MDR1基因多态性与乳腺癌紫杉联合蒽环类药物化疗疗效的关系

目的:探讨多药耐药基因(MDR1)多态性对乳腺癌紫杉联合蒽环类(TA)化疗疗效的预测价值.方法:利用PCR-RFLP技术对142例乳腺癌患者进行MDRl基因变异检测,观察其多态性分布;并对其中接受TA方案的具有完整疗效评价资料的63例新辅助化疗患者,开展MDR1 12外显子C1236T、21外显子G2677T/A和26外显子C3435T基因多态性与化疗疗效的相关分析.结果:C1236T、G2677T/A和C3435T在142例中国汉族乳腺癌女性人群中的变异频率分别为70.7%、55.0%和46.5%.其中,3435TT基因型在63例新辅助化疗患者中表现出与TA疗效的关联,其有效率(23.1%)显著低于携带C等位基因的患者(73.5%;X2=9.125,P=0.003).3个位点多态之间存在连锁不均衡性,携带3435C-2677G单体型的患者,化疗有效率(72.1%)高于其他单体型携带者(40.0%;X2=5.962,P=0.015),携带3435T-2677T或3435T-1236T单体型者,化疗有效率(54.3%或54.9%)低于对应的其他单体型携带者(82.4%和91.7%;X2=4.128和X2=4.118,P均为0.042);携带有3435T-2677T-1236T单体型者,化疗有效率(54.3%)低于其他单体型携带者(82.4%;X2=4.128,P=0.042).结论:MDR1 C3435T基因型及其与G2677T/A和(或)C1236T的单体型检测对于乳腺癌TA联合化疗疗效的预测具有重要参考价值.     

人肺癌组织MDR1基因多态性与P-gp表达相关性的探讨

目的:探讨人肺癌组织MDR1 C3435T和G2677T/A位点基因多态性与P-gp表达之间是否存在相关性.方法:免疫组化方法分析31例肺癌组织中P-gp的表达量,RFLP-PCR鉴定31例肺癌组织MDR1 C3435T和G2677T/A位点基因型.χ2检验分析基因型与P-gp表达量之间的关系.结果: 两位点基因型分布频率符合Hardy-weinberg平衡.免疫组化结果显示,P-gp表达量有较大差别.经χ2检验,C3435T位点基因型与P-gp表达有关,野生型与突变型和杂合型相比,差异有统计学意义,χ2=7.142,P=0.025.表达量趋势为C/C相似文献   

MDR1基因多态性与其在乳腺癌患者中表达水平的关系

目的:探讨MDR1基因多态性与其在乳腺癌患者癌组织中表达水平的关系。方法:筛选93例乳腺癌组织及26例配对癌旁组织,利用PCR-RFLP技术检测MDR1 exon12(1236)、exon21(2677)、exon26(3435)3个位点的多态性,以RT-qPCR技术对MDR1 mRNA进行相对定量,分析不同基因型患者间MDR1基因的表达水平。结果:93例乳腺癌组织中均有不同程度MDR1基因的表达;C1236T、G2677T/A和C3435T各基因型与MDR1表达水平之间均未显示统计学差异(F=0.047,P=0.954;F=0.364,P=0.833和F=0.173,P=0.841);但其中2 6例癌组织MDR1 mRNA表达水平,明显高于其对应的癌旁组织(3.83±5.27 vs 1.81±4.42;t=2.522,P=0.018)。结论:癌组织可能易发生多药耐药,MDR1表达差异的遗传学基础还有待进一步研究。     

