UCN - 01（7 - 羟基星孢菌素）通过干扰信号转导来抑制人乳腺癌异种移植瘤的生长。

UCN-01 (7-hydroxystaurosporine) inhibits the growth of human breast cancer xenografts through disruption of signal transduction.

作者信息

Koh Junichi, Kubota Tetsuro, Migita Tomofusa, Abe Sadanori, Hashimoto Mitsumasa, Hosoda Yoichiro, Kitajima Masaki

机构信息

Department of Surgery, Saitama Social Insurance Hospital, 4-9-3, Kitaurawa, Saitama-shi, Japan.

出版信息

Breast Cancer. 2002;9(1):50-4. doi: 10.1007/BF02967547.

DOI:10.1007/BF02967547

PMID:12196722

Abstract

BACKGROUND

7-Hydroxystaurosporine (UCN-01), originally isolated as a phospholipid-dependent protein kinase C inhibitor, has been shown to have antitumor activity against several human cancer cell lines. UCN-01 inhibits cell cycle progression from the G1 to S phase by inhibition of cyclin-dependent kinase (CDK) activity and induction of intrinsic CDK inhibitor protein, leading to dephosphorylation of retinoblastoma (Rb) protein.

MATERIALS AND METHODS

The antitumor activity of UCN-01 has been investigated against three human breast carcinoma strains serially transplanted into nude mice, including estrogen-dependent MCF-7, Br-10, and estrogen-independent MX-1. When the inoculated tumors started growing exponentially, UCN-01 (7.5 mg/kg) was administered intraperitoneally on five consecutive days a week for 2 weeks. The antitumor effect was evaluated as the lowest T/C ratio (%) during the experiments, where T was the relative mean tumor weight of the treated group and C was that of the control group. At the end of UCN-01 administration expression of p21, a protein of the CDK inhibitor