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研究生:魏振峰
研究生(外文):Wei,Cheng-Fung
論文名稱:中藥藥引純成分對乳癌抗藥性蛋白(BCRP)功能調控之研究
論文名稱(外文):Study of functional modulation of breast cancer resistance protein (BCRP) from pure constituents of Chinese herbal enhancers
指導教授:鮑力恆鮑力恆引用關係
學位類別:碩士
校院名稱:國防醫學院
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:160
中文關鍵詞:乳癌抗藥性蛋白
外文關鍵詞:BCRP
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Breast cancer resistance protein(BCRP)在人體中廣泛分佈於正常組織中之細胞表層,尤其腸道細胞中 BCRP 造成藥物吸收不佳的情況,而影響藥物治療的效果。若能有效的調控 BCRP 之功能,不僅可以增加藥物腸道吸收,提高口服生體可用率,也降低個體間藥物吸收的差異,便可以增加抗癌藥物的療效。本論文研究目的即在天然中草藥中研究及尋找 BCRP 調控劑,以改善口服藥物之生體可用率、減少個體間藥物吸收的差異及降低抗癌藥物之多重抗藥性。
本實驗是用 H460/MX20當體外篩選試驗之細胞株,研究中草藥對BCRP 調控模式藥物 (mitoxantrone) 能力之影響。BCRP 功能性活性之評估可於BCRP 調控劑存在下,經流式細胞儀 (flow cytometer) 測定活細胞內累積 mitoxantrone 之螢光強度。細胞內mitoxantrone 之螢光強度增大即表示mitoxantrone於細胞內累積量增加。完成八十三種中草藥純成分之篩選,其研究結果顯示具 BCRP 調控作用的中藥藥引在0.5 M時,HUCHE 63 及 79 細胞內 mitoxantrone 蓄積量分別可增加為控制組的1.6及2.3倍 ( P<0.001) ;在5 M時,HUCHE 79、63、64、10、81和 11細胞內 mitoxantrone 蓄積量可增加為控制組的 1.8~3.3倍 ( P<0.001) ;在50 M時,HUCHE 14、44、10、11、79、63、26、81、64、37、77、01 和 34 細胞內 mitoxantrone 蓄積量可增加為控制組的 2.8~3.8倍 (P<0.001)。由體外篩選之結果可推測抑制BCRP功能之中藥藥引與口服藥物(經由 BCRP 運送)合併服用,可能會改善口服藥物之生體可用率。
進一步驗證上述體外有效成份在體內是否可以抑制腸道 BCRP 功能,而改善 BCRP 受質的口服吸收。體內實驗是以Topotecan為模式藥物於S.D. rat口服先給予HUCHE 79 (25 mg/kg),30分後再給予Topotecan (2 mg/kg),輔以液相層析串聯質譜儀進行Topotecan分析,結果顯示HUCHE 79可以明顯改善Topotecan吸收,使血中藥物濃度曲線下面積增加2倍 (P<0.05),推測其是抑制腸道BCRP 的作用,改善了口服藥物吸收。
由以上實驗結果得知,中藥藥引純成份 HUCHE 79可以改善Topotecan口服吸收之藥物動力學,因此未來開發BCRP調控劑的研究方面,HUCHE 79則將會是具有開發潛力的物質。
Physiologically, breast cancer resistance protein(BCRP)is widely expressed in the epithelial cells of tissue . In the intestine especially, BCRP causes the mal-absorption of drugs which then result in clinical therapeutic failure. However, the effective inhibition of BCRP mediated drug efflux can help improving the drug absorption in the intestinal tract, increasing bioavailability, decreasing the individual variability of drug absorption and restoring drug cytotoxic effect in cancer cells. The purpose of this research is to study potent BCRP modulators from Chinese herbal enhancers (CHEs) in order to improve drug bioavailability, decrease individual variability of drug absorption and reduce multidrug resistance in cancer therapy.
Our goal to this experiment was to setup and characterize a screening method using H460/MX20 cell line to study the effect of CHEs on BCRP-mediated transport of a model substrate, mitoxantrone (MX). The functional activities of BCRP can be estimated by measuring the fluorescent intensity of MX under flow cytometer to see the retention of MX in the presence of BCRP modulators. The increased fluorescent intensity indicated that the intracellular accumulation of MX elevated.
83 pure constituents selected from CHEs had been completed. The results indicated that the efflux of BCRP was significantly inhibited by some CHEs in concentration dependent manner. At 0.5 uM, the intracellular retention of MX of HUCHE 79 and 63 were significantly increased 1.6 to 2.3 fold (p<0.001) as compared with the control. On the other hand, HUCHE 79, 63, 64, 10, 81 and 11 at 5 uM were significantly increased 1.8 to 3.3 fold (p<0.001), and HUCHE 14, 44, 10, 11, 79, 63, 26, 81, 64, 37, 77, 0.1 and 34 at 50 uM were increased 2.8 to 3.8 fold (p<0.001) as compared with the control. The results of in vitro screening studies suggested that coadministration of BCRP-reversing CHE and BCRP-transporting oral drugs may improve the bioavailability of some orally drugs in vivo transported by BCRP.
The potent CHEs on the modulation of BCRP function will be further evaluated in vivo. The in vivo experiment was done by using the specific substrate of BCRP, topotecan, as a model substrate. Sprague-Dawley (S.D.) rats were first given HUCHE 79 (25 mg/kg), and 30 minutes after topotecan was administered p.o. (gavagingly) with or without CHEs. The plasma of the S.D. rats was then drawn and the concentration of topotecan was quantified by a liquid chromatography/tandem mass spectrometer (LC/MS/MS). The plasma concentration of topotecan following oral administration was significantly increased by coadministration of topotecan and HUCHE 79 in S.D. rats. The area under the curve (AUC) of topotecan following oral administration was strikingly increased 2 fold as compared with control. These results showed that HUCHE 79 increased the absorption of topotecan in small intestine.
Therefore, HUCHE 79 may improve pharmacokinetics of orally administered topotecan and it may be the potential substance in the future development of BCRP modulator researches.
正文目錄
頁次
第一章 緒論
一、 研究背景………………………………………………… 1
二、 乳癌抗藥性蛋白(BCRP)的起源………………………… 5
三、 ABCG family 的種類…………………………………… 8
四、 乳癌抗藥性蛋白的結構與分佈………………………… 13
五、 BCRP 的受質…………………………………………… 22
六、 BCRP 的抑制劑………………………………………… 25
七、 BCRP 的單一核苷酸多型性…………………………… 31
八、 BCRP 的生理意義……………………………………… 35
九、 BCRP 的臨床意義……………………………………… 41
十、 Flavonoids 與中藥藥引之簡介………………………… 45
十一、 體內、外模式藥物之選擇……………………………… 52
十二、 研究目的………………………………………………… 55
第二章 試劑與儀器
第一節 藥品與試劑……………………………………………… 57
第二節 細胞株…………………………………………………… 63
第三節 儀器……………………………………………………… 63
第三章 實驗方法
【體外篩選實驗方法】
第一節 H460及H460/MX20 細胞株…………………………… 65
第二節 細胞培養基配製………………………………………… 65
第三節 細胞繼代培養…………………………………………… 66
第四節 細胞計數及存活測試…………………………………… 67
第五節 篩選平台之確效-抑制細胞上 BCRP 功能之實驗… 68
壹、不同 Fumitrimorgin C(FTC)濃度對 BCRP 功能之影響 68
貳、抑制 H460/MX20 上 BCRP 功能之不同時間試驗……… 69
第六節 篩選平台之確效-Mitoxantrone 於細胞中累積之實驗 70
壹、H460/MX20 細胞內累積不同濃度之 mitoxantrone 試驗… 70
貳、H460/MX20 細胞內累積 mitoxantrone 之不同時間試驗 71
叁、H460/MX20 細胞於不同溫度下累積 mitoxantrone 之試驗 71
第七節 篩選平台之確效—H460/MX20 細胞上 P-gp 與 MRPs 活性的測試………………………………………
72
第八節 篩選平台之確效—溶劑對 H460/MX20 細胞之影響… 73
第九節 評估中草藥純成分調控 BCRP 效果………………… 74
【體內實驗方法】
第一節 動物………………………………………………………… 77
第二節 體內模式藥物……………………………………………… 77
第三節 動物口服給藥實驗………………………………………… 78
1. 控制組……………………………………………………… 78
2. 實驗組……………………………………………………… 78
第四節 Topotecan 的分析方法…………………………………… 78
1. 分析條件…………………………………………………… 78
2. 檢品處理…………………………………………………… 79
3. 校正曲線製作……………………………………………… 79
4. 數據處理及統計方法……………………………………… 80
第四章 結果與討論…………………………………………………
【體外篩選實驗】 84
第一節 篩選平台確效之相關實驗結果…………………………… 85
壹、不同 Fumitrimorgin C (FTC)濃度對 BCRP 功能之影響 85
貳、抑制 H460/MX20 上 BCRP 功能之不同時間試驗……… 86
參、H460/MX20 細胞內累積不同濃度之 mitoxantrone 試驗… 86
肆、H460/MX20 細胞內累積 mitoxantrone 之不同時間試驗… 87
伍、H460/MX20 細胞於不同溫度下累積 mitoxantrone 之試驗 88
陸、H460/MX20 細胞上 P-gp 與 MRPs 活性的測試………… 89
柒、溶劑對 H460/MX20 細胞之影響………………………… 89
第二節 評估中草藥純成分調控 BCRP 功能之結果……………… 91
【體內動物實驗】 110
第三節 評估具潛力之中藥藥引於體內動物實驗之結果………… 110
壹、動物體內模式藥物Topotecan……………………………… 110
貳、Topotecan 分析方法………………………………………… 110
參、動物口服Topotecan 之相關實驗………………………… 111
第五章 結論………………………………………………………… 130
第六章 參考文獻…………………………………………………… 131