ABCB1 C3435T、G2677AT基因形态与癌痛患者疼痛感知的相关性研究

目的:研究ABCB1 C3435T、G2677AT基因形态与癌痛患者疼痛感知的关系。方法:临床纳入2016年9月至2018年9月期间我院收治的185例恶性肿瘤患者组织病理学标本,将其中有癌痛的患者116例作为癌痛组,无癌痛的患者69例作为无痛组。应用三维聚丙烯酰胺凝胶DNA芯片技术检验患者ABCB1 C3435T、G2677AT基因分型情况,并分析ABCB1 C3435T、G2677AT基因形态与癌症患者癌痛的关系。结果:两组患者C3435T基因野生型、杂合子及突变型分布频率对比差异无统计学意义（P>0.05）。两组患者G2677AT基因野生型、杂合子及突变型分布频率对比差异无统计学意义（P>0.05）。疼痛程度不同的患者C3435T和G2677AT基因型分布频率无差异（P>0.05）。癌痛组患者C3435T与G2677AT不同基因型间组内对比NRS评分差异无统计学意义（P>0.05）;C3435T与G2677AT相同基因型对比NRS评分差异无统计学意义（P>0.05）。结论:ABCB1 C3435T与G2677AT基因形态与癌痛患者疼痛感知并无直接关联,尚需进一步进行深入研究。     

MDR1基因单核苷酸多态性与肝细胞肝癌预后的关系

[目的]探讨多药耐药基因1（multidrug resistance gene 1,MDR1）C1236T及C3435T单核苷酸多态性（SNP）与肝细胞肝癌（HCC）预后间关系。[方法]以36例HCC根治术患者为对象,同时建立50例对照组,PCR-SSCP法检测其静脉血标本C1236T及C3435T SNP,比较分析C1236T及C3435T SNP与HCC预后的关系。[结果]HCC组与对照组的基因分布无统计学差异（P〉0.05）。C3435T基因型CC、CT、TT型中位无瘤生存时间依次为164.5d、340.0d和369.5d,C1236T基因型CC、CT、TT型中位无瘤生存时间依次为201.0d、415.0d、260.0d,MDR1基因多态性与HCC复发相关。[结论]C3435T SNP可作为肝癌根治术的预后因素之一。     

晚期非小细胞肺癌患者XPG基因及MDR1基因单核苷酸多态性与铂类化疗疗效的相关性

目的探讨DNA修复基因XPG以及多药耐药基因MDR1的单核苷酸多态性与晚期非小细胞肺癌患者对铂类为主的化疗方案敏感性的关系。方法经病理确诊的晚期NSCLC患者101例,采用DDP为主的化疗方案,化疗2～3个周期后进行临床疗效评价。以PCR-RLFP方法进行XPG、MDR-1的基因型分析,比较不同基因型对化疗敏感性的影响。结果携带MDR1-3435等位基因C/C的患者的化疗有效率为57.8%,显著高于至少携带1个T等位基因的26.8%（OR=0.272,95%CI=0.117～0.635,P（0.05））;携带MDR1-2677至少1个T等位基因的患者的化疗有效率12.8%要显著低于其他基因型患者的58.1%（OR=17.999,95%CI=4.938～65.599,P（0.01）;而XPG各基因型与化疗敏感性的关系没有显著性的差异。结论MDR1基因多态性与NSCLC患者对铂类药物的化疗敏感性相关,基因XPG的多态性是否与铂类药物化疗的敏感性是否具有相关性尚需进一步的研究。     

