The pharmacological phenotype of combined multidrug-resistance mdr1a/1b- and mrp1-deficient mice.
The pharmacological phenotype of combined multidrug-resistance mdr1a/1b- and mrp1-deficient mice.
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多重耐药 mdr1a/1b 和 mrp1 缺陷小鼠的药理学表型。
作者：
Dennis R. Johnson;R. A. Finch;Z. Lin;Caroline J. Zeiss;Alan C. Sartorelli
两大类质膜蛋白以不同的作用机制从细胞中主动挤出广泛的结构多样的疏水性两亲性药物，导致多药耐药性。为了研究这些ATP结合盒转运蛋白对癌症化疗药物毒性的重要性，我们使用了mdr 1a和mdr 1b基因均遗传缺陷的小鼠[mdr 1a/1b（-/-）小鼠]、mrp 1基因[mrp 1（-/-）小鼠]以及mdr 1a/1b和mrp 1组合基因[mdr 1a/1b（-/-），mrp 1（-/-）小鼠]和来自野生型小鼠和三种基因敲除动物的胚胎成纤维细胞。主要使用长春新碱和依托泊苷评价输出泵缺陷的后果。mdr 1a/1b和mrp 1这三种基因缺陷的小鼠对长春新碱的毒性增加128倍，对依托泊苷的毒性增加3-5倍;长春新碱和依托泊苷对三重基因敲除小鼠的胚胎成纤维细胞的毒性也增加。当以治疗剂量使用时，通常不会对骨髓和胃肠道粘膜产生毒性，但在mdr 1a/1b（-/-）、mrp 1（-/-）小鼠中会对这些组织造成广泛损伤。研究结果表明，P-糖蛋白和mrpl是骨髓和胃肠道粘膜中长春新碱和依托泊苷的代偿性转运蛋白，并强调了联合抑制这些外排泵可能增加毒性。
Two major classes of plasma membrane proteins that actively extrude a wide range of structurally diverse hydrophobic amphipathic antineoplastic agents from cells, with different mechanisms of action, lead to multidrug resistance. To study the importance of these ATP-binding cassette transporters to the toxicity of cancer chemotherapy agents, we have used mice genetically deficient in both the mdr1a and mdr1b genes [mdr1a/1b(-/-) mice], the mrp1 gene [mrp1(-/-) mice], and the combined genes mdr1a/1b and mrp1 [mdr1a/1b(-/-), mrp1(-/-) mice] and embryonic fibroblasts derived from wild-type mice and from the three gene knockout animals. The consequences of export pump deficiencies were evaluated primarily using vincristine and etoposide. Mice deficient in the three genes, mdr1a/1b and mrp1, exhibited a 128-fold increase in toxicity to vincristine and a 3-5-fold increase in toxicity to etoposide; increased toxicity to embryonic fibroblast cells from triple knockout mice also occurred with vincristine and etoposide. Vincristine, which normally does not express toxicity to the bone marrow and to the gastrointestinal mucosa when used at therapeutic doses, caused extensive damage to these tissues in mdr1a/1b(-/-), mrp1(-/-) mice. The findings indicate that the P-glycoprotein and mrpl are compensatory transporters for vincristine and etoposide in the bone marrow and the gastrointestinal mucosa and emphasize the potential for increased toxicities by the combined inhibition of these efflux pumps.
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影响因子：
11.2
作者：
A. Lorico;G. Rappa;R. A. Finch;Di Yang;R. A. Flavell;Alan C. Sartorelli
通讯作者：
A. Lorico;G. Rappa;R. A. Finch;Di Yang;R. A. Flavell;Alan C. Sartorelli
尽管环孢素可以逆转 P-糖蛋白，但视网膜母细胞瘤中的多药耐药蛋白 (MRP) 表达与化疗的罕见失败相关。
影响因子：
11.2
作者：
Chan,HS;Lu,Y;Grogan,TM;Haddad,G;Hipfner,DR;Cole,SP;Deeley,RG;Ling,V;Gallie,BL
通讯作者：
Gallie,BL
影响因子：
11.2
作者：
G. Rappa;A. Lorico;R. Flavell;A. Sartorelli
通讯作者：
G. Rappa;A. Lorico;R. Flavell;A. Sartorelli
MRP 基因的双敲除导致体外药物敏感性增加。
影响因子：
11.2
作者：
Lorico,A;Rappa,G;Flavell,RA;Sartorelli,AC
通讯作者：
Sartorelli,AC
DOI：
10.1073/pnas.88.6.2065
发表时间：
1991-03-01
影响因子：
11.1
作者：
TAKETO, M;SCHROEDER, AC;OVERBEEK, PA
通讯作者：
OVERBEEK, PA