van Ark-Otte J, Samelis G, Rubio G, Lopez Saez J B, Pinedo H M, Giaccone G
University Hospital Vrije Universiteit, Department of Oncology, Amsterdam, The Netherlands.
Oncol Rep. 1998 Jan-Feb;5(1):249-55.
Drug sensitivity was studied for the tubulin inhibitors taxol, taxotere, rhizoxin and for doxorubucin and cisplatin, in human lung and breast cancer cell lines, including drug-selected cell lines, overexpressing the membrane transporter P-glycoprotein (Pgp) or the multidrug resistance protein (MRP). All tubulin-inhibiting agents were more potent than doxorubicin and cisplatin in all cell lines. In the drug resistance-selected cell lines (doxorubicin or mitoxantrone resistant) there was cross-resistance between the tubulin inhibitors and the selecting agent; however, MRP overexpressing cells were relatively less resistant to taxanes than the Pgp overexpressing cells. Polymerization of microtubules after exposure to taxol was observed in drug sensitive cell lines, but not in resistant cell lines, even at high taxol concentrations and after long exposure times. In the Pgp overexpressing cell lines, steady accumulation of 14C-taxol was defective and could be reverted by verapamil. MRP overexpressing cells did not have a significant accumulation defect of taxol, compared to the parental cell lines, and verapamil did not have any effect. These data confirm that the Pgp overexpression is an important mechanism of resistance to taxanes and rhizoxin in human lung and breast tumor cells. However, the presence of mechanisms other than transport defects may play an important role in non-Pgp expressing cells, and these may include an altered function of tubulins.
在人肺癌和乳腺癌细胞系中，包括药物选择的细胞系，对微管蛋白抑制剂紫杉醇、多西他赛、根霉素以及阿霉素和顺铂的药物敏感性进行了研究，这些细胞系过表达膜转运蛋白P-糖蛋白（Pgp）或多药耐药蛋白（MRP）。在所有细胞系中，所有微管蛋白抑制剂都比阿霉素和顺铂更有效。在耐药选择的细胞系（阿霉素或米托蒽醌耐药）中，微管蛋白抑制剂与选择剂之间存在交叉耐药性；然而，与过表达Pgp的细胞相比，过表达MRP的细胞对紫杉烷的耐药性相对较低。在药物敏感细胞系中观察到暴露于紫杉醇后微管的聚合，但在耐药细胞系中未观察到，即使在高紫杉醇浓度和长时间暴露后也是如此。在过表达Pgp的细胞系中，14C-紫杉醇的稳定积累存在缺陷，并且可以被维拉帕米逆转。与亲本细胞系相比，过表达MRP的细胞对紫杉醇没有明显的积累缺陷，并且维拉帕米没有任何作用。这些数据证实，Pgp过表达是人类肺癌和乳腺肿瘤细胞对紫杉烷和根霉素耐药的重要机制。然而，除转运缺陷之外的机制的存在可能在非Pgp表达细胞中起重要作用，并且这些机制可能包括微管蛋白功能的改变。
