急性髓细胞白血病乳腺癌耐药蛋白的临床研究
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摘要
目的:探讨乳腺癌耐药蛋白(BCRP)与急性髓细胞白血病(AML)的临床特征、药物敏感性、预后的关系。
方法:应用半定量逆转录.聚合酶链反应(RT-PCR)检测5例对照组及20例AML患者治疗不同时期的骨髓单个核细胞中BCRP基因表达水平;应用流式细胞术(FCM)检测20例AML标本的骨髓单个核细胞BCRP蛋白水平;并运用MTT比色法检测20例AML标本骨髓单个核细胞在抗肿瘤药物不同浓度下(2.5-40ug/ml)的体外药物敏感性。
结果:25例标本(20例AML,5例对照)BCRP基因表达水平个体差异性较大,从0到1.950不等。对照组和AML组BCRP基因表达水平,分别为0.047±0.0401、0.302±0.33(P=0.002)。20例AML患者中BCRP mRNA表达量各不相同,由低到高依次为初治敏感组(5例)、复发组(8例)和临床耐药组(11例),平均表达水平分别为0.052±0.037、0.254±0.288、0.372±0.364,初治敏感组与临床耐药组差异显著(P=0.001)。12例初治AML患者BCRP mRNA表达阳性者5例,CR11例,CR1率20.0%;阴性者7例,CR15例,CR1率71.4%,二者差异显著(P=0.0000)。AML不同FAB分型中BCRP基因表达水平及阳性率也有差异,M_5最高,其次是M_3、M_4,M_2最低,M_5与M_2 BCRP相对表达量分别为0.447±0.4260、0.177±0.269(P=0.206),阳性率分别为50%、25%(P=0.325)。FCM检测BCRP蛋白不同程度表达,9例阳性者均值为37%(区间12.2-93.7%),初治敏感组最低,0.0385±0.0358,复发组和耐药组则明显增高,分别为0.2026±0.2443、0.2905±0.2962,与初治敏感组相比较,均具有统计学意义(P＜0.05)。与BCRP mRNA表达相关性比较显示,11例BCRP蛋白表达阴性者有4例为BCRP mRNA表达阳性。MTT法提示,对20例AML样本的骨髓单个核细胞,柔红霉素在16倍峰浓度下的抑制率高于单倍峰浓度,分别为(33.87±16.36)%、(16.36±18.37)%(P＜0.05),呈现浓度依赖性现象。就高敏例数而言,16倍峰浓度下为4例,占20%,而单倍峰浓度下仅为1例,占5%,两者之间差异有显著性(P＜0.05)。在16倍峰浓度下,柔红霉素对初治敏感组和临床耐药组、BCRP mRNA阳性表达组(7例)和阴性表达组(13例)的平均抑制率明显不同,分别为(44.49±20.89)%、(20.89±9.34)%(P＜0.05),(20.58±3.67)%、(39.26±15.25)%(P＜0.05)。
结论:AML患者的BCRP基因表达水平显著高于对照组;BCRPmRNA阳性的初治者CR率低于阴性者;临床耐药组BCRP基因表达水平明显高于敏感组;AML各亚型BCRP基因表达情况无显著差异性;耐药组与复发组的BCRP基因表达水平明显高于初治敏感组;不同BCRP基因表达水平的细胞对药物呈现浓度依赖性现象,16倍峰浓度下高度敏感率高于单倍峰浓度(P＜0.05)。16倍峰浓度下,柔红霉素对初治敏感组的平均抑制率高于耐药组,BCRP mRNA阳性表达组的平均抑制率高于阴性表达组。
The leukemia is one of the most familiar malignant diseases in mankind, the death rate occupies to the 6-8th in the malignant tumor,and stand first in child and crowds under 35 years of ages.In our country,the adult leukemia regards the acute leukemia as principle,accounting for 80%in total of leukemia,and the acute myelocytic leukemia(AML)be known as the majority (1.62/100,000).The chemistry medicine treatment is still the first choose with AML now,it's complete release(CR)rate can reach to 60%-80%,but most sufferers relapse within 2 years,the second chemotherapy curative effect isn't good,the further research confirmed someone who is in initial treatment but not easily to release and most recidivists bear a multidrug resistance(MDR),as a result,the research of the drug resistant mechanism in leukemia and the choice of sensitive medicine treatment are the keys,which would raise chemotherapy curative effect and prolong the patient duration even to cure.The BCRP is a recently detection and a new medicine of ejecting medicine as a pump which related the tumor multidrug resistance,be a kind of the half transport.In the last few years,the researchs of BCRP in domestic and international were indicated that the BCRP bears drug resistance and prognosis of AML,being an independent factor of the AML drug resistance,and there wasn't any correlation with the classic MDR.The research discovers that the increase of BCRP mRNA expression hints the possibility of the disease relapse.BCRP mRNA level is so important to the judge of prog and the treatment in patients.For inquiry into the relationship of BCRP and the clinical characteristic,the medicine sensitivity,the prog of AML,this research chooses 20 AML hospitalization from three affiliated hospitals of jilin university and so on.Median age is 41.5 years old(21-55),male 8 examples(40%),feminine 12 examples(60%)among them.By the FAB typing,M_1 1 example,M_2 4 examples,M_3 6 examples,M_4 3 examples,M_5 6 example.Matched contro1:5 examples,AA 1 example,nomal 2 examples and ITP 2 examples among them.According to the course of illness,there is divided into the initial treatment set and the replase set.According to the clinic diagnosis standard,is divided into the sensitiveness set and the drug resistance set.we adopt RT-PCR to examine 5 matched controls and the expression level of the BCRP gene in the pit cell of 20 AMLs;FCM examines the BCRP protein level in marrow pit cells of 20 AML samples;Combine the usage MTT method that observed the medicine sensitivity at a different density (2.5-40ug/ml)of a anti- tumor medicine.