表 目 錄
頁次
表1-1 人類ABC運輸蛋白家族…………………………………… 10
表1-2 BCRP 之受質………………………………………………… 24
表1-3 在不同種族中,人類 BCRP/ABCG2 非同義取代之 SNPs 所發生之頻率………………………………………………… 34
表1-4 中藥藥引來源簡介 49
表4-1 體外模式篩選83種中藥藥引抑制 BCRP 功能之排序…… 101
表4-2 體外篩選方式不同濃度下之 HUCHE 79 及 63 對調控 BCRP 作用之結果……………………………………………
104
表4-3 體外篩選方式不同濃度下之 HUCHE 64 及 10 對調控 BCRP 作用之結果……………………………………………
105
表4-4 體外篩選方式不同濃度下之 HUCHE 81 及 11 對調控 BCRP 作用之結果……………………………………………
106
表4-5 細胞篩選模式試驗中的試驗參數…………………………… 108
表4-6 Topotecan 於老鼠血漿中同日間之精密度與準確度試驗結果………………………………………………………………
119
表4-7 Topotecan 於老鼠血漿中異日間之精密度與準確度試驗結果………………………………………………………………
120
表4-8 Topotecan 於老鼠血漿中同日間確效之精密度與準確度試驗………………………………………………………………
121
表4-9 Topotecan 於老鼠血漿中異日間確效之精密度與準確度試驗………………………………………………………………
121
表4-10 S.D. rat 餵食中藥藥引HUCHE 63(50 mg/kg)後,口服給予Topotecan(2 mg/kg)與控制組之藥物動力學參數比較…
123
表4-11 S.D. rat 餵食中藥藥引HUCHE 10(9 mg/kg)後,口服給予Topotecan(2 mg/kg)與控制組之藥物動力學參數比較…
125
表4-12 S.D. rat 餵食中藥藥引HUCHE 64(9 mg/kg)後,口服給予Topotecan(2 mg/kg)與控制組之藥物動力學參數比較…
127
表4-13 S.D. rat 餵食中藥藥引HUCHE 79(25 mg/kg)後,口服給予Topotecan(2 mg/kg)與控制組之藥物動力學參數比較…
129






