Table 1 - uploaded by Dennis Kim
Content may be subject to copyright.
Source publication
Background
This study explored the impact of genetic polymorphisms in cytochrome P450 (CYP) enzymes and transporters on the plasma trough concentration of imatinib mesylate (IM) and clinical response in chronic myeloid leukemia (CML).Patients and methodsIn total, 82 patients with CML who had been administered 400 mg IM daily for over 6 months were...
Context in source publication
Similar publications
A number of theories have been postulated to describe the etiology of Chronic Myeloid Leukemia (CML), such as genetic alterations and alterations in cytokine production. A combination of inflammatory cytokines has an important role in cancer development. The aim of this hospital based case-control study was to screen for variations located in promo...
Objective. The tyrosine kinase inhibitors have markedly changed the disease course for patients with Ph+ and/or BCR-ABL1
+ chronic myeloid leukemia (CML). This study was embarked upon to assess the long-term effects of imatinib therapy on survival in adult Nigerian patients with CML. Methods. All adult patients on imatinib (400–600 mg) seen from Ju...
Chronic myeloid leukemia (CML) accounts for approximately 15% of adult leukemias. Forty percent of patients with CML are asymptomatic, in whom the disease is detected solely based on laboratory abnormalities. Since the introduction of tyrosine kinase inhibitor therapy in 2001, CML has become a chronic disease for the majority of patients. Primary c...
The use of BCR-ABL1 tyrosine kinase inhibitors (TKI) has led to excellent clinical responses in patients with chronic phase chronic myeloid leukemia (CML). However these inhibitors have been less effective as single agents in the terminal blast phase (BP). We show that pyrvinium, a FDA-approved anthelminthic drug, selectively targets BP-CML CD34+ p...
Imatinib Mesylate, also known as Gleevec or ST1-571, is a tyrosine-kinase inhibitor used as the gold standard medication for the
chronic myeloid leukemia (CML); Imatinib has indeed deeply revolutionized the CML therapy allowing most patients to have a
good quality of life. Despite its beneficial effects, Imatinib has significant side effects such a...
Citations
... Our findings correlate with the results of different studies on various ethnic populations investigating this problem. For instance, recent investigations of CYP3A5*3 and dose-adjusted imatinib trough concentrations 20,21 in different Asian populations did not reveal a significant correlation between the genotypes and the imatinib plasma trough concentrations and clinical response frequencies. Similar studies of the association between the polymorphism and the imatinib trough plasma levels also demonstrated an absence of the correlation 22,23 . ...
Background & objectives:
Imatinib mesylate (IM) is a reliable first line treatment for chronic myeloid leukaemia (CML). Nevertheless, despite promising results, a considerable proportion of patients develop resistance to the drug. Cytochrome P450 (CYP) enzymes play a crucial role in IM metabolism. Thus, point mutations in CYP genes may modify IM enzyme activity resulting in insufficient treatment response. This investigation was aimed to identify the functional impact of CYP3A5*3, CYP3A4*18 and CYP2B6*6 polymorphisms on the IM response in patients with CML in Azerbaijan.
Methods:
Genotyping of CYP3A5*3, CYP3A4*18 and CYP2B6*6 was performed in 153 patients (102 IM non-responders and 51 IM responders) with CML by the PCR-restriction fragment length polymorphism (RFLP) assays. The odds ratios (ORs) with 95 per cent confidence intervals (CIs) were applied to assess the association between allelic variants and IM therapy outcome. The results were validated by sequencing.
Results:
The frequency of the CYP3A4*18 allele was considerably lower in the responder's group (97.1 vs. 100%; P=0.036). For CYP3A5*3, the allelic frequency was slightly higher among the IM responders (100 vs. 99.02%) with no significant difference. Although patients heterozygous (TC) for CYP2B6*6 demonstrated a higher risk of acquiring resistance (OR 1.04; 95% CI: 0.492-2.218), differences were not significant (P=0.909). In addition, the homozygous genotype (TT) demonstrated a lower risk of unresponsiveness (OR 0.72; 95% CI: 0.283-1.836), but associations were not significant (P=0.491).
Interpretation & conclusions:
Our results demonstrated that CYP3A4*18 was significantly associated with IM treatment response in patients with CML in Azerbaijan, whereas rather common CYP3A5*3 was identified to have no such association.
... After screening the titles and abstracts of articles, 47 studies were excluded because they were deemed repetitive or unqualified. After reading 28 potentially eligible papers, six studies from the literature met our inclusion criteria [14][15][16][17][18][19]. The study by Rajamani et al. did not report imatinib plasma Ctrough for individual genotypes, but the authors provided the data on our request [14]. ...