CYP3A5、MDR1和COX-2单核苷酸多态性与晚期非小细胞肺癌化疗疗效关系的探讨

目的 探讨CYP3A5、MDR1和COX-2单核苷酸多态性是否与长春瑞滨、铂类药物对晚期非小细胞肺癌(NSCLC)化疗疗效有关.方法 对69例采用长春瑞滨、铂类方案化疗的晚期NSCLC患者(中国汉族)的CYP3A5(*3)、MDR1 21外显子上的2677 G>T位点、26外显子3435 C>T位点及其单体型和COX-2启动子区的-1195 G>A位点用限制内切酶片段多态性-多聚酶链反应(RFLP-PCR)的方法进行基因分型,结合临床化疗效果进行分析,采用卡方检验分析各位点基因型与化疗疗效之间的关系.结果 MDR1 3435位点野生纯合子(C/C)患者疗效明显高于杂合子(C/T)和突变纯合子(T/T)患者(P=0.033).MDR1 2677位点野生纯合子(G/G)患者疗效明显高于其他基因型患者(P=0.012).MDR1 2677 G-3435 C单体型患者疗效稍高于其他单体型(P=0.063).CYP3A5*3位点基因型与长春瑞滨、铂类方案疗效无关.COX-2-1195 G>A位点野生型(G/G)疗效稍高于其他基因型(P=0.067),但差异无统计学意义.结论 MDR13435 C>T位点基因型和MDR1 2 677 G>A/T位点基因型可以用于预测长春瑞滨、铂类方案对晚期NSCLC患者的疗效.     

转化生长因子-β1基因启动子多态性与肝癌关系的研究

 目的　研究转化生长因子β1（TGF-β1）基因启动子多态性各等位基因及基因型在肝癌（HCC）患者中的分布频率,初步分析其基因型及血清水平与HCC的相关性。方法　采用限制性片段长度多态性聚合酶链反应（PCR-RFLP）技术,检测102例HCC患者和110例健康对照TGF-β1的基因多态性,包括TGF-β1基因启动子-800G／A、-509C／T位点,采用酶联免疫吸附试验（ELISA）检测血清TGF-β1水平。结果　HCC患者TGF-β1水平显著高于对照组[（51.06 ± 9.74）μg／L ,（22.12 ± 8.67）μg／L,t＝22.884,P＜0.01],TGF-β1基因-800G／A位点多态性在HCC组和健康对照组中的分布差异无统计学意义（P＞0.05）,而TGF-β1基因-509C／T多态性各等位基因及基因型频率在两组人群中的分布差异有统计学意义（P＜0.05）;等位基因频率的相对风险分析发现,T等位基因携带者患HCC的风险是C等位基因的1.822倍（OR＝1.822,95 %CI：1.238～2.682,t＝22.884,P＜0.01）,携带T等位基因的HCC患者血清TGF-β1水平高于不携带者[（53.52±10.07）μg／L ,（ 43.57±9.89 ）μg／L,t＝3.898, P＜0.01]。结论　 TGF-β1基因-509C／T多态性与HCC之间存在相关关系;携带T等位基因的个体可能通过促进TGF-β1的高度表达而增加HCC的发病风险。     

亚甲基四氢叶酸还原酶基因单核苷酸多态性与儿童急性淋巴细胞白血病的相关性

 【摘要】　目的　探讨亚甲基四氢叶酸还原酶基因（MTHFR）单核甘酸多态性与儿童急性淋巴细胞白血病（ALL）发病风险的关系。方法　分别收集45例ALL患儿（ALL组）及45名健康儿童（对照组）外周血各2 ml,提取基因组DNA,应用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）法,检测MTHFR C677T和A1298C基因型,比较不同基因型对儿童ALL发病风险的影响。采用Logistic回归模型计算比值比（OR）和95 %可信区间（95 % CI）。结果　对照组MTHFR 677CC、CT和TT基因型基因分布频率分别为31.1 %（14／45）、51.1 %（23／45）和17.7 %（8／45）,ALL组3种基因型分布频率分别为51.1 %（23／45）、40.0 %（18／45）和8.9 %（4／45）,两者比较差异有统计学意义（χ2＝7.48,P＝0.04）;MTHFR 677 T等位基因在ALL组中的检出率为48.8 %（22／45）,在对照组中的检出率为69.9 %（31／45）;T等位基因携带者发生ALL的风险是CC基因型的0.4倍（95 % CI 0.21～0.83）。对照组MTHFR 1298AA、AC和CC基因型基因分布频率分别为57.8 %、40.0 %和2.2 %,ALL组中3种基因型分布频率分别为18.8 %、44.4 %和6.8 %,两者比较差异无统计学意义（χ2＝11.23,P＝0.23）;MTHFR 1298 C等位基因ALL组中的检出率为42.2 %（19／45）,对照组中的检出率为51.1 %（23／45）;C等位基因的存在并不会提高儿童ALL发生的风险（OR＝1.3,95 % CI 0.21～0.83）。结论　MTHFR 677 T等位基因的存在会显著降低儿童发生ALL的风险,而MTHFR 1298各基因型与儿童ALL的发生均无明显相关性。     