The results showing:The BCRP mRNA of 20 AML sufferers expresses quantity in high and low dissimilarity,the expressed level in control and AMLs shows an individual difference,from 0-1.950.The average expression level of 5 normal persons is 0.047±0.040,the expression level of 20 AML sufferers is 0.302±0.331,was analysised by covariance having the difference (P=0.002).In 20 AMLs,7 BCRP mRNA expressions are masccline,13 express negative.In 12 examples of the initial treatment AML sufferers,5 examples express masculine of the BCRP mRNA,CR1 1 example,CR1 rate is 20.0%;The BCRP mRNA expressing negative are 7 examples,CR1 5 examples,the CR1 rate is 71.4%,the difference have already shown the covariance meaning(P=0.0000).Combine the related data of the clinic diagnosis,the BCRP mRNA of the initial sensitive treatment set is lowest,average is 0.052±0.037;The relapse set and drug resistance set are higher,0.254±0.288 and 0.372±0.364.Leaming by covariance examination,there had covariance meaning among the initial sensitive treatment set and the replase set,drug resistance set(P＜0.05).But it's no meaning between the replase set and drug resistance set(P＞0.05).the BCRP masculine in 5 initial sensitive set is 1 example,the masculine rate is 20%,the BCRP masculine in 11 drug resistance set are 5 examples,the masculine rate reaches to 45.4%,learning by statistical analyzation have the difference(P＜0.05).In 20 AMLs,in addition to M_1,M_6,the M_7 number less,in 5 second types,all have the expression of BCRP gene.M_5 6 examples,the BCRP opposite expression level is the tallest,measure to 0.340±0.368,M_2 4 examples,the expression level is lowest,measure to 0.177±0.269,but the analysis learning by covariance didn't show the difference(P=0.206).In each type,the masculine rate of the BCRP gene expression also has difference.The M_5 is the tallest,there be 3 masccline examples in 6 samples,the rate is 50%,then M_3,M_4,M_2 secondly,distinguish to 33.3%,33.3%,25%,through the analysis,its difference didn't show meaning.The BCRP protein expression have different degree in relapse set,initial sensitive treatment set and drug resistance set,the difference shows meaning (P＜0.05),but relapse set and drug resistance set,the difference doesn't show meaning(P＞0.05).9 examples are masculine of BCRP protein expression in 20 AML sufferers,at different clinical stage,the masccline rate dissimilarity,the initial sensitive treatment set is lowest,an only 5 examples are masculine,the rate is 20%(1/5),3 masculine in 8 relapse examples,the rate is 37.5%(3/8),the masculine rate of the clinic drug resistance set is tallest,45.4%.(5/11).And in mRNA related analytical manifestation,4 examples express negative of the BCRP protein but the mRNA expression is masculine,both have no relativity.The inhibition ratio of DNR checks single cell with 20 AMLs is difference,16-folds densities is higher than single density,equally inhibition ratio is(33.87±16.36)%,(16.3±18.37)%,there is presented a density dependence phenomenon.Regard to the high sensitive examples in 20 AMLs,there are 4 examples under the 16-folds densities,under the single density it si only for 1 example,the difference has already shown statistic meaning(P＜0.05).At single density,the inhibition ratio of DNR to the initial sensitive treatment set is(27.59±25.12)%,the drug resistance set is(11.03±14.55)%,the difference didn't have meaning(P=0.115).Under the 16-folds density,the inhibition ratio of DNR to the initial sensitive treatment set shows(44.49±20.89)%,the drug resistance set is(20.89±9.34)%,the difference shows meaning(P=0.025).Under the single density,the inhibition ratio of DNR to the negative set is(24.09±18.68)%,the masccline set is(1.99±0.80)%,there has a statistic meaning(P=0.001).Under 16-folds densities,the inhibition ratio of DNR to the negative expression set is(39.26±15.25)%,the masccline expression set is(20.58±3.67)%(P=0.002).
On the whole,the CR rate of the BCRP mRNA masccline be lower than negative in the initial treatment AML;compareing the BCRP gene expression level of the clinical drug resistance set and the sensitive set,the former is obviously high in the latter;The BCRP expression of each AML type didn't show difference obviously;The expression level of the BCRP protein comparison,the initial treatment sensitive set and drug resistance set,relapses set show much difference,but relapses set and drug resistance set doesn't show difference;The repellency to medicine of the different BCRP expression cell a obvious amount of-effect relation(P＜0.05).Under 16-fold densities,comparing the inhibition ratio of NDR cure,the sensitive set is super than the drug set, BCRP mRNA masccline set be super than negative set(P＜0.05).