... Association between ABCB1 c.3435C>T, c.2677G>T, and c.1236C>T and Imatinib C trough Levels A summary of random-effect models for the association between ABCB1 c.3435C>T, c.2677G>T, c.1236C>T, and imatinib C trough levels is reported in Table 5. Seven studies including 649 patients administered with imatinib 400 mg per day were available for the association between ABCB1 c.3435C>T and imatinib plasma C trough levels [14][15][16][17][18][19], according to recessive (CC + CT vs. TT), dominant (CC vs. CT + TT), or additive (CC vs. CT vs. TT) models. The meta-analysis revealed no difference in imatinib plasma C trough among different ABCB1 c.3435C>T genotypes according to any model (Table 5 and Figure 2). ...
... The same trend was maintained when considering the dominant model, where homozygous carriers of the ABCB1 c.2677 G allele showed lower imatinib C trough when compared to the T/A allele carriers (C trough , 1078.5 ng/mL vs. 1475.9 ng/mL, p = 0.06) ( Five studies involving 467 patients were available for the association between ABCB1 c.1236C>T and imatinib plasma Ctrough [14,16,18,19], according to recessive (CC + CT vs. TT), dominant (CC vs. CT + TT), or additive (CC vs. CT vs. TT) models. The meta-analysis did not highlight any difference in imatinib plasma Ctrough among ABCB1 c.1236C>T genotypes according to any genetic model (Table 5 and Figure 4). ...
Adequate imatinib plasma levels are necessary to guarantee an efficacious and safe treatment in gastrointestinal stromal tumor (GIST) and chronic myeloid leukemia (CML) patients. Imatinib is a substrate of the drug transporters ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) that can affect its plasma concentration. In the present study, the association between three genetic polymorphisms in ABCB1 (rs1045642, rs2032582, rs1128503) and one in ABCG2 (rs2231142) and the imatinib plasma trough concentration (Ctrough) was investigated in 33 GIST patients enrolled in a prospective clinical trial. The results of the study were meta-analyzed with those of other seven studies (including a total of 649 patients) selected from the literature through a systematic review process. The ABCG2 c.421C>A genotype demonstrated, in our cohort of patients, a borderline association with imatinib plasma trough levels that became significant in the meta-analysis. Specifically, homozygous carriers of the ABCG2 c.421 A allele showed higher imatinib plasma Ctrough with respect to the CC/CA carriers (Ctrough, 1463.2 ng/mL AA, vs. 1196.6 ng/mL CC + AC, p = 0.04) in 293 patients eligible for the evaluation of this polymorphism in the meta-analysis. The results remained significant under the additive model. No significant association could be described between ABCB1 polymorphisms and imatinib Ctrough, neither in our cohort nor in the meta-analysis. In conclusion, our results and the available literature studies sustain an association between ABCG2 c.421C>A and imatinib plasma Ctrough in GIST and CML patients.
... However, the different studies published until now show contradictory results [56]. Most of them did not find a statistically significant correlation [57][58][59][60][61] and therefore no OCT-1 genetic variant has been identified as influencing the efficacy of imatinib, which is why its clinical applicability is not possible due to the limited evidence [56]. The conception that OCT-1 is the principal uptake transporter for imatinib comes from in vitro studies which showed that some agents known to inhibit OCT-1 also inhibited imatinib uptake into leukemic cells. ...
Most malignant hematological diseases are generally a consequence of acquired mutations or rearrangements in cell replication processes. Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease that results from acquired genetic and epigenetic alterations in hematopoietic progenitor cells. Despite the advances made in understanding the pathogenesis of this disease, the overall survival of patients remains very low due to the high relapse rate. Pharmacogenetics and massive sequencing studies have allowed the identification of new recurrent mutations with significant prognostic impact in AML; furthermore, it seems likely that whole genome sequencing will soon become a standard diagnostic test, which will allow the molecular diagnosis of patients. Therefore, it is necessary to develop molecular targets that open new therapeutic perspectives and allow individualized treatment of patients with this aggressive disease. Chronic myeloid leukemia (CML) is the first neoplastic disease for which a characteristic genetic alteration was described. It has, by definition, a genetic marker, the BCR::ABL1 rearrangement, as a consequence of the t9;22(q34;q11) translocation. Its study is essential for the diagnosis of this entity and also for monitoring the response to treatment. Drugs known as tyrosine kinase inhibitors (TKIs) that target the BCR::ABL1 protein (oral targeted therapy) are the conventional treatment of CML, representing a change of paradigm in the management of oncohematological patients.