DNA修复基因XRCC1单核苷酸多态性与非霍奇金淋巴瘤遗传易感性的关系

 目的　探讨DNA修复基因XRCC1 R280H、XRCC1 TSS+29C／T单核苷酸多态性与非霍奇金淋巴瘤（NHL）易感性的关系。方法　运用MassARRAY技术对73例NHL病例和540名健康对照的DNA修复基因XRCC1多态性进行检测,比较其不同基因型与淋巴瘤患病风险的关系。结果　XRCC1 R280H中G、A基因频率在对照组和病例组中分布差异有统计学意义（P＝0.001）,而XRCC1 TSS+29C／T中T、C的基因频率在两组中的分布差异无统计学意义 （P＝0.383）。进一步的分析表明,在XRCC1 R280H中,与携带GG野生纯合子基因型者比较,携带至少一个A等位基因者（GA或AA）患淋巴瘤的风险显著降低（P＜0.001,OR＝0.309,95 % CI＝0.168～0.567）。而在XRCC1 TSS+29C／T中,CC和CT与基因TT比较,携带C基因者会增加淋巴瘤的发病风险（P＝0.472,OR＝1.262,95 % CI＝0.669～2.379）。结论　DNA修复基因XRCC1 R280H的基因多态性与NHL的发生密切相关。     

Multidrug resistance-1 gene polymorphisms associated with treatment outcomes in de novo acute myeloid leukemia

Multidrug resistance-1 (MDR-1) gene single nucleotide polymorphisms (SNPs) have been identified as associated with the treatment outcomes of acute myeloid leukemia (AML) in Caucasians; yet, similar evidence is lacking for Asian populations. A total of 101 AML patients were enrolled in the current study. Two MDR1 SNPs (C3435T and G2677T/A) were analyzed with PCR/RFLP assay. As regards C3435T polymorphism, C/C genotype was significantly correlated with lower functional P-glycoprotein (P-gp) activity in leukemic blasts (7.5%) compared with C/T (10.7%) or T/T genotype (19.9%, p = 0.029). In genotypic analyses, C/C at -3435 (p = 0.05) and G/G at -2677 (p = 0.04) were strongly associated with a higher probability of complete remission (CR). In addition, the 3-year event-free survival (EFS) was higher in G/G genotype at -2677 (60.6%) than nonG/G (21.9%; p = 0.0241), in C/C at -3435 was higher than nonC/C genotype (p = 0.0139), and was higher in GC haplotype homozygote (58.2%) than nonGC homozygote (22.6%; p = 0.0427). In a multivariate analysis, the group without GC haplotype showed worse EFS (p = 0.030), with unfavorable cytogenetic risk (p = 0.008). However, no differences were noted in overall survival according to the MDR1 SNPs (p = 0.491 for C3435T and p = 0.955 for G2677T/A).     

Multidrug resistance gene (MDR1) polymorphisms correlate with imatinib response in chronic myeloid leukemia