方法:应用半定量逆转录.聚合酶链反应(RT-PCR)检测5例对照组及20例AML患者治疗不同时期的骨髓单个核细胞中BCRP基因表达水平;应用流式细胞术(FCM)检测20例AML标本的骨髓单个核细胞BCRP蛋白水平;并运用MTT比色法检测20例AML标本骨髓单个核细胞在抗肿瘤药物不同浓度下(2.5-40ug/ml)的体外药物敏感性。
结果:25例标本(20例AML,5例对照)BCRP基因表达水平个体差异性较大,从0到1.950不等。对照组和AML组BCRP基因表达水平,分别为0.047±0.0401、0.302±0.33(P=0.002)。20例AML患者中BCRP mRNA表达量各不相同,由低到高依次为初治敏感组(5例)、复发组(8例)和临床耐药组(11例),平均表达水平分别为0.052±0.037、0.254±0.288、0.372±0.364,初治敏感组与临床耐药组差异显著(P=0.001)。12例初治AML患者BCRP mRNA表达阳性者5例,CR11例,CR1率20.0%;阴性者7例,CR15例,CR1率71.4%,二者差异显著(P=0.0000)。AML不同FAB分型中BCRP基因表达水平及阳性率也有差异,M_5最高,其次是M_3、M_4,M_2最低,M_5与M_2 BCRP相对表达量分别为0.447±0.4260、0.177±0.269(P=0.206),阳性率分别为50%、25%(P=0.325)。FCM检测BCRP蛋白不同程度表达,9例阳性者均值为37%(区间12.2-93.7%),初治敏感组最低,0.0385±0.0358,复发组和耐药组则明显增高,分别为0.2026±0.2443、0.2905±0.2962,与初治敏感组相比较,均具有统计学意义(P＜0.05)。与BCRP mRNA表达相关性比较显示,11例BCRP蛋白表达阴性者有4例为BCRP mRNA表达阳性。MTT法提示,对20例AML样本的骨髓单个核细胞,柔红霉素在16倍峰浓度下的抑制率高于单倍峰浓度,分别为(33.87±16.36)%、(16.36±18.37)%(P＜0.05),呈现浓度依赖性现象。就高敏例数而言,16倍峰浓度下为4例,占20%,而单倍峰浓度下仅为1例,占5%,两者之间差异有显著性(P＜0.05)。在16倍峰浓度下,柔红霉素对初治敏感组和临床耐药组、BCRP mRNA阳性表达组(7例)和阴性表达组(13例)的平均抑制率明显不同,分别为(44.49±20.89)%、(20.89±9.34)%(P＜0.05),(20.58±3.67)%、(39.26±15.25)%(P＜0.05)。
结论:AML患者的BCRP基因表达水平显著高于对照组;BCRPmRNA阳性的初治者CR率低于阴性者;临床耐药组BCRP基因表达水平明显高于敏感组;AML各亚型BCRP基因表达情况无显著差异性;耐药组与复发组的BCRP基因表达水平明显高于初治敏感组;不同BCRP基因表达水平的细胞对药物呈现浓度依赖性现象,16倍峰浓度下高度敏感率高于单倍峰浓度(P＜0.05)。16倍峰浓度下,柔红霉素对初治敏感组的平均抑制率高于耐药组,BCRP mRNA阳性表达组的平均抑制率高于阴性表达组。
The leukemia is one of the most familiar malignant diseases in mankind, the death rate occupies to the 6-8th in the malignant tumor,and stand first in child and crowds under 35 years of ages.In our country,the adult leukemia regards the acute leukemia as principle,accounting for 80%in total of leukemia,and the acute myelocytic leukemia(AML)be known as the majority (1.62/100,000).The chemistry medicine treatment is still the first choose with AML now,it's complete release(CR)rate can reach to 60%-80%,but most sufferers relapse within 2 years,the second chemotherapy curative effect isn't good,the further research confirmed someone who is in initial treatment but not easily to release and most recidivists bear a multidrug resistance(MDR),as a result,the research of the drug resistant mechanism in leukemia and the choice of sensitive medicine treatment are the keys,which would raise chemotherapy curative effect and prolong the patient duration even to cure.The BCRP is a recently detection and a new medicine of ejecting medicine as a pump which related the tumor multidrug resistance,be a kind of the half transport.In the last few years,the researchs of BCRP in domestic and international were indicated that the BCRP bears drug resistance and prognosis of AML,being an independent factor of the AML drug resistance,and there wasn't any correlation with the classic MDR.The research discovers that the increase of BCRP mRNA expression hints the possibility of the disease relapse.BCRP mRNA level is so important to the judge of prog and the treatment in patients.For inquiry into the relationship of BCRP and the clinical characteristic,the medicine sensitivity,the prog of AML,this research chooses 20 AML hospitalization from three affiliated hospitals of jilin university and so on.Median age is 41.5 years old(21-55),male 8 examples(40%),feminine 12 examples(60%)among them.By the FAB typing,M_1 1 example,M_2 4 examples,M_3 6 examples,M_4 3 examples,M_5 6 example.Matched contro1:5 examples,AA 1 example,nomal 2 examples and ITP 2 examples among them.According to the course of illness,there is divided into the initial treatment set and the replase set.According to the clinic diagnosis standard,is divided into the sensitiveness set and the drug resistance set.we adopt RT-PCR to examine 5 matched controls and the expression level of the BCRP gene in the pit cell of 20 AMLs;FCM examines the BCRP protein level in marrow pit cells of 20 AML samples;Combine the usage MTT method that observed the medicine sensitivity at a different density (2.5-40ug/ml)of a anti- tumor medicine.