... Seong et al. analyzed the impact of SNPs in cytochrome P450 enzymes and drug transporters on the imatinib concentration in plasma and clinical response in CML patients. They concluded that rs2231142 (421C>A) situated in ABCG2 is highly associated with MMR achieved by CML patients (24). In contrast, Takahashi et al. showed that homozygotes AA in the same SNP had a higher imatinib concentration than CC (25). ...
Introduction
Functional single-nucleotide polymorphisms (SNPs) in genes regulating cellular uptake, elimination, and metabolism of xenobiotics may potentially influence the outcome of chronic myeloid leukemia (CML) patients treated with BCR-ABL1 tyrosine kinase inhibitors (TKI). Dasatinib, a second-generation TKI, is a substrate of the ABC-superfamily xenobiotic transporters ABCB1 (MDR1, Pg-P) and ABCG2 (BCRP). Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are involved in the control of expression of ABCB1 and ABCG2.
Aim of the study
In this study, we assessed the impact of inherited variants in ABCB1, ABCG2, PXR, and CAR genes on dasatinib efficacy and toxicity in CML.
Materials and methods
Sixty-one tagging SNPs in ABCB1, ABCG2, PXR, and CAR genes were analyzed by real-time quantitative PCR with specific probes in 86 CML patients who failed imatinib therapy.
Results
We found the associations between SNPs rs7787082 (ABCB1, OR = 0.2; 95% CI = 0.06-0.66, p = 0.008), rs12505410 (ABCG2, OR = 3.82; 95% CI = 1.38-10.55; p = 0.010), and rs3114018 (ABCG2, OR = 0.24; 95% CI = 0.08-0.71; p = 0.010) and the probability of achieving CCyR. Furthermore, progression-free survival (PFS) was significantly influenced by SNPs rs3732357 (HR = 0.2, 95% CI = 0.26-0.70; p = 0.001), rs3732360 (HR = 0.59; 95% CI = 0.38-0.93; p = 0.020), rs11917714 (HR = 0.58; 95% CI = 0.36-0.92; p = 0.020), and rs3732359 (HR = 0.57; 95% CI = 0.36-0.91; p = 0.024) in PXR; rs2307418 (HR = 2.02; 95% CI = 1.19-3.43; p = 0.048) in CAR; and rs2235023 (HR = 2.49; 95% CI = 1.13-5.50; p = 0.011) and rs22114102 (HR = 1.90; 95% CI = 1.00-3.63; p = 0.028) in ABCB1. Moreover, overall survival (OS) was impacted by rs3842 (HR = 1.84; 95% CI = 1.01-3.33; p = 0.012) and rs2235023 (HR = 2.28; 95% CI = 1.03 = 5.02; p = 0.027) in ABCB1, rs11265571 (HR = 1.59; 95% CI = 0.82-3.08; p = 0.037) and rs2307418 (HR = 73.68; 95% CI = 4.47-1215.31; p = 0.003) in CAR, and rs3732360 (HR = 0.64; 95% CI = 0.40 = 1.04; p = 0.049) in PXR. Taking into account the influence of the tested SNPs on treatment toxicity, we found a significant relationship between allele G of polymorphism in the ABCB1 rs7787082 (OR = 4.46; 95% CI = 1.38-14.39 p = 0.012) and hematological complications assuming the codominant gene inheritance model as well as a significant correlation between the presence of minor allele (G) of SNP rs2725256 in the ABCG2 gene (OR = 4.71; 95% CI = 1.20-18.47; p = 0.026) and the occurrence of non-hematological complications assuming a recessive gene inheritance model.
Conclusion
Our data suggest that inherited variants in the genes encoding for proteins involved in the transport of xenobiotics may modify the toxicity and efficacy of dasatinib therapy in CML patients.
... The meta-analysis by Zheng et al. showed that the 2677G or 3435T allele predicted a worse response to imatinib in CML patients, whereas the 1236CC genotype was associated with better response in CML patients from Asian regions [88]. Although ABCB2 has also been suggested to alter imatinib kinetics [165], this has not been adequately clinically proven [166,167]. It should be noted that all the above observations were from studies conducted in adult patients. ...