圖 目 錄
頁次
圖1-1 運輸蛋白及酵素在腸、肝細胞中之相關功能示意圖……… 4
圖1-2 ABCG運輸蛋白家族之親緣樹狀圖……………………… 11
圖1-3 ABCG運輸蛋白家族表現之位置圖……………………… 12
圖1-4A 典型ABC之全運輸蛋白結構示意圖……………………… 16
圖1-4B ABC運輸蛋白之 NBD 示意圖…………………………… 16
圖1-4C ABCG2/BCRP之半運輸蛋白結構示意圖………………… 16
圖1-5 BCRP運輸蛋白之結構示意圖…………………………… 17
圖1-6 ABCG2/BCRP運輸蛋白在人類血腦障壁、幹細胞及胎盤中所扮演保護之功能示意圖………………………………
18
圖1-7 ABCG2/BCRP運輸蛋白在人類肝及腸中所扮演物質在體內動向之功能示意圖………………………………………
19
圖1-8 BCRP mRNA 於人類大、小腸道中各部位之表現量…… 20
圖1-9 人類腸道(A)十二指腸(B)空腸(C)迴腸(D)大腸中運輸蛋白 (ABC家族與SLC家族) mRNA之表現量………………
21
圖1-10 BCRP之抑制劑…………………………………………… 30
圖1-11 人類 BCRP/ABCG2 之 SNPs 在空間上相對位置之相關性……………………………………………………………
33
圖1-12 外來物質(xenobiotics)於體內經phase Ⅰ、phase Ⅱ 及phase III系統代謝之過程…………………………………
38
圖1-13 Porphyrin 在體內之生合成及其被 BCRP/ABCG2 運送之過程………………………………………………………
39
圖1-14 Mexotrexate(MTX)流入(influx)細胞內與排出(efflux)細胞外之運送過程…………………………………………
40
圖1-15 GF120918對口服topotecan生體可用率之影響………… 44
圖1-16 Flavonoids 基本結構 48
圖3-1 評估中草藥純成分調控 BCRP 效果之篩選平台流程圖… 76
圖3-2 動物實驗口服給藥流程圖………………………………… 81
圖3-3 動物檢品處理的步驟……………………………………… 82
圖3-4 標準曲線之各濃度的配置方法…………………………… 83
圖4-1 分別選用不同濃度之 BCRP 專一性抑制劑Fumitrimorgin C加至 H460/MX20 細胞株上,觀察不同濃度 FTC 對細胞上 BCRP 功能之影響……………………………………