The results showing:The BCRP mRNA of 20 AML sufferers expresses quantity in high and low dissimilarity,the expressed level in control and AMLs shows an individual difference,from 0-1.950.The average expression level of 5 normal persons is 0.047±0.040,the expression level of 20 AML sufferers is 0.302±0.331,was analysised by covariance having the difference (P=0.002).In 20 AMLs,7 BCRP mRNA expressions are masccline,13 express negative.In 12 examples of the initial treatment AML sufferers,5 examples express masculine of the BCRP mRNA,CR1 1 example,CR1 rate is 20.0%;The BCRP mRNA expressing negative are 7 examples,CR1 5 examples,the CR1 rate is 71.4%,the difference have already shown the covariance meaning(P=0.0000).Combine the related data of the clinic diagnosis,the BCRP mRNA of the initial sensitive treatment set is lowest,average is 0.052±0.037;The relapse set and drug resistance set are higher,0.254±0.288 and 0.372±0.364.Leaming by covariance examination,there had covariance meaning among the initial sensitive treatment set and the replase set,drug resistance set(P＜0.05).But it's no meaning between the replase set and drug resistance set(P＞0.05).the BCRP masculine in 5 initial sensitive set is 1 example,the masculine rate is 20%,the BCRP masculine in 11 drug resistance set are 5 examples,the masculine rate reaches to 45.4%,learning by statistical analyzation have the difference(P＜0.05).In 20 AMLs,in addition to M_1,M_6,the M_7 number less,in 5 second types,all have the expression of BCRP gene.M_5 6 examples,the BCRP opposite expression level is the tallest,measure to 0.340±0.368,M_2 4 examples,the expression level is lowest,measure to 0.177±0.269,but the analysis learning by covariance didn't show the difference(P=0.206).In each type,the masculine rate of the BCRP gene expression also has difference.The M_5 is the tallest,there be 3 masccline examples in 6 samples,the rate is 50%,then M_3,M_4,M_2 secondly,distinguish to 33.3%,33.3%,25%,through the analysis,its difference didn't show meaning.The BCRP protein expression have different degree in relapse set,initial sensitive treatment set and drug resistance set,the difference shows meaning (P＜0.05),but relapse set and drug resistance set,the difference doesn't show meaning(P＞0.05).9 examples are masculine of BCRP protein expression in 20 AML sufferers,at different clinical stage,the masccline rate dissimilarity,the initial sensitive treatment set is lowest,an only 5 examples are masculine,the rate is 20%(1/5),3 masculine in 8 relapse examples,the rate is 37.5%(3/8),the masculine rate of the clinic drug resistance set is tallest,45.4%.(5/11).And in mRNA related analytical manifestation,4 examples express negative of the BCRP protein but the mRNA expression is masculine,both have no relativity.The inhibition ratio of DNR checks single cell with 20 AMLs is difference,16-folds densities is higher than single density,equally inhibition ratio is(33.87±16.36)%,(16.3±18.37)%,there is presented a density dependence phenomenon.Regard to the high sensitive examples in 20 AMLs,there are 4 examples under the 16-folds densities,under the single density it si only for 1 example,the difference has already shown statistic meaning(P＜0.05).At single density,the inhibition ratio of DNR to the initial sensitive treatment set is(27.59±25.12)%,the drug resistance set is(11.03±14.55)%,the difference didn't have meaning(P=0.115).Under the 16-folds density,the inhibition ratio of DNR to the initial sensitive treatment set shows(44.49±20.89)%,the drug resistance set is(20.89±9.34)%,the difference shows meaning(P=0.025).Under the single density,the inhibition ratio of DNR to the negative set is(24.09±18.68)%,the masccline set is(1.99±0.80)%,there has a statistic meaning(P=0.001).Under 16-folds densities,the inhibition ratio of DNR to the negative expression set is(39.26±15.25)%,the masccline expression set is(20.58±3.67)%(P=0.002).
On the whole,the CR rate of the BCRP mRNA masccline be lower than negative in the initial treatment AML;compareing the BCRP gene expression level of the clinical drug resistance set and the sensitive set,the former is obviously high in the latter;The BCRP expression of each AML type didn't show difference obviously;The expression level of the BCRP protein comparison,the initial treatment sensitive set and drug resistance set,relapses set show much difference,but relapses set and drug resistance set doesn't show difference;The repellency to medicine of the different BCRP expression cell a obvious amount of-effect relation(P＜0.05).Under 16-fold densities,comparing the inhibition ratio of NDR cure,the sensitive set is super than the drug set, BCRP mRNA masccline set be super than negative set(P＜0.05).
引文
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13、 Maliepaard M,Scheffer GL,Faneyle IF,et al.Subcellular localization and distribution of the breast cancer resisitance protein transporter in normal human tissues.Cancer Res.2001,61:3458-3464.
14、 Scheffer GL,Malipaard M,Asriane LM,et al.Breast cancer resistance protein is localized at the plasma membrane in mitoxantrone and Topotecan-resistant cell lines.Cancer Res.2000,60:2589-2593.
15、 Valera ET,Lucio-Eterovic AK,Neder L,et al.Quantitative PCR analysis of the expression profile of genes related to multiple drug resistance in tumors of the central nervous system. J Neurooncol.2007,85(1): 1-10.
16、 Jonker JW,Buitelaar M,Wagenaar E,et al.The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proceedings of the National Academy of Sciences of the USA.2002,99:15649-15654.
17、 Zhou S,Morris JJ,Barnes Y,et al.Bcrp1 gene expression is required for normal numbers of side population stem cells in mice,and confers relative protection to mitoxantrone in hematopoietic cells in vivo.Proceedings of the National Academy of Sciences of the USA.2002,99:12339-12344.
18、 Biren Saraiya,Murugesan Gounder,Jayeeta Dutta,et al.Sequential topoisomerase targeting and analysis of mechanisms of resistance to topotecan in patients with acute myelogenous leukemia.Anti-Cancer Drugs.2008,19:411-420
19、 Ifergan I,Shafran A,Jansen G, et al.Folate deprivation results in the loss of breast cancer resistance protein (BCRP/ABCG2) expression. A role for BCRP in cellular folate homeostasis.Journal of Biologcal Chemistry.2004,279:25527-25534.