Pediatric cancer treatment has evolved significantly in recent decades. The implementation of risk stratification strategies and the selection of evidence-based chemotherapy combinations have improved survival outcomes. However, there is large interindividual variability in terms of chemotherapy-related toxicities and, sometimes, the response among this population. This variability is partly attributed to the functional variability of drug-metabolizing enzymes (DME) and drug transporters (DTS) involved in the process of absorption, distribution, metabolism and excretion (ADME). The DTS, being ubiquitous, affects drug disposition across membranes and has relevance in determining chemotherapy response in pediatric cancer patients. Among the factors affecting DTS function, ontogeny or maturation is important in the pediatric population. In this narrative review, we describe the role of drug uptake/efflux transporters in defining pediatric chemotherapy-treatment-related toxicities and responses. Developmental differences in DTS and the consequent implications are also briefly discussed for the most commonly used chemotherapeutic drugs in the pediatric population.
... As has been reported recently, CYP3A4*18 is associated with response to Imatinib (IM) therapy in chronic myeloid leukemia (CML) patients in the Azerbaijani population, while CYP3A5*3 has no relationship with the response to IM (Asadov et al., 2019). In contrast with results in the Azerbaijani population, studies in various ethnic populations demonstrated no statistically significant correlation between CYP3A4*18 and IM response (Gota et al., 2012, Seong et al., 2013, Maddin et al., 2016. However, these results are considered preliminary, and the clinical significance of these SNPs in the Azerbaijani population remains to be further investigated in larger cohorts. ...
The aim of this study was to identify the frequency of both CYP3A4*18 and CYP3A5*3 polymorphisms in the Azerbaijani population.
We identified CYP3A4*18 and CYP3A5*3 allelic and genotype frequencies in 100 Azerbaijani individuals by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The results were confirmed by next-generation and Sanger sequencing.
In conclusion, this small-scale study suggests that 95% of Azerbaijani individuals with CYP3A5*3/*3 genotype might fail to express CYP3A5 protein. Therefore, our results highlight the importance of genotyping of CYP3A5*3 and CYP3A4*18 as well as demonstrate a demand for further investigations to evaluate their clinical relevance using a larger sample size.
... Further, the risk for adverse drug reactions cannot be overlooked while using second generation TKIs as first line treatment of CML in adults. The interest of many researchers has developed to find out any association of drug resistance and lack of response to TKI in the presence of germline polymorphisms in drug-metabolizing enzymes (DMEs) genes [3] and significant associations of favorable TKI therapeutic outcome (particularly of Imatinib) and polymorphic defects in GST and CYP has been documented [7,8]. These polymorphisms may regulate drug uptake, metabolic activation and elimination. ...
Background
Cytochrome P450 (CYP) and glutathione S transferases (GSTs) are important biotransforming enzymes responsible for detoxification of anticancer drugs and carcinogens. Polymorphisms in these enzymes may greatly influence the susceptibility to CML and overall efficacy of tyrosine kinase inhibitors. This study was aimed to estimate the possible influence of the polymorphisms of GSTs and CYP in the occurrence of CML as well as in predicting therapeutic outcome of nilotinib therapy in Pakistani CML patients.
Methods
The polymorphic variability in CYP 1A1*2C, GSTP1 (A3131G), GSTT1 and GSTM1 was assessed either by RFLP or multiplex PCR. The BCR ABL1 transcripts were quantified by qPCR to monitor response to nilotinib.
Results
The CYP1A1*2C heterozygous and GSTP1 homozygous polymorphisms seemed to be a contributing factor in developing CML. Altogether, there were 12 non-responders, 66 responders and 21 partial responders. The most frequent genotype was null GSTM1 in responders followed by CYP 1A1 and GSTP1 -wild type ( p = < 0.05). Whereas, homozygous GSTP1 and GSTT1 null genotype is significantly higher only among nilotinib non-responders.
Conclusion
Hence, it can be concluded that wild type CYP1A1, GSTP1 and null GSTM1 may be frequently linked to favorable outcome in patients treated with nilotinib as depicted by sustained deep molecular response in most CML patients.
... These results suggest that ABCG2 c.421C>A is a moderate factor in the modulation of imatinib pharmacokinetics. Although previous studies showed similar results regarding the effect of ABCG2 c.421C>A on the imatinib pharmacokinetics (Breedveld et al., 2005), some studies showed a significant difference in imatinib pharmacokinetics only in the dominant model (i.e., c.421 CC + CA vs. AA) or a gene-dose dependent effect on imatinib pharmacokinetics with no statistical significance (Petain et al., 2008;Takahashi et al., 2010;Seong et al., 2013). Given the discrepancies between the results of previous studies and those of the present study, we can postulate, a priori, that other factors may mask the effect of the ABCG2, including plasma AGP levels and demographic characteristics (Takahashi and Miura, 2011). ...