94
圖4-2 抑制 H460/MX20 上 BCRP 功能之不同時間試驗…… 95
圖4-3 H460/MX20 細胞內累積不同濃度之 mitoxantrone試驗 96
圖4-4 H460/MX20 細胞內累積mitoxantrone之不同時間試驗… 97
圖4-5 H460/MX20 細胞內於不同溫度累積mitoxantrone之試驗 98
圖4-6 H460/MX20 細胞上 P-gp 與 MRPs 活性的測試……… 99
圖4-7 不同種類或濃度之溶劑對H460/MX20細胞株之影響…… 100
圖4-8 體外篩選方式不同濃度下之 HUCHE 79 及 63 對調控 BCRP 作用之曲線圖………………………………………
104
圖4-9 體外篩選方式不同濃度下之 HUCHE 64 及 10 對調控 BCRP 作用之曲線圖………………………………………
105
圖4-10 體外篩選方式不同濃度下之 HUCHE 81 及 11 對調控 BCRP 作用之曲線圖………………………………………
106
圖4-11 中藥藥引自身之背景螢光值……………………………… 107
圖4-12 每次篩選實驗中,陽性控制組相對之平均螢光強度值… 109
圖4-13 Topotecan (LLOQ: 5 ng/ml) 於老鼠血漿中之液相層析串聯質譜儀圖譜…………………………………………… 118
圖4-14 Topotecan 於老鼠血漿中同日間之標準曲線…………… 119
圖4-15 Topotecan 於老鼠血漿中異日間之標準曲線…………… 120
圖4-16 S.D. rat 餵食中藥藥引HUCHE 63(50 mg/kg)後,口服給予Topotecan(2 mg/kg)與控制組之血中濃度比較……
122
圖4-17 S.D. rat 餵食中藥藥引HUCHE 10(9 mg/kg)後,口服給予Topotecan(2 mg/kg)與控制組之血中濃度比較……
124
圖4-18 S.D. rat 餵食中藥藥引HUCHE 64(9 mg/kg)後,口服給予Topotecan(2 mg/kg)與控制組之血中濃度比較……
126
圖4-19 S.D. rat 餵食中藥藥引HUCHE 79(25 mg/kg)後,口服給予Topotecan(2 mg/kg)與控制組之血中濃度比較……
128
附錄圖
1-1 體外篩選方式 50 μM HUCHE 1、3~6 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖…………………… 142
附錄圖
1-2 體外篩選方式 50 μM HUCHE 7~11 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖…………………… 143
附錄圖
1-3 體外篩選方式 50 μM HUCHE 12~16 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖…………………… 144
附錄圖
1-4 體外篩選方式 50 μM HUCHE 17~21 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖…………………… 145
附錄圖
1-5 體外篩選方式 50 μM HUCHE 22~26 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖…………………… 146
附錄圖
1-6 體外篩選方式 50 μM HUCHE 27~31 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖…………………… 147
附錄圖
1-7 體外篩選方式 50 μM HUCHE 32~36 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖…………………… 148
附錄圖
1-8 體外篩選方式 50 μM HUCHE 37~41 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖…………………… 149
附錄圖
1-9 體外篩選方式 50 μM HUCHE 42~46 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖…………………… 150
附錄圖
1-10 體外篩選方式 50 μM HUCHE 47~51 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖…………………… 151
附錄圖
1-11 體外篩選方式 50 μM HUCHE 52~56 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖…………………… 152
附錄圖
1-12 體外篩選方式 50 μM HUCHE 57~61 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖…………………… 153
附錄圖
1-13 體外篩選方式 50 μM HUCHE 62~66 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖…………………… 154
附錄圖
1-14 體外篩選方式 50 μM HUCHE 67~71 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖…………………… 155
附錄圖
1-15 體外篩選方式 50 μM HUCHE 72~76 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖…………………… 156
附錄圖
1-16 體外篩選方式 50 μM HUCHE 2、77~83 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖………………… 157
附錄圖
1-17 體外篩選方式 5 μM HUCHE 14、10、11、79、63 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖……… 158
附錄圖
1-18 體外篩選方式 5 μM HUCHE 26、81、64、37、77 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖……… 159
附錄圖
1-19 體外篩選方式 0.5 μM HUCHE 26、81、64、37、77 及正向控制組10 μM FTC對調控 BCRP 作用之比較圖……… 160
Ahmed-Belkacem A, Pozza A, Macalou S, Perez-Victoria JM, Boumendjel A, Di Pietro A. Inhibitors of cancer cell multidrug resistance mediated by breast cancer resistance protein (BCRP/ABCG2). Anticancer Drugs. 17(3): 239-43, 2006.

Allikmets R, Schriml LM, Hutchinson A, Romano-Spica V, Dean M. A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Res. 58(23): 5337–39, 1998.

Allen JD, van Loevezijn A, Lakhai JM, van der Valk M, van Tellingen O, Reid G, Schellens JH, Koomen GJ, Schinkel AH. 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. Mol Cancer Ther. 1(6): 417-25, 2002.

Assaraf YG. The role of multidrug resistance efflux transporters in antifolate resistance and folate homeostasis. Drug Resist Updat. 9(4): 227-46, 2006.

Ader P, Wessmann A, Wolffram S. Bioavailability and metabolism of the flavonol quercetin in the pig. Free Radic Biol Med. 28(7): 1056-67, 2000.

Backstrom G, Taipalensuu J, Melhus H, Brandstrom H, Svensson AC, Artursson P,
Kindmark A. Genetic variation in the ATP-binding cassette transporter gene ABCG2 (BCRP) in a Swedish population. Eur J Pharm Sci. 18(5): 359-64, 2003.

Biedler JL, Riehm H. Cellular resistance to actinomycin D in Chinese
hamster cells in vitro: Cross-resistance, radioautographic, and cytogenetic
studies. Cancer Res. 30(4): 1174-84, 1970.