20、 Zhou S,Schuetz JD,Bunting KD,et al.The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype.Nature Medicine.2001,7:1028-1034.
21、 Scharenberg CW, Harkey M,&Torok-Storb B.The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors.Blood.2002,99:507-512.
22、 Krishnamurthy P,Ross DD,Nakanishi T,et al.The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. Journal of Biological Chemistry.2004,279:24218-24225.
23、 Rabindran SK,He H,Singh M,et al.Reversal of a novel multidrug resistance mechanism inhuman colon carcinoma cells by fumitrem orgin C.Cancer Research. 1998,58:5850-5858.
24、 Allen JD,van Loevezijn A,Lakhai JM,et al.Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C. Molecular Cancer Therapeutics.2002,1 (6) :417-425.
25、 Doyle LA,&Ross DD.Multidrag resistance mediated by the breast cancer resistance protein BCRP(ABCG2).Oncogene.2003,22:7340-7358.
26、 Caroline Henrike Storch,Robert Ehehalt,Walter Emil Haefeli,et al.Localization of the human breast cancer resistance protein (BCRP/ABCG2) in lipid rafts/caveolae and modulation of its activity by cholesterol in vitro.Pharmacol Exp Ther.2007 Oct,323(1):257-264.
27、 Dean M,Fojo T,Bates S.Tumour stem cells and drag resistance.Nat Rev Cancer.2005,5:275-284.
28、 Morita H,Koyama K,Sugimoto Y,et al.Antimitortic activity and reversal of breast cancer resistance protein-mediated drag resistance by stilbenoids from Bletilla striata [J].Bioorg Med Chem Lett.2005,15(4): 1051-1054.
29、 Imai Y,Tsukahara S,Asada S,et al.Phytoestrogens flavonoids reverse breast cancer resistance protein ABCG2-mediated multidrug resistance[J].Cancer Res.2004,64(12):4346-4352
30、 Wang X,Morris ME.Effects of the flavonoid chrysin on nitrofurantoin pharmacokinetics in rats: potential involvement of ABCG2.Drug Metab Dispos.2007,35(2):268-274.
31、 Henriksen U,Gether U,Litman T.Effect of Walker A mutation(K86M) on oligomerization and surface targeting of the multidrug resistance transporter ABCG2[J].J Cell Sci.2005,118(7):1417-1426.
32、 Kruijtzer CM,Beijnen JH,&Schellens JH.Improvement of oral drug treatment by temporary inhibition of drug transporters and/or cytochrome P450 in the gastrointestinal tract and liver:anoverview.The Oncologist.2002,7:516-530.
33、 Brooks,Tracy A,O'Loughlin,et al.The 4'-O-benzylated doxorubicin analog WP744 overcomes resistance mediated by P-glycoprotein, multidrug resistance protein and breast cancer resistance protein in cell lines and acute myeloid leukemia cells.Investigational New Drugs.2007,25(2):115-122.
34、 Imai Y,Ishikawa E,Asada S,et al.Estrogen-mediated post tranccriptional down-regulation of breast cancer resistance protein/ABCG2[J].Cancer Res.2005,65(2):596-604.
35、 Qadir M,O'Loughlin KL,Fricke SM,et al.Cyclosporin A is a broad-spectrum multidrug resisitance modulator[J].Clin Cancer Res.2005,11(6):2320-2326.
36、 Ozvegy LC,V á rady G,Koblos G,et al.Function-dependent conformational changes of the ABCG2 multidrug transporter modify its interaction with a monoclonal antibody on the cell surface[J].J Biol Chem.2005,280(6):4219-4227.
37、 Ee PL,He X,Ross DD,et al.Modulation of breast cancer resistance protein(BCRP/ABCG2) gene expression using RNA interference [J].Mol Cancer Ther.2004,3(12):1577-1583.
38、 Kowalski P,Stein U,Scheffer GL,et al.Modulation of the atypical multidrug-resistant phenotype by a hammerhead ribozyme directed against the ABC transporter BCRP/MXR/ABCG2.Cancer Gene Therapy.2002,9(7):579-586.
39、 Kowalski P,Surowiak P,Lage H.Reversal of different drug-resistant phenotypes by an autocatalytic multiarget multiribozyme directed against the transcrits of the ABC transporters MDRl/P-gp,MRP2,and BCRP.Mol Ther.2005,11(4):508-522.
40、 Faneyte IF,Kristel PM,Maliepaard M,et al.Expression of the breast cancer resistance protein in breast cancer[J].Clin Cancer Res.2002,8(4):1068-1074.
41、 Burger H,Foekens JA,Look MP,et al.RNA expression of breast cancer resistance protein,lung resistance related protein, mutidrug resistance associated proteins 1 and 2,and multidrug resistance genel in breast cancer correlation with chemotherapeutic response [J].Clin Cancer Res.2003,9(2):827-836.
42、 Yoh KJshii G,Yokose T,et al.Breast cancer resistance protein impacts clinical outcome in platinum-based chemotherapy for advanced non-small cell lung cancer [J].Clin Cancer Res.2004,10(5): 1691-1697.
43、 Diestra JE,Condom E,Del muro XG.,et al.Expression of multidrug resistance proteins P-glycoprotein,multidrug resistance proteinl,breast cancer resistance protein and lung resistance related protein in locally advanced bladder cancer treated with neoadjuvant chemotherapy,biological and clinical implications[J].J Urol.2003,170(4):1383-1387.