The human multidrug resistance gene (MDR1, ABCB1) codes for P-glycoprotein (P-gp) that affects the pharmacokinetics of many drugs. MDR1 single nucleotide polymorphisms (SNPs) are associated with drug clearance. Imatinib is a substrate of P-gp-mediated efflux. We investigated the MDR1 T1236C, G 2677T/A, and C3435T polymorphism in 52 patients with chronic myeloid leukemia treated with imatinib. The distribution of MDR1 1236, 2677, or 3435 genotypes was significantly different between the resistance patients and sensitivity patients. The resistance incidence correlated with the number of T alleles at locus 1236 and 3435. Resistance was higher for patients homozygous for the 1236T allele when compared to patients with CT/CC genotype groups (75% vs. 31.3%, P = 0.004). For the G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with genotype AG/AT/AA, when compared to other genotype groups (TT/GT/GG, P = 0.02). Patients with 3435 TT/CT genotypes showed a higher resistance when compared with patients with CC genotype (59.4% vs. 25%, P = 0.023). In conclusion, determination of 1236T, C3435T, and G2677T MDR1 polymorphisms might be useful in response prediction to therapy with imatinib in patients with CML.     

Influence of Genotype and Haplotype of MDR1 (C3435T,G2677A/T,C1236T) on the Incidence of Breast Cancer - a Case-Control Study in Jordan

Background: Breast cancer is the leading cause of cancer death among women and the second in humans worldwide. Many published studies have suggested an association between MDR1 polymorphisms and breast cancer risk. Our aim was to study the association between genetic polymorphism of MDR1 at three sites (C3435T, G2677A/T, and C1236T) and their haplotype and the risk of breast cancer in Jordanian females. Materials and Methods: A case-control study involving 150 breast cancer cases and 150 controls was conducted. Controls were age-matched to cases. The polymerase chain reaction/restriction fragment length polymorphism (PCRRFLP) technique and sequencing were performed to analyse genotypes. Results: The distribution of MDR1 C3435T genotypes differed between cases and controls [cases, CC 45.3%, CT 41.3%, and TT 13.3%; controls, CC 13.4%, CT 43.3%, and TT 30.2%, p < 0.001]. Similarly, the distribution of G2677A/T significantly differed [cases, GG 43.1 %, GT+GA 50.9% and AA+TT 6%; controls, GG 29.6 %, GT+GA 50.9%, and AA+TT 19.4%, p = 0.004]. On the other hand, genotype and allelotype distribution of C1236T was not statistically different between cases and controls (p=0.56 and 0.26, respectively). The CGC haplotype increased the risk to breast cancer by 2.5-fold compared to others, while TGC and TTC haplotypes carried 2.5- and 5-fold lower risk of breast cancer, respectively. Conclusions: Genetic polymorphisms of MDR1 C3435T and G2677A/T, but not C1236T, are associated with increased risk of breast cancer. In addition, CGC, TGC and TTC haplotypes have different impacts on the risk of breast cancer. Future, larger studies are needed to validate these findings.     

MDR1 gene variants, indoor insecticide exposure, and the risk of childhood acute lymphoblastic leukemia.

OBJECTIVE: The multidrug resistance (MDR) 1 gene encodes a membrane transporter called P-glycoprotein, which plays an important role in protecting cells against lipophilic xenobiotics by way of an ATP-dependent cellular efflux mechanism. Among children enrolled in the Northern California Childhood Leukemia Study, we examined the susceptibility conferred by MDR1 single nucleotide polymorphisms (SNP) and predicted haplotypes and whether they modify the association between indoor insecticide exposure and risk of childhood acute lymphoblastic leukemia (ALL). METHODS: Buccal cell DNA from ALL cases (n = 294) and controls (n = 369) individually matched on gender, date of birth, Hispanic status, and maternal race were whole genome amplified and genotyped for four MDR1 SNPs, T-129C (rs3213619), C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642). Detailed and time-specific information on household pesticide use was obtained using in-home interviews with the mother. RESULTS: Allele frequencies in non-Hispanic White and Hispanic controls were similar, and with the exception of T-129C, seemed to be in strong linkage disequilibrium. Overall, the SNPs considered individually or within haplotypes (C1236T-G2677T/A-C3435T) were not significantly associated with childhood ALL. However, we observed strong evidence of a differential effect of indoor insecticide exposure (interaction odds ratio, 0.31; 95% confidence interval, 0.15-0.64; P = 0.025) on risk of ALL between carriers and noncarriers of haplotype CGC. CONCLUSION: These preliminary data suggest that children carrying the haplotype CGC may be less susceptible to the leukemogenic effects of indoor insecticide exposures. Future studies are needed to confirm these findings.     

