Fukuda T, Kakihara T, Kamishima T, Ohnishi Y, Naito M, Kishi K, Shibata A, Tsuruo T
Second Department of Pathology, Niigata University School of Medicine, Japan.
Leuk Res. 1994 Sep;18(9):709-15. doi: 10.1016/0145-2126(94)90071-x.
New adriamycin (ADR) resistant human leukemic cell lines (KY-ADR1 and KY-ADR2) have been established. KY-ADR1 was selected from a cytosine arabinoside (Ara C) resistant cell line by gradually increasing the concentration of ADR and KY-ADR2 from the parental cell line, KY-821, by the same method. The IC50s of both cell lines were 4.3 x 10(-5) and 3.6 x 10(-5) M ADR, respectively. Both lines revealed a similar cross resistance to various anticancer drugs, but KY-ADR1 was resistant to Ara C, whereas KY-ADR2 was sensitive. MDR1 gene was over-expressed and P-glycoprotein was expressed on the cytoplasmic membrane in both lines. Neither verapamil nor cyclosporin A could completely reverse ADR resistance. In addition, no significant changes in topoisomerase II and glutathione-s-transferase levels were detected. These findings indicate that ADR resistance in both cell lines is mainly mediated by P-glycoprotein and some other mechanism may be present. Interestingly, growth of both cell lines was stimulated by natural IL-1 and not affected by TNF alpha and IFN gamma, whereas growth of parental KY-821 was inhibited by these factors. These cell lines will provide new biological aspects on drug resistant leukemic cells.
已建立了新的阿霉素（ADR）耐药人白血病细胞系（KY-ADR1和KY-ADR2）。KY-ADR1是从阿糖胞苷（Ara C）耐药细胞系中通过逐渐增加ADR浓度筛选出来的，而KY-ADR2是通过同样的方法从亲本细胞系KY-821中筛选出来的。两种细胞系的半数抑制浓度（IC50）分别为4.3×10^(-5)和3.6×10^(-5) M ADR。两种细胞系对各种抗癌药物均表现出相似的交叉耐药性，但KY-ADR1对Ara C耐药，而KY-ADR2敏感。两株细胞系中多药耐药基因1（MDR1）均过度表达，细胞质膜上均有P-糖蛋白表达。维拉帕米和环孢素A均不能完全逆转ADR耐药性。此外，未检测到拓扑异构酶II和谷胱甘肽S-转移酶水平有显著变化。这些发现表明，两种细胞系中的ADR耐药主要由P-糖蛋白介导，可能还存在其他一些机制。有趣的是，天然白细胞介素-1（IL-1）可刺激两种细胞系的生长，而肿瘤坏死因子α（TNFα）和干扰素γ（IFNγ）对其生长无影响，而亲本KY-821细胞系的生长则受到这些因子的抑制。这些细胞系将为耐药白血病细胞提供新的生物学研究方向。