44、 Sabine L,Dorina M,Eveline S,et al.The role of breast cancer resistance protein in acute lymphoblastic Leukemia.Clinical Cancer Res.2003,11 (1):5171 -5177.
45、 Sauerbrey A,Sell W,Steinbach D,et al.Expression of the BCRP gene (ABCG2/MXR/ABCP) in childhood acute lymphoblastic leukaemia[J].BrJ Haematol.2002,118 (1):147-150.
46、 Ross DD,Karp JE,Chen TT,et al.Expression of breast cancer resistance protein in blast cells from patient with acute leukemia.Blood.2000,96(1): 365-368.
47、 Ren JH,Du XY,Guo XN,et al.Relationship between resistance to chemotherapy and expression of breast cancer resistance protein BCRP) in acute leukemia.Journal of Experimental Hematology.2004,12(1):55-58.
48、 Steinbach D,Sell W,Voigt A,et al.BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia [J].Leukemia,2002,16 (8):1443-1447.
49、 Vanden MM,Wiemer EA.Sonnevel'd A,et al.Increased expression of the breast cancer resistance protein(BCRP) in relapsed or refraetory acute myeloid leukemia(AML).Leukemia.2002,16(5):833-839.
50、 van der Kolk DM,Vellenga E,Scheffer GL,et al.Expression and activity of breast cancer resistance protein (BCRP) in de novo and relapsed acute myeloid leukemia.Blood.2002,99(10):3763-3770.
51、Erinl L,Kate M,Yan W,et al.Overexpression of wild-type breast cancer resistance protein mediates methotrexate resistance.Cancer Res.2002,9(1):5035-5040.
52、 Brian L,Anne M, Barnes YX,et al.Low levels of ABCG2 expression in adult AML blast samples.Blood.2002,12(15): 4594-4601.
53、 Zhang S,Yang X,Marilyn E,et al.Flavonoids are inhibitors of Breast cancer resistance protein(ABCG2)-mediated transport.Mol Pharmacol.2004,65(5):1208-1216.
54、 Peter J,Glen S,Franklin C,et al.Imatinib Mesylate is a potent inhibitor of the ABCG2(BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro.Cancer Res.2004,64(4):2333-2337.
55、 Stein D,Sell M,et al.BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia. Leukemia.2002,16(3):1443-1447.
2、 Leith CP,Kopecky KJ,Chen IM,et al.Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein,MRP1,and LRP in acute myeloid leukemia:a Southwest Oncology Group study.Blood. 1999,94:1068.-1099.
3、 Doyle LA,YangW,Abruzzo LV,et al.A multidrug resistance transporter from humanMCF-7 breast cancer cells.Proc NatiAcad SciU SA.1998,95:15665-15670.
4、 Vanden-Heuvel-Eibrink MM, Wiemer EA, Prins A,et al.Increased expression of the breast cancer resistance protein (BCRP) in relapsed or refractory acute myeloid leukemia(AML)[J]. Leukemia.2002,16(5):833-839.
5、 Ren JH,DU XY,GUO XN,et al.Relationship between resistance to chemotherapy and expression of breast cancer resistance protein (BCRP) gene in patients with acute leukemia[J].Journal of Experimental Hematology.2004,12(1):55-58.
7、 Steinbach D,Sell W,Voigt A,et al.BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia[J].Leukemia.2002,16(8): 1443-1447.
8、任金海,杜行严,郭晓楠;急性自血病细胞的乳腺癌耐药蛋白基因表达与化疗耐药的关系;中国实验血液学杂志;2004;12(1):55-58.
9、朱兴虎,李健勇,王玮等;恶性血液病中乳腺癌耐药蛋白基因的表达;医药论坛杂志;2006;27(3):5-7
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11、袁建辉,贺智敏,吕辉等;乳腺癌耐受蛋白介导的5-氟尿嘧啶耐受及机制;中国药理学与毒理学杂志;2005;19(5):357-362.
12、李文通,周庚寅,宋现让等;MCF-7/BCRP细胞系的建立及其生物学特征;山东大学学报(医学版);2005;43(6):469-472
13.Perego P,De CesareM,De Isabella P,Carenini N,Beggiolin G,Pezzoni G,et al.A novel 7-modified camptothecin analog overcomes breast cancer resistance protein-associated resistance in a mitoxantroneoselected colon carcinoma cell line[J].Cancer Res.2001,61(16):6034-6037.
14.Ross DD.Novel mechanisms of drug resistance in leukemia.Leukemia.2000,14(3):467-473.
1、 Schinkel AH, & Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family:an overview.Advanced Drug Delivery Reviews.2003,55:3-29.
2、 Doyle LA,Yang W,Abruzzo LV,et al.A multidrug resistance transporter from human MCF-7 breast cancer cells.Proceedings of the National Academy of Sciencesof the USA. 1998,95:15665-15670.
3、 Xu J,Liu Y,Yang Y,Bates S, et al.Characterization of oligomeric human half-ABC transporter ATP-binding cassette ABCG2.Journal of Biological Chemistry.2004,279:19781-19789.
4、 Honjo Y, Hrycyna CA,Yan QW,et al.Acquired mutations in the MXR/BCRP/ABCPgene alter substrate specificity in MXR/BCRP/ABCP overexpressing cells.Cancer Research.2001,61:6635-6639.