Association of C3435T,C1236T and C4125A Polymorphisms of the MDR-1 Gene in Egyptian Children with Acute Lymphoblastic Leukaemia

Background: P-glycoprotein (P-gp), a membrane transporter encoded by the multidrug resistance-1 (MDR1) gene,influences pharmacokinetics and metabolism of anticancer drugs and contributes to multidrug resistance phenotypein acute lymphoblastic leukemia (ALL). Genetic variation ofMDR1 in ALL patients is increasingly recognized asa factor influencing response to treatment. Aim: To investigate the possible role of MDR-1 gene polymorphisms(C3435T, C1236T and C4125A) as risk factors for the development and clinical outcome of ALL in Egyptian children.Materials and Methods: Genotyping of MDR-1 C3435T, C1236T and C4125A single nucleotide polymorphisms(SNPs) was accomplished using a polymerase chain reaction–restriction fragment length polymorphism (RFLP-PCR)assay with 120 childhood ALL patients and 100 healthy controls. Results: Homozygous T with the C3435T SNP showeda protective effect as compared to homozygous C (OR=0.748) while heterozygous CT correlated with a poor outcome(high risk, drug unresponsiveness, relapse and high percentage of death). Additionally, the T allele of the C1236T SNPshowed a significant relation with ALL risk (OR=1.6). However, there were no significant differences in the genotypeand allele frequencies of MDR-1 SNPs between patients and controls. Only one genotype (CC) and one allele ofMDR-1 (C4125A) were seen. Neither CA/AA genotypes nor A alleles were present in ALL patients and normal controls.TC was the predominant haplotype in both groups, while CT proved to be minor. The cumulative incidence of relapsewas higher with the CC genotype of C1236T as compared with TT. Conclusion: From our preliminary data, the CTgenotype of C3435T is associated with a poor ALL outcome while the CC genotype of C1236T is related with anincreased incidence of relapse. Although our results provide assistance for oncologist choice of individual therapeuticstrategy taking the patient genetic repertoire into consideration, further investigations with larger sample size shouldbe conducted to validate our results.     

Haplotype Analysis of MDR1 and Risk for Cervical Cancer in Northeastern Thailand

Objective: The aim of this study was to investigate the association between genotype and haplotype of MDR1 (C1236T, G2677T/A and C3435T) and the risk for cervical cancer in Northeastern Thai women. Methods: An age-matched case-control study involving squamous cell cervical cancer (SCCA) patients (n=204) and healthy controls (n=204) was enrolled for MDR1 genotyping by real-time PCR method. Results: The genotype distribution of MDR1 in both patients and controls was not significantly different (p>0.05). The haplotype analysis showed that T-T-T was the most common haplotype in this population. Significantly increased risk of cervical cancer was observed in carriers of T-T-C and C-G-T haplotypes with ORs of 1.86 (95%CI=1.02-3.39, p=0.0416) and 2.00 (95%CI=1.18-3.40, p=0.0140), respectively. Analysis of 2677-3435 haplotype showed increased risk for cervical cancer in G-T (OR=1.55; 95% CI=1.12-2.13, p=0.0432) and T-C (OR=1.91; 95%CI=1.05-3.47, p=0.0325). Conclusion: The results provide evidence that haplotype of MDR1 may be an important risk factor for cervical cancer development in Northeastern Thai women.     

ABCB1 genetic variation influences the toxicity and clinical outcome of patients with androgen-independent prostate cancer treated with docetaxel.