Breedveld P, Zelcer N, Pluim D, Sonmezer O, Tibben MM, Beijnen JH, Schinkel AH, van Tellingen O, Borst P, Schellens JH. Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. Cancer Res. 64(16): 5804-11, 2004.

Breedveld P, Beijnen JH, Schellens JH. Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs. Trends Pharmacol Sci. 27(1): 17-24, 2006.

Choudhuri S, Klaassen CD. Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int J Toxicol. 25(4): 231-59, 2006.

Chang G. Structure of MsbA from Vibrio cholera: A Multidrug Resistance ABC Transporter Homolog in a Closed Conformation. J Mol Biol. 330(2): 419-30, 2003.

Chen ZS, Robey RW, Belinsky MG, Shchaveleva I, Ren XQ, Sugimoto Y, Ross DD, Bates SE, Kruh GD. Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport. Cancer Res. 63(14): 4048-54, 2003.

Cole SPC, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AMV, Deeley RG. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science. 258(5088): 1650-3, 1992.

Couture L, Nash JA, Turgeon J. The ATP-Binding Cassette Transporters and Their Implication in Drug Disposition: A Special Look at the Heart. Pharmacol Rev. 58(2): 244-58, 2006.

Cooray HC, Janvilisri T, van Veen HW, Hladky SB, Barrand MA. Interaction of the breast cancer resistance protein with plant polyphenols. Biochem Biophys Res Commun. 317(1): 269-75, 2004.

Danø K. Active outward transport of daunomycin in resistant Ehrlich ascites
tumor cells. Biochim Biophys Acta. 323(3): 466-83, 1973.

De Bruin M, Miyake K, Litman T, Robey R, Bates SE. Reversal of resistance by GF120918 in cell lines expressing the ABC half-transporter, MXR. Cancer Lett. 146(2): 117-26, 1999.

Diestra JE, Scheffer GL, Catala I, Maliepaard M, Schellens JH, Scheper RJ, Germa-Lluch JR, Izquierdo MA. Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material. J Pathol. 198(2): 213-9, 2002.

Doyle LA, Rishi AK. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci. 95(26): 15665–70, 1998.

Doyle LA, Ross DD. Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene. 22(47): 7340-58, 2003.

Englund G, Rorsman F, Ronnblom A, Karlbom U, Lazorova L, Grasjo J, Kindmark A, Artursson P. Regional levels of drug transporters along the human intestinal tract: co-expression of ABC and SLC transporters and comparison with Caco-2 cells. Eur J Pharm Sci. 29(3): 269-77, 2006.

Erlichman C, Boerner SA, Hallgren CG, Spieker R, Wang XY, James CD,
Scheffer GL, Maliepaard M, Ross DD, Bible KC, Kaufmann SH. The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10- hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein- mediated drug efflux. Cancer Res. 61(2): 739-48, 2001.

Gutmann H, Hruz P, Zimmermann C, Beglinger C, Drewe J. Distribution of breast cancer resistance protein (BCRP/ABCG2) mRNA expression along the human GI tract. Biochem Pharmacol. 70(5): 695-9, 2005.

Gupta A, Zhang Y, Unadkat JD, Mao Q. HIV protease inhibitors are inhibitors but not substrates of the human breast cancer resistance protein (BCRP/ABCG2). J Pharmacol Exp Ther. 310(1): 334-41, 2004.

Galijatovic A, Otake Y, Walle UK, Walle T. Extensive metabolism of the flavonoid chrysin by human Caco-2 and Hep G2 cells. Xenobiotica. 29(12): 1241-56, 1999.

Higgins CF. ABC transporters: From microorganisms to man. Annu. Rev. Cell Biol. 8: 67–113, 1992.

Ho RH, Kim RB. Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther. 78(3): 260-77, 2005.

Houghton PJ, Germain GS, Harwood FC, Schuetz JD, Stewart CF, Buchdunger E, Traxler P. Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res. 64(7): 2333-7, 2004.

Huang L, Wang Y, Grimm S. ATP-dependent transport of rosuvastatin in membrane vesicles expressing breast cancer resistance protein. Drug Metab Dispos. 34(5): 738-42, 2006.

Honjo Y, Hrycyna CA, Yan QW, Medina-Perez WY, Robey RW, van de Laar A, Litman T, Dean M, Bates SE. Acquired mutations in the MXR/BCRP/ABCP gene alter substrate specificity in MXR/BCRP/ABCP-overexpressing cells. Cancer Res. 61(18): 6635-9, 2000.

Henrich CJ, Bokesch HR, Dean M, Bates SE, Robey RW, Goncharova EI, Wilson JA, McMahon JB. A high-throughput cell-based assay for inhibitors of ABCG2 activity. J Biomol Screen. 11(2): 176-83, 2006.

Imai Y, Asada S, Tsukahara S, Ishikawa E, Tsuruo T, Sugimoto Y. Breast cancer resistance protein exports sulfated estrogens but not free estrogens. Mol Pharmacol. 64(3): 610-8, 2003.

Imai Y, Tsukahara S, Asada S, Sugimoto Y. Phytoestrogens/flavonoids reverse breast cancer resistance protein/ABCG2-mediated multidrug resistance. Cancer Res. 64(12): 4346-52, 2004.

