Different Effects of FK317 on Multidrug‐resistant Tumor in vivo and in vitro
Different Effects of FK317 on Multidrug‐resistant Tumor in vivo and in vitro
复制标题
FK317对体内和体外多重耐药肿瘤的不同作用
DOI：
--
复制
发表时间：
1998
期刊：
影响因子：
--
通讯作者：
K. Shimomura
中科院分区：
文献类型：
--
作者：
Y. Naoe;M. Inami;Shoji Takagaki;S. Matsumoto;I. Kawamura;F. Nishigaki;S. Tsujimoto;T. Manda;K. Shimomura
FK 317是一种新型取代的二氢苯并恶嗪，在体外和体内研究了其对多药耐药（MDR）肿瘤细胞的抗肿瘤作用。FK 317对裸鼠皮下移植瘤的生长有明显的抑制作用。植入的KB-V1长春碱（VLB）抗性人表皮癌KB细胞以及亲本细胞（KB-3 - 1）。然而，在体外研究中，KB-V1对FK 317的耐药性远高于对VLB和阿霉素（ADM）的耐药性。通过加入维拉帕米逆转了这种耐药性，从而也降低了KB-V1细胞中FK 317的细胞内蓄积。FK 317在人和小鼠血液中孵育后，显示其迅速代谢为单脱乙酰化形式，并缓慢进一步代谢为双脱乙酰化形式。随着FK 317乙酰基的去除，KB-V1和SBC-3/ADM（ADM耐药的人肺癌）的耐药指数降低。此外，FK 317可完全抑制KB-V1质膜中[3 H]叠氮平对P-糖蛋白的光标记，但不受脱乙酰代谢产物的抑制。这些结果表明，FK 317代谢为脱乙酰化形式，其不与P-糖蛋白结合，并掺入MDR细胞中，引起细胞毒性效应。
FK317, a novel substituted dihydrobenzoxazine, was examined for antitumor effects on multidrug‐resistant (MDR) tumor cells in vitro and in vivo. In nude mice, FK317 markedly inhibited the growth of s.c. implanted KB‐V1 vinblastine (VLB)‐resistant human epidermal carcinoma KB cells, as well as the parent cells (KB‐3‐1). However, KB‐V1 showed much greater resistance to FK317 than to VLB and adriamycin (ADM) in the in vitro study. This resistance was reversed by the addition of verapamil, whereby intracellular accumulation of FK317 in the KB‐V1 cells was also decreased. After incubation of FK317 in human and mouse blood, it was shown to be rapidly metabolized to a monodeacetylated form, and slowly metabolized further to a dideacetylated form. With the removal of the acetyl groups from FK317, resistance indexes in KB‐V1 and SBC‐3/ADM, ADM‐resistant human lung carcinoma, decreased. In addition, photolabeling of P‐glycoprotein with [3H]azidopine in KB‐V1 plasma membrane was completely inhibited by FK317, but not by the deacetylated metabolites. These results indicate that FK317 is metabolized to deacetylated forms, which do not bind to P‐glycoprotein and are incorporated into MDR cells, causing cytotoxic effects.
登录
查看更多内容
影响因子：
3.6
作者：
J. Zamora;H. Pearce;W. T. Beck
通讯作者：
J. Zamora;H. Pearce;W. T. Beck
DOI：
10.1073/pnas.83.12.4538
发表时间：
1986-06-01
影响因子：
11.1
作者：
RONINSON, IB;CHIN, JE;PASTAN, I
通讯作者：
PASTAN, I
多重耐药细胞中 P-糖蛋白的光亲和标记。
影响因子：
2.4
作者：
Safa,AR
通讯作者：
Safa,AR
影响因子：
3.9
作者：
Wortham, Matthew;Czerwinski, Maciej;Wan, Yu-Jui Yvonne
通讯作者：
Wan, Yu-Jui Yvonne
DOI：
--
发表时间：
1981
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Elbaum,D;Nagel,RL
通讯作者：
Nagel,RL