PURPOSE: Polymorphisms that are associated with ABCB1 expression and function may be linked to treatment efficacy and the development of neutropenia and neurotoxicity in patients with androgen-independent prostate cancer receiving docetaxel. EXPERIMENTAL DESIGN: Patients with androgen-independent prostate cancer treated with docetaxel alone (n = 23) or docetaxel and thalidomide (n = 50) were genotyped for the ABCB1 1236C>T, 2677 G>T/A, and 3435 C>T alleles by direct sequencing, and diplotypes were constructed using an EM algorithm. The data were then compared with duration to onset of peripheral neuropathy, neutropenia grade, and survival after docetaxel. RESULTS: For patients receiving docetaxel alone, individuals carrying a diplotype consisting of the 1236C-2677G-3435C linked alleles had improved overall survival after treatment (P = 0.0017). Additionally, patients treated with docetaxel and thalidomide carrying a diplotype consisting of the 2677T-3435T haplotype had a shorter median survival (P = 0.045). After adjusting for a particular set of polymorphisms and diplotype groupings, a hazard ratio of 10.87 was found for patients carrying the 2677GG genotype versus patients carrying other genotypes (P = 0.0048) in the docetaxel and thalidomide cohort. Among both treatment arms together, individuals carrying the 2677GG genotype also had a significantly longer time to neuropathy (P = 0.035). Finally, there was a strong trend toward patients carrying the 2677TT-3435TT diplotype having higher grades of neutropenia (P = 0.053). CONCLUSION: The data suggest that docetaxel-induced neuropathy, neutropenia grade, and overall survival could be linked to ABCB1 allelic variants with ensuing negative implications for docetaxel treatment in patients carrying ABCB1 variant genotypes.     

Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer

BACKGROUND: The authors investigated whether ABCB1, ABCC2, and ABCG2 genetic polymorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: Blood samples from 107 NSCLC patients treated with irinotecan and cisplatin chemotherapy were used for genotyping ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCC2 (-24C > T, 1249G > A, 3972C > T), and ABCG2 (34G > A, 421C > A) polymorphisms. Genotypes were correlated with irinotecan-PK, toxicity, tumor response, and survival. RESULTS: Among 8 polymorphisms, 3435TT and 2677TT were associated with AUC(SN-38G) and CL(SN-38G). When haplotypes are assigned, 2677TT/3435TT carriers showed significantly lower AUC(SN-38G) (P = .006), whereas 2677GG/3435CC carriers showed significantly higher AUC(SN-38) (P = .039). These findings suggest that 2677TT and 3435TT variants are associated with higher efflux activity. In toxicity, the 2677G/T or A was associated with grade 4 neutropenia. The 2677GG carriers showed significantly lower absolute neutrophil count during the 1(st) cycle (P = .012) as well as entire course of chemotherapy (P = .042). The 3435TT was associated with higher frequency of grade 3 diarrhea (P = .047). In tumor response, ABCC2 -24TT and 3972TT genotypes were associated with higher response rates (P = .031 and .046, respectively) and longer progression-free survival (P = .035 and .038, respectively), which was sustained in haplotype analysis. CONCLUSIONS: Specific polymorphisms of ABCB1 and ABCC2 can influence disposition and tumor response to irinotecan by regulating transporter activity. These findings may help to individualize irinotecan-based chemotherapy in patients with advanced NSCLC.     

Correlation between genetic polymorphisms of the hOCT1 and MDR1 genes and the response to imatinib in patients newly diagnosed with chronic-phase chronic myeloid leukemia

The association between seven polymorphisms in the genes hOCT1 and MDR1, encoding for imatinib transporter proteins, and the response to imatinib 400 mg/daily was investigated in 65 patients newly diagnosed with chronic-phase chronic myeloid leukemia. The AA genotype at the rs6935207 hOCT1 polymorphic locus was not detected in patients with inadequate response to imatinib. The CC genotype at the rs1045642 (C3435T) MDR1 locus was associated with primary failure, whereas a T allele at the rs2032582 (G2677T/A) MDR1 locus seemed to protect from primary failure. Beside, the MDR1 haplotype 1236T-2677G-3435C was more frequently found in patients primarily resistant to imatinib.