... In the present study evaluation of the effects of polymorphisms on imatinib pharmacokinetics showed no statistically significant effects on imatinib disposition. Similarly, other studies concluded that none of these polymorphisms influenced imatinib pharmacokinetics (Petain et al., 2008;Seong et al., 2013); Dickens et al. revealed that the SNPs did not affect the transporter activity of human P-glycoprotein in vitro (Dickens et al., 2013). We, therefore, suggested that ABCB1 polymorphisms might play a minor role in the disposition of imatinib. ...
Imatinib is transported extracellularly by ABCB1 and ABCG2 efflux transporters and bound to alpha-1-acid glycoprotein (AGP) in the bloodstream. However, the clinical and pharmacokinetic effects of ABCB1 and ABCG2 on imatinib were inconsistent in the previous literature and have not been confirmed. Therefore, in the present study, we explored the effects of the ABCG2 and ABCB1 genetic polymorphisms on imatinib pharmacokinetics in association with plasma AGP levels in healthy subjects. Twenty-seven healthy individuals were recruited, genotyped for ABCG2 and ABCB1, and given a single oral dose of 400 mg imatinib. Plasma imatinib concentrations were measured and its pharmacokinetics was assessed with respect to ABCG2 (c.421C>A and c.34G>A) and ABCB1 (c.1236C>T, c.2677C>T/A, and c.3435C>T) genotypes, and plasma AGP levels. AGP levels showed a strong positive correlation with imatinib pharmacokinetics. ABCG2 c.421C>A single nucleotide polymorphism showed a statistically significant effect on imatinib pharmacokinetics in low plasma AGP levels groups (<80 mg/dl); subjects with high plasma AGP levels (n = 5, ≥80 mg/dl) were excluded. The results indicate that plasma AGP levels and ABCG2 polymorphisms modulated imatinib pharmacokinetics; however, the effects of the ABCG2 transporter was masked at high plasma AGP levels.
... A case report also documented that an RCC patient homologous for Q141K suffered from toxic side effects of sunitinib treatment, such as severe thrombocytopenia, transaminase elevation, severe hypoxia due to pleural effusion and pulmonary edema, in parallel with efficacious treatment of the tumor [179]. Although the expression of ABCG2-Q141K in cancer cells resulted in elevated sensitivity to imatinib [114,173], the in vivo effect of Q141K on imatinib accumulation/response is controversial [180][181][182][183][184][185]. ...
Several polymorphisms and mutations in the human ABCG2 multidrug transporter result in reduced plasma membrane expression and/or diminished transport function. Since ABCG2 plays a pivotal role in uric acid clearance, its malfunction may lead to hyperuricemia and gout. On the other hand, ABCG2 residing in various barrier tissues is involved in the innate defense mechanisms of the body; thus, genetic alterations in ABCG2 may modify the absorption, distribution, excretion of potentially toxic endo- and exogenous substances. In turn, this can lead either to altered therapy responses or to drug-related toxic reactions. This paper reviews the various types of mutations and polymorphisms in ABCG2, as well as the ways how altered cellular processing, trafficking, and transport activity of the protein can contribute to phenotypic manifestations. In addition, the various methods used for the identification of the impairments in ABCG2 variants and the different approaches to correct these defects are overviewed.
... The results of the studies analyzing the imatinib response are also conflicting. While in-vitro studies found increased accumulation and imatinib sensitivity in variant expressing cells, several in-vivo studies show no effect of 421 C > A on the imatinib concentration [200][201][202][203][204]. In contrast however, a recent meta-analysis of 23 studies identified a significant effect of 421 C > A on the success of imatinib treatment in CML patients at least in Asian populations [205]. ...
Introduction
Interindividual differences in drug response are a frequent clinical challenge partly due to variation in pharmacokinetics. ATP-binding cassette (ABC) transporters are crucial determinants of drug disposition. They are subject of gene regulation and drug-interaction; however, it is still under debate to which extend genetic variants in these transporters contribute to interindividual variability in bioavailability for a wide range of drugs.
Areas covered
This review discusses the current literature on the impact of genetic variants in ABCB1, ABCG2 as well as ABCC1, ABCC2 and ABCC3 on pharmacokinetics and drug response. The aim was to evaluate if results from recent studies would increase the evidence for potential clinically relevant pharmacogenetic effects.
Expert opinion
: Although enormous efforts have been made to investigate the effects of ABC transporter genotypes on drug pharmacokinetics and response, the majority of studies showed only weak if any associations. Despite few unique results, studies mostly failed to confirm earlier findings or still remained inconsistent. The impact of genetic variants on drug bioavailability is only minor and other factors regulating the transporter expression and function seem to be more critical. In our opinion, the findings on the so far investigated genetic variants in ABC efflux transporters are not suitable as predictive biomarkers.