5、 Zamber CP,Lamba JK,Yasuda K,et al.Natural allelic variants of breast cancer resistance protein(BCRP) and their relationship to BCRP expression in human intestine.Pharmacogenetics.2003,13:19-28.
6、 Mizuarai S,Aozasa N,Kotani H,et al.Single nucleotide polymorphisms result in impaired membrane localization and reduced atpase activity in multidrug transporter ABCG2.International Journal of Cancer.2004,109:238-246.
7、 Sparreboom A,Gelderblom H,Marsh S,et al.Diflomotecan pharmacokinetics in relation to ABCG2 421C&A genotype.Clinical Pharmacology and Therapeutics.2004,76:38-44.
8、 Huang L,Wang Y,Grimm S.ATP-dependent transport of rosuvastatin in membrane vesicles expressing breast cancer resistance protein.Drug Metab Dispos.2006,34:738-742.
9、 Zhang W,Yu BN,He YJ,et al. Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males.Clin Chim Acta,2006,373:99-103.
10、 Ujhelly O,Ozvegy C,Varady G,et al.Application of a human multidrug transporter (ABCG2) variant as selectable marker in gene transfer to progenitor cells. Human Gene Therapy, 2003,14:403-412.
11、Bailey-Dell KJ,Hassel B,Doyle LA,et al.Promoter characterization and genomic organization of the human breast cancer resistance protein (ATP-binding cassette transporterG2) gene.Biochimica et Biophysica Acta.2001,1520:234-241.
12、 Ee PL,Kamalakaran S,Tonetti D,et al.Identification of a novel estrogen response element in the breast cancer resistance protein (ABCG2) gene. Cancer Research.2004,64:1247-1251.
13、 Maliepaard M,Scheffer GL,Faneyle IF,et al.Subcellular localization and distribution of the breast cancer resisitance protein transporter in normal human tissues.Cancer Res.2001,61:3458-3464.
14、 Scheffer GL,Malipaard M,Asriane LM,et al.Breast cancer resistance protein is localized at the plasma membrane in mitoxantrone and Topotecan-resistant cell lines.Cancer Res.2000,60:2589-2593.
15、 Valera ET,Lucio-Eterovic AK,Neder L,et al.Quantitative PCR analysis of the expression profile of genes related to multiple drug resistance in tumors of the central nervous system. J Neurooncol.2007,85(1): 1-10.
16、 Jonker JW,Buitelaar M,Wagenaar E,et al.The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proceedings of the National Academy of Sciences of the USA.2002,99:15649-15654.
17、 Zhou S,Morris JJ,Barnes Y,et al.Bcrp1 gene expression is required for normal numbers of side population stem cells in mice,and confers relative protection to mitoxantrone in hematopoietic cells in vivo.Proceedings of the National Academy of Sciences of the USA.2002,99:12339-12344.
18、 Biren Saraiya,Murugesan Gounder,Jayeeta Dutta,et al.Sequential topoisomerase targeting and analysis of mechanisms of resistance to topotecan in patients with acute myelogenous leukemia.Anti-Cancer Drugs.2008,19:411-420
19、 Ifergan I,Shafran A,Jansen G, et al.Folate deprivation results in the loss of breast cancer resistance protein (BCRP/ABCG2) expression. A role for BCRP in cellular folate homeostasis.Journal of Biologcal Chemistry.2004,279:25527-25534.
20、 Zhou S,Schuetz JD,Bunting KD,et al.The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype.Nature Medicine.2001,7:1028-1034.
21、 Scharenberg CW, Harkey M,&Torok-Storb B.The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors.Blood.2002,99:507-512.
22、 Krishnamurthy P,Ross DD,Nakanishi T,et al.The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. Journal of Biological Chemistry.2004,279:24218-24225.
23、 Rabindran SK,He H,Singh M,et al.Reversal of a novel multidrug resistance mechanism inhuman colon carcinoma cells by fumitrem orgin C.Cancer Research. 1998,58:5850-5858.
24、 Allen JD,van Loevezijn A,Lakhai JM,et al.Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C. Molecular Cancer Therapeutics.2002,1 (6) :417-425.
25、 Doyle LA,&Ross DD.Multidrag resistance mediated by the breast cancer resistance protein BCRP(ABCG2).Oncogene.2003,22:7340-7358.
26、 Caroline Henrike Storch,Robert Ehehalt,Walter Emil Haefeli,et al.Localization of the human breast cancer resistance protein (BCRP/ABCG2) in lipid rafts/caveolae and modulation of its activity by cholesterol in vitro.Pharmacol Exp Ther.2007 Oct,323(1):257-264.
27、 Dean M,Fojo T,Bates S.Tumour stem cells and drag resistance.Nat Rev Cancer.2005,5:275-284.
28、 Morita H,Koyama K,Sugimoto Y,et al.Antimitortic activity and reversal of breast cancer resistance protein-mediated drag resistance by stilbenoids from Bletilla striata [J].Bioorg Med Chem Lett.2005,15(4): 1051-1054.
29、 Imai Y,Tsukahara S,Asada S,et al.Phytoestrogens flavonoids reverse breast cancer resistance protein ABCG2-mediated multidrug resistance[J].Cancer Res.2004,64(12):4346-4352
30、 Wang X,Morris ME.Effects of the flavonoid chrysin on nitrofurantoin pharmacokinetics in rats: potential involvement of ABCG2.Drug Metab Dispos.2007,35(2):268-274.
31、 Henriksen U,Gether U,Litman T.Effect of Walker A mutation(K86M) on oligomerization and surface targeting of the multidrug resistance transporter ABCG2[J].J Cell Sci.2005,118(7):1417-1426.