Ishikawa T, Tamura A, Saito H, Wakabayashi K, Nakagawa H. Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design. Naturwissenschaften. 92(10): 451-63, 2005.

Imai Y, Nakane M, Kage K, Tsukahara S, Ishikawa E, Tsuruo T, Miki Y, Sugimoto Y. C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance. Mol Cancer Ther. 1(8): 611-6, 2002.

Ishikawa T. The ATP-dependent glutathione S-conjugate export pump. Trends Biochem Sci. 17(11): 463-8, 1992.

Ifergan I, Shafran A, Jansen G, Hooijberg JH, Scheffer GL, Assaraf YG. Folate deprivation results in the loss of breast cancer resistance protein (BCRP/ABCG2) expression. A role for BCRP in cellular folate homeostasis. J Biol Chem. 279(24): 25527-34, 2004.

Jonker JW, Smit JW, Brinkhuis RF, Maliepaard M, Beijnen JH, Schellens JH, Schinkel AH. Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst. 92(20): 1651-6, 2000.

Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in
Chinese hamster ovary cell mutants. Biochim Biophys Acta. 455(1): 152-62, 1976.

Ji Y, Morris ME. Effect of organic isothiocyanates on breast cancer resistance protein (ABCG2)-mediated transport. Pharm Res. 21(12): 2261-9, 2004.

Jonker JW, Buitelaar M, Wagenaar E, Van Der Valk MA, Scheffer GL, Scheper RJ, Plosch T, Kuipers F, Elferink RP, Rosing H, Beijnen JH, Schinkel AH. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc Natl Acad Sci U S A. 99(24): 15649-54, 2002.

Kruijtzer CM, Beijnen JH, Rosing H, ten Bokkel Huinink WW, Schot M, Jewell RC, Paul EM, Schellens JH. Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol. 20(13): 2943-50, 2002.

Kuppens IE, Breedveld P, Beijnen JH, Schellens JH. Modulation of oral drug bioavailability: from preclinical mechanism to therapeutic application. Cancer Invest. 23(5): 443-64, 2005.

Kusuhara H, Sugiyama Y. ATP-binding cassette, subfamily G (ABCG family). Pflugers Arch. 453(5): 735-44, 2006.

Kobayashi D, Ieiri I, Hirota T, Takane H, Maegawa S, Kigawa J, Suzuki H, Nanba E, Oshimura M, Terakawa N, Otsubo K, Mine K, Sugiyama Y. Functional assessment of ABCG2 (BCRP) gene polymorphisms to protein expression in human placenta. Drug Metab Dispos. 33(1): 94-101, 2005.

Kondo C, Suzuki H, Itoda M, Ozawa S, Sawada J, Kobayashi D, Ieiri I, Mine K, Ohtsubo K, Sugiyama Y. Functional analysis of SNPs variants of BCRP/ABCG2. Pharm Res. 21(10): 1895-903, 2004.

Krishnamurthy P, Schuetz JD. The ABC transporter Abcg2/Bcrp: role in hypoxia mediated survival. Biometals. 18(4): 349-58, 2005.

Kruijtzer CM, Beijnen JH, Rosing H, ten Bokkel Huinink WW, Schot M, Jewell RC, Paul EM, Schellens JH. Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol. 20(13): 2943-50, 2002.

Kruijtzer CM, Beijnen JH, Rosing H, ten Bokkel Huinink WW, Schot M, Jewell RC, Paul EM, Schellens JH. Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol. 20(13): 2943-50, 2002.

Lee JS, Scala S, Matsumoto Y, Dickstein B, Robey R, Zhan Z, Altenberg G,
Bates SE. Reduced drug accumulation and multidrug resistance in human
breast cancer cells without associated P-glycoprotein or MRP overexpression. J Cell Biochem. 65(4): 513-26, 1997.

Litman T, Druley TE, Stein WD, Bates SE. From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance. Cell Mol Life Sci. 58(7): 931-59, 2001.

Miyake K, Mickley L, Litman T, Zhan Z, Robey R, Cristensen B, Brangi M, Greenberger L, Dean M, Fojo T, Bates SE. Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes. Cancer Res. 59(1): 8–13, 1999.

Mao Q, Unadkat JD. Role of the breast cancer resistance protein (ABCG2) in drug transport. AAPS J. 7(1): 118-33, 2005.

Minderman H, Suvannasankha A, O'Loughlin KL, Scheffer GL, Scheper RJ,
Robey RW, Baer MR. Flow cytometric analysis of breast cancer resistance protein expression and function. Cytometry. 48(2): 59-65, 2002.

Minderman H, O'Loughlin KL, Pendyala L, Baer MR. VX-710 (biricodar) increases drug retention and enhances chemosensitivity in resistant cells overexpressing P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein. Clin Cancer Res. 10(5): 1826-34, 2004.

Mathijssen RH, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G,
Sparreboom A. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res. 7(8): 2182-94, 2001.

Mizuarai S, Aozasa N, Kotani H. Single nucleotide polymorphisms result in impaired membrane localization and reduced atpase activity in multidrug transporter ABCG2. Int J Cancer. 109(2): 238-46, 2004.

