Jonker J W, Smit J W, Brinkhuis R F, Maliepaard M, Beijnen J H, Schellens J H, Schinkel A H
Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
J Natl Cancer Inst. 2000 Oct 18;92(20):1651-6. doi: 10.1093/jnci/92.20.1651.
Breast cancer resistance protein (BCRP/MXR/ABCP) is a multidrug-resistance protein that is a member of the adenosine triphosphate-binding cassette family of drug transporters. BCRP can render tumor cells resistant to the anticancer drugs topotecan, mitoxantrone, doxorubicin, and daunorubicin. To investigate the physiologic role of BCRP, we used polarized mammalian cell lines to determine the direction of BCRP drug transport. We also used the BCRP inhibitor GF120918 to assess the role of BCRP in protecting mice against xenobiotic drugs. Bcrp1, the murine homologue of BCRP, was expressed in the polarized mammalian cell lines LLC-PK1 and MDCK-II, and the direction of Bcrp1-mediated transport of topotecan and mitoxantrone was determined. To avoid the confounding drug transport provided by P-glycoprotein (P-gp), the roles of Bcrp1 in the bioavailability of topotecan and the effect of GF120918 were studied in both wild-type and P-gp-deficient mice and their fetuses.
Bcrp1 mediated apically directed transport of drugs in polarized cell lines. When both topotecan and GF120918 were administered orally, the bioavailability (i.e., the extent to which a drug becomes available to a target tissue after administration) of topotecan in plasma was dramatically increased in P-gp-deficient mice (greater than sixfold) and wild-type mice (greater than ninefold), compared with the control (i.e., vehicle-treated) mice. Furthermore, treatment with GF120918 decreased plasma clearance and hepatobiliary excretion of topotecan and increased (re-)uptake by the small intestine. In pregnant GF120918-treated, P-gp-deficient mice, relative fetal penetration of topotecan was twofold higher than that in pregnant vehicle-treated mice, suggesting a function for BCRP in the maternal-fetal barrier of the placenta.
Bcrp1 mediates apically directed drug transport, appears to reduce drug bioavailability, and protects fetuses against drugs. We propose that strategic application of BCRP inhibitors may thus lead to more effective oral chemotherapy with topotecan or other BCRP substrate drugs.
乳腺癌耐药蛋白（BCRP/MXR/ABCP）是一种多药耐药蛋白，属于三磷酸腺苷结合盒式药物转运体家族。BCRP可使肿瘤细胞对抗癌药物拓扑替康、米托蒽醌、阿霉素和柔红霉素产生耐药性。为研究BCRP的生理作用，我们使用极化哺乳动物细胞系来确定BCRP药物转运的方向。我们还使用BCRP抑制剂GF120918来评估BCRP在保护小鼠免受外源性药物影响方面的作用。BCRP的小鼠同源物Bcrp1在极化哺乳动物细胞系LLC-PK1和MDCK-II中表达，并确定了Bcrp1介导的拓扑替康和米托蒽醌转运方向。为避免P-糖蛋白（P-gp）提供的混淆药物转运，在野生型和P-gp缺陷型小鼠及其胎儿中研究了Bcrp1在拓扑替康生物利用度方面的作用以及GF120918的影响。
Bcrp1在极化细胞系中介导药物的顶端定向转运。当口服拓扑替康和GF120918时，与对照（即给予赋形剂处理）小鼠相比，P-gp缺陷型小鼠（大于六倍）和野生型小鼠（大于九倍）血浆中拓扑替康的生物利用度（即给药后药物可被靶组织利用的程度）显著增加。此外，用GF120918处理可降低拓扑替康的血浆清除率和肝胆排泄，并增加小肠的（再）摄取。在怀孕的经GF120918处理的P-gp缺陷型小鼠中，拓扑替康的相对胎儿渗透率比怀孕的经赋形剂处理的小鼠高两倍，表明BCRP在胎盘的母胎屏障中发挥作用。
Bcrp1介导顶端定向药物转运，似乎会降低药物生物利用度，并保护胎儿免受药物影响。我们提出，因此，战略性应用BCRP抑制剂可能会导致使用拓扑替康或其他BCRP底物药物进行更有效的口服化疗。