32、 Kruijtzer CM,Beijnen JH,&Schellens JH.Improvement of oral drug treatment by temporary inhibition of drug transporters and/or cytochrome P450 in the gastrointestinal tract and liver:anoverview.The Oncologist.2002,7:516-530.
33、 Brooks,Tracy A,O'Loughlin,et al.The 4'-O-benzylated doxorubicin analog WP744 overcomes resistance mediated by P-glycoprotein, multidrug resistance protein and breast cancer resistance protein in cell lines and acute myeloid leukemia cells.Investigational New Drugs.2007,25(2):115-122.
34、 Imai Y,Ishikawa E,Asada S,et al.Estrogen-mediated post tranccriptional down-regulation of breast cancer resistance protein/ABCG2[J].Cancer Res.2005,65(2):596-604.
35、 Qadir M,O'Loughlin KL,Fricke SM,et al.Cyclosporin A is a broad-spectrum multidrug resisitance modulator[J].Clin Cancer Res.2005,11(6):2320-2326.
36、 Ozvegy LC,V á rady G,Koblos G,et al.Function-dependent conformational changes of the ABCG2 multidrug transporter modify its interaction with a monoclonal antibody on the cell surface[J].J Biol Chem.2005,280(6):4219-4227.
37、 Ee PL,He X,Ross DD,et al.Modulation of breast cancer resistance protein(BCRP/ABCG2) gene expression using RNA interference [J].Mol Cancer Ther.2004,3(12):1577-1583.
38、 Kowalski P,Stein U,Scheffer GL,et al.Modulation of the atypical multidrug-resistant phenotype by a hammerhead ribozyme directed against the ABC transporter BCRP/MXR/ABCG2.Cancer Gene Therapy.2002,9(7):579-586.
39、 Kowalski P,Surowiak P,Lage H.Reversal of different drug-resistant phenotypes by an autocatalytic multiarget multiribozyme directed against the transcrits of the ABC transporters MDRl/P-gp,MRP2,and BCRP.Mol Ther.2005,11(4):508-522.
40、 Faneyte IF,Kristel PM,Maliepaard M,et al.Expression of the breast cancer resistance protein in breast cancer[J].Clin Cancer Res.2002,8(4):1068-1074.
41、 Burger H,Foekens JA,Look MP,et al.RNA expression of breast cancer resistance protein,lung resistance related protein, mutidrug resistance associated proteins 1 and 2,and multidrug resistance genel in breast cancer correlation with chemotherapeutic response [J].Clin Cancer Res.2003,9(2):827-836.
42、 Yoh KJshii G,Yokose T,et al.Breast cancer resistance protein impacts clinical outcome in platinum-based chemotherapy for advanced non-small cell lung cancer [J].Clin Cancer Res.2004,10(5): 1691-1697.
43、 Diestra JE,Condom E,Del muro XG.,et al.Expression of multidrug resistance proteins P-glycoprotein,multidrug resistance proteinl,breast cancer resistance protein and lung resistance related protein in locally advanced bladder cancer treated with neoadjuvant chemotherapy,biological and clinical implications[J].J Urol.2003,170(4):1383-1387.
44、 Sabine L,Dorina M,Eveline S,et al.The role of breast cancer resistance protein in acute lymphoblastic Leukemia.Clinical Cancer Res.2003,11 (1):5171 -5177.
45、 Sauerbrey A,Sell W,Steinbach D,et al.Expression of the BCRP gene (ABCG2/MXR/ABCP) in childhood acute lymphoblastic leukaemia[J].BrJ Haematol.2002,118 (1):147-150.
46、 Ross DD,Karp JE,Chen TT,et al.Expression of breast cancer resistance protein in blast cells from patient with acute leukemia.Blood.2000,96(1): 365-368.
47、 Ren JH,Du XY,Guo XN,et al.Relationship between resistance to chemotherapy and expression of breast cancer resistance protein BCRP) in acute leukemia.Journal of Experimental Hematology.2004,12(1):55-58.
48、 Steinbach D,Sell W,Voigt A,et al.BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia [J].Leukemia,2002,16 (8):1443-1447.
49、 Vanden MM,Wiemer EA.Sonnevel'd A,et al.Increased expression of the breast cancer resistance protein(BCRP) in relapsed or refraetory acute myeloid leukemia(AML).Leukemia.2002,16(5):833-839.
50、 van der Kolk DM,Vellenga E,Scheffer GL,et al.Expression and activity of breast cancer resistance protein (BCRP) in de novo and relapsed acute myeloid leukemia.Blood.2002,99(10):3763-3770.
51、Erinl L,Kate M,Yan W,et al.Overexpression of wild-type breast cancer resistance protein mediates methotrexate resistance.Cancer Res.2002,9(1):5035-5040.
52、 Brian L,Anne M, Barnes YX,et al.Low levels of ABCG2 expression in adult AML blast samples.Blood.2002,12(15): 4594-4601.
53、 Zhang S,Yang X,Marilyn E,et al.Flavonoids are inhibitors of Breast cancer resistance protein(ABCG2)-mediated transport.Mol Pharmacol.2004,65(5):1208-1216.
54、 Peter J,Glen S,Franklin C,et al.Imatinib Mesylate is a potent inhibitor of the ABCG2(BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro.Cancer Res.2004,64(4):2333-2337.
55、 Stein D,Sell M,et al.BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia. Leukemia.2002,16(3):1443-1447.