Moran RG. Roles of folylpoly-gamma-glutamate synthetase in therapeutics with tetrahydrofolate antimetabolites: an overview. Semin Oncol. 26(2): 24-32, 1999.

Morris ME, Zhang S. Flavonoid-drug interactions: effects of flavonoids on ABC transporters. Life Sci. 78(18): 2116-30, 2006.

Manach C, Morand C, Demigne C, Texier O, Regerat F, Remesy C. Bioavailability of rutin and quercetin in rats. FEBS Lett. 409(1): 12-6, 1997.

Nielsen DL. Mechanisms and functional aspects of multidrug resistance in
Ehrlich ascites tumour cells. Dan Med Bull. 51(4): 393-414, 2004.

Nakagawa M, Schneider E, Dixon KH, Horton J, Kelley K, Morrow C, Cowan KH.Reduced intracellular drug accumulation in the absence of Pglycoprotein(mdr1) overexpression in mitoxantrone-resistant human MCF-7 breast cancer cells. Cancer Res. 52(22): 6175–81, 1992.

Ozvegy C, Varadi A, Sarkadi B. Characterization of drug transport, ATP hydrolysis, and nucleotide trapping by the human ABCG2 multidrug transporter. Modulation of substrate specificity by a point mutation. J Biol Chem. 277(50): 47980-90, 2002.

Richard B. Transporters and Drug Discovery: Why, When, and How. Mol Pharm. 3 (1): 26 -32, 2006.

Platzer P, Schaden S, Thalhammer T, Hamilton G, Rosenberg B, Silgoner I,
Jager W. Biotransformation of topotecan in the isolated perfused rat liver: identification of three novel metabolites. Anticancer Res. 18(4): 2695-700, 1998.

Rajendra R, Gounder MK, Saleem A, Schellens JH, Ross DD, Bates SE,
Sinko P, Rubin EH. Differential effects of the breast cancer resistance protein on the cellular accumulation and cytotoxicity of 9-aminocamptothecin and 9-nitrocamptothecin. Cancer Res. 63(12): 3228-33, 2003.

Rabindran SK, He H, Singh M, Brown E, Collins KI, Annable T,
Greenberger LM. Reversal of a novel multidrug resistance mechanism in human colon carcinoma cells by fumitremorgin C. Cancer Res. 58(24): 5850-8, 1998.

Rabindran SK, Ross DD, Doyle LA, Yang W, Greenberger LM. Fumitremorgin C reverses multidrug resistance in cells transfected with the breast cancer resistance protein. Cancer Res. 60(1): 47-50, 2000.

Ross DD, Karp JE, Chen TT, Doyle LA. Expression of breast cancer resistance protein in blast cells from patients with acute leukemia. Blood. 96(1): 365-8, 2000.

Rosing H, Herben VM, van Gortel-van Zomeren DM, Hop E, Kettenes-van den Bosch JJ, ten Bokkel Huinink WW, Beijnen JH. Isolation and structural confirmation of N-desmethyl topotecan, a metabolite of topotecan. Cancer Chemother Pharmacol. 39(6): 498-504, 1997.

Robey RW, Honjo Y, van de Laar A, Miyake K, Regis JT, Litman T, Bates SE.
A functional assay for detection of the mitoxantrone resistance protein, MXR (ABCG2). Biochim Biophys Acta. 1512(2): 171-82,2001.

Sarkadi B, Homolya L, Szakacs G, Varadi A. Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system. Physiol Rev. 86(4): 1179-236, 2006.

Stewart CF, Leggas M, Schuetz JD, Panetta JC, Cheshire PJ, Peterson J,Daw N, Jenkins JJ 3rd, Gilbertson R, Germain GS, Harwood FC, Houghton PJ. Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice. Cancer Res. 64(20): 7491-9, 2004.

Sugimoto Y, Tsukahara S, Imai Y, Sugimoto Y, Ueda K, Tsuruo T. Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists. Mol Cancer Ther. 2(1): 105-12, 2003.

Stouch TR, Gudmundsson O. Progress in understanding the structure- activity relationships of P-glycoprotein. Adv Drug Deliv Rev. 54(3): 315-28, 2002.

Schellens JH, Maliepaard M, Scheper RJ, Scheffer GL, Jonker JW, Smit JW,
Beijnen JH, Schinkel AH. Transport of topoisomerase I inhibitors by the breast cancer resistance protein. Potential clinical implications. Ann N Y Acad Sci. 922: 188-94, 2000.

Sparreboom A, Gelderblom H, Marsh S, Ahluwalia R, Obach R, Principe P, Twelves C, Verweij J, McLeod HL. Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype. Clin Pharmacol Ther. 76(1): 38-44, 2004.

Scalbert A, Manach C, Morand C, Remesy C, Jimenez L. Dietary polyphenols and the prevention of diseases. Crit Rev Food Sci Nutr. 45(4): 287-306, 2005.

Tseng E, Kamath A, Morris ME. Effect of organic isothiocyanates on the P-glycoprotein- and MRP1-mediated transport of daunomycin and vinblastine. Pharm Res. 19(10): 1509-15, 2002.

