common among Africans and Caucasians. Together, these data indicate that plasma IM concentration monitoring and prospective ABCG2 421C>A genotyping may improve the efficacy of IM therapy, particularly among Asian CML patients.
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24 In patients without a CCyR, mutation analysis of the bcr-abl fusion transcript was performed using the Invader assay,31 which detects 25 mutations, including M244V, L248VR, G250E, Q252H, Q252R, Y253F, Y253H, E255K, E255V, E279K, F311L, T315A, T315I, F317L, M351T, F359IV, V379I, L387M, H396P, H396R, S417Y, E459K and F486S.
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ABCB1 p.Glu255Val 20720558:24:215
status: NEW[hide] Can P-glycoprotein mediate resistance to nilotinib... Pharmacol Res. 2013 Jan;67(1):79-83. doi: 10.1016/j.phrs.2012.10.012. Epub 2012 Oct 26. Kosztyu P, Dolezel P, Mlejnek P
Can P-glycoprotein mediate resistance to nilotinib in human leukaemia cells?
Pharmacol Res. 2013 Jan;67(1):79-83. doi: 10.1016/j.phrs.2012.10.012. Epub 2012 Oct 26., [PMID:23103446]
Abstract [show]
The effect of P-glycoprotein (P-gp, ABCB1, MDR1) expression on cell resistance to nilotinib was studied in human leukaemia cells. We used K562/Dox cells overexpressing P-gp and their variants (subclones) with a gradually decreased P-gp expression. These subclones were established by stable transfection of K562/Dox cells with a plasmid vector expressing shRNA targeting the ABCB1 gene. Functional analysis of P-gp using a specific fluorescent probe indicated gradually decreased dye efflux which was proportional to the P-gp expression. We observed that K562/Dox cells overexpressing P-gp contained a significantly reduced intracellular level of nilotinib when compared to their counter partner K562 cells, which do not express P-gp. This effect was accompanied by a decreased sensitivity of the K562/Dox cells to nilotinib. Importantly, cells with downregulated expression of P-gp gradually lost their ability to decrease the intracellular level of nilotinib although they still significantly decreased the intracellular level of daunorubicin (DNR). Accordingly, cells with the reduced expression of P-gp concomitantly failed to provide resistance to nilotinib, however, they exhibited a significant resistance to DNR. Taken together, we demonstrated that the conclusion as to whether P-gp is involved in nilotinib resistance or not strongly depends on its expression at protein level.
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14 Preclinical studies indicated that nilotinib is effective against several Bcr-Abl mutant forms that are found in patients with a diagnosis of Ph+ CML such as E255V, M351T, Q252H/R, Y253F, F317L, and E355G.
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ABCB1 p.Glu255Val 23103446:14:158
status: NEW[hide] SLC22A1-ABCB1 haplotype profiles predict imatinib ... PLoS One. 2012;7(12):e51771. doi: 10.1371/journal.pone.0051771. Epub 2012 Dec 18. Singh O, Chan JY, Lin K, Heng CC, Chowbay B
SLC22A1-ABCB1 haplotype profiles predict imatinib pharmacokinetics in Asian patients with chronic myeloid leukemia.
PLoS One. 2012;7(12):e51771. doi: 10.1371/journal.pone.0051771. Epub 2012 Dec 18., [PMID:23272163]
Abstract [show]
OBJECTIVE: This study aimed to explore the influence of SLC22A1, PXR, ABCG2, ABCB1 and CYP3A5 3 genetic polymorphisms on imatinib mesylate (IM) pharmacokinetics in Asian patients with chronic myeloid leukemia (CML). PATIENTS AND METHODS: Healthy subjects belonging to three Asian populations (Chinese, Malay, Indian; n = 70 each) and CML patients (n = 38) were enrolled in a prospective pharmacogenetics study. Imatinib trough (C(0h)) and clearance (CL) were determined in the patients at steady state. Haplowalk method was applied to infer the haplotypes and generalized linear model (GLM) to estimate haplotypic effects on IM pharmacokinetics. Association of haplotype copy numbers with IM pharmacokinetics was defined by Mann-Whitney U test. RESULTS: Global haplotype score statistics revealed a SLC22A1 sub-haplotypic region encompassing three polymorphisms (rs3798168, rs628031 and IVS7+850C>T), to be significantly associated with IM clearance (p = 0.013). Haplotype-specific GLM estimated that the haplotypes AGT and CGC were both associated with 22% decrease in clearance compared to CAC [CL (10(-2) L/hr/mg): CAC vs AGT: 4.03 vs 3.16, p = 0.017; CAC vs CGC: 4.03 vs 3.15, p = 0.017]. Patients harboring 2 copies of AGT or CGC haplotypes had 33.4% lower clearance and 50% higher C(0h) than patients carrying 0 or 1 copy [CL (10(-2) L/hr/mg): 2.19 vs 3.29, p = 0.026; C(0h) (10(-6) 1/ml): 4.76 vs 3.17, p = 0.013, respectively]. Further subgroup analysis revealed SLC22A1 and ABCB1 haplotypic combinations to be significantly associated with clearance and C(0h) (p = 0.002 and 0.009, respectively). CONCLUSION: This exploratory study suggests that SLC22A1-ABCB1 haplotypes may influence IM pharmacokinetics in Asian CML patients.
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116 Upon further analysis, non-synonymous mutations were detected in the BCR-ABL kinase domain in these two patients - a double mutation at loci G250E and E255V in the former patient and a single mutation at Y253H in the latter patient.
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ABCB1 p.Glu255Val 23272163:116:151
status: NEW