Wright K A, Twentyman P R
MRC Clinical Oncology and Radiotherapeutics Unit, Cambridge, U.K.
Eur J Cancer. 1993;29A(3):389-94. doi: 10.1016/0959-8049(93)90393-t.
Cyclosporin A (CsA) is an effective modifier of multidrug resistance. We have studied (a) the possibility that cells grown in increasing concentrations of CsA acquire cellular resistance to the agent and, (b) whether such cells have a multidrug resistant phenotype. Sublines of the EMT6 mouse tumour cell line were developed which were able to grow in 75 and 200 micrograms/ml of CsA, respectively. The resistant sublines grew slowly in the presence of CsA but reverted to control growth rates, whilst maintaining resistance, when the drug was removed. P-glycoprotein (Pgp) was not detectable in the resistant sublines by immunocytochemistry. The CsA-resistant cells were not cross-resistant to doxorubicin or vincristine but showed a clear degree of cross-resistance to the calcium transport blocker, verapamil. Cellular accumulation of both [3H]CsA and [3H]daunorubicin was significantly increased in the EMT6/CsA200R subline compared with the parent line. In the EMT6 parent line, which expresses very low levels of Pgp, 10-30-fold sensitisation to doxorubicin may be achieved using 0.1-5 microgram/ml of CsA. Similar sensitisation by CsA was also seen in the CsA-resistant sublines.
环孢素A（CsA）是一种有效的多药耐药调节剂。我们研究了：（a）在浓度不断增加的CsA中生长的细胞获得对该药物的细胞耐药性的可能性，以及（b）此类细胞是否具有多药耐药表型。建立了EMT6小鼠肿瘤细胞系的亚系，它们分别能够在75微克/毫升和200微克/毫升的CsA中生长。耐药亚系在CsA存在下生长缓慢，但在去除药物后恢复到对照生长速率，同时保持耐药性。通过免疫细胞化学在耐药亚系中未检测到P-糖蛋白（Pgp）。CsA耐药细胞对阿霉素或长春新碱没有交叉耐药性，但对钙转运阻滞剂维拉帕米表现出明显程度的交叉耐药性。与亲代细胞系相比，[3H]CsA和[3H]柔红霉素在EMT6/CsA200R亚系中的细胞蓄积均显著增加。在表达极低水平Pgp的EMT6亲代细胞系中，使用0.1-5微克/毫升的CsA可实现对阿霉素10-30倍的致敏作用。在CsA耐药亚系中也观察到CsA的类似致敏作用。