Tamura A, Watanabe M, Saito H, Nakagawa H, Kamachi T, Okura I, Ishikawa T. Functional validation of the genetic polymorphisms of human ATP-binding cassette (ABC) transporter ABCG2: identification of alleles that are defective in porphyrin transport. Mol Pharmacol. 70(1): 287-96, 2006.

Troger U, Stotzel B, Martens-Lobenhoffer J, Gollnick H, Meyer FP. Drug points: Severe myalgia from an interaction between treatments with pantoprazole and methotrexate. BMJ. 324(7352): 1497, 2002.

Tanaka Y, Slitt AL, Leazer TM, Maher JM, Klaassen CD. Tissue distribution and hormonal regulation of the breast cancer resistance protein (Bcrp/Abcg2) in rats and mice. Biochem Biophys Res Commun. 326(1): 181-7, 2005.

Venter JC, Adams MD, Myers EW, Li PW et al. The Sequence of the Human Genome Science. 291: 1304-50, 2002

Van Herwaarden AE, Schinkel AH. The function of breast cancer resistance protein in epithelial barriers, stem cells and milk secretion of drugs and xenotoxins. Trends Pharmacol Sci. 27(1): 10-6, 2006.

Volk EL, Farley KM, Wu Y, Li F, Robey RW, Schneider E. Overexpression of wild-type breast cancer resistance protein mediates methotrexate resistance. Cancer Res. 62(17): 5035-40, 2002.

Volk EL, Schneider E. Wild-type breast cancer resistance protein (BCRP/ABCG2) is a methotrexate polyglutamate transporter. Cancer Res. 63(17): 5538-43, 2003.

Van der Kolk DM, Vellenga E, Scheffer GL, Muller M, Bates SE, Scheper RJ, de Vries EG. Expression and activity of breast cancer resistance protein (BCRP) in de novo and relapsed acute myeloid leukemia. Blood. 99(10): 3763-70, 2002.

Wakabayashi K, Tamura A, Saito H, Onishi Y, Ishikawa T. Human ABC transporter ABCG2 in xenobiotic protection and redox biology. Drug Metab Rev. 38(3): 371-91, 2006.

Yang CJ, Horton JK, Cowan KH, Schneider E. Cross-resistance to camptothecin analogues in a mitoxantrone-resistant human breast carcinoma cell line is not due to DNA topoisomerase I alterations. Cancer Res. 55(18): 4004-9, 1995.

Yang CH, Schneider E, Kuo ML, Volk EL, Rocchi E, Chen YC.
BCRP/MXR/ABCP expression in topotecan-resistant human breast carcinomacells. Biochem Pharmacol. 60(6): 831-7, 2000.

Yanase K, Tsukahara S, Mitsuhashi J, Sugimoto Y. Functional SNPs of the breast cancer resistance protein-therapeutic effects and inhibitor development. Cancer Lett. 234(1): 73-80, 2006.

Yamazaki, M., Fujimoto, H., and Kawasaki, T. Chemistry of tremorgenic
Metabolites. I. Fumitremorgin A from Aspergillus fumigatus. Chem.
Pharm. Bull. 28: 245–254, 1980.

Yang CH, Huang CJ, Yang CS, Chu YC, Cheng AL, Whang-Peng J, Yang PC. Gefitinib reverses chemotherapy resistance in gefitinib-insensitive multidrug resistant cancer cells expressing ATP-binding cassette family protein. Cancer Res. 65(15): 6943-9, 2005.

Yoh K, Ishii G, Yokose T, Minegishi Y, Tsuta K, Goto K, Nishiwaki Y, Kodama T, Suga M, Ochiai A. Breast cancer resistance protein impacts clinical outcome in platinum-based chemotherapy for advanced non-small cell lung cancer. Clin Cancer Res. 10(5): 1691-7, 2004.

Zhang Y, Gupta A, Wang H, Zhou L, Vethanayagam RR, Unadkat JD, Mao Q. BCRP transports dipyridamole and is inhibited by calcium channel blockers. Pharm Res. 22(12): 2023-34, 2005.

Zamber CP, Lamba JK, Yasuda K, Farnum J, Thummel K, Schuetz JD, Schuetz EG. Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine. Pharmacogenetics. 13(1): 19-28, 2003.

Zhang W, Yu BN, He YJ, Fan L, Li Q, Liu ZQ, Wang A, Liu YL, Tan ZR, Fen-Jiang, Huang YF, Zhou HH. Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males. Clin Chim Acta. 373(1): 99-103, 2006.

Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, Lagutina I, Grosveld GC, Osawa M, Nakauchi H, Sorrentino BP. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med. 7(9): 1028-34, 2001.

Zhao ID, Goldman ID. Resistance to antifolates. Oncogene. 22(47): 7431–57, 2003.

Zeng H, Chen ZS, Belinsky MG, Rea PA, Kruh GD. Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res. 61(19): 7225-32, 2001.

Zhang S, Yang X, Morris ME. Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport. Mol Pharmacol. 65(5): 1208-16, 2004.

Zhang S, Wang X, Sagawa K, Morris ME. Flavonoids chrysin and benzoflavone, potent breast cancer resistance protein inhibitors, have no significant effect on topotecan pharmacokinetics in rats or mdr1a/1b (-/-) mice. Drug Metab Dispos. 33(3): 341-8, 2005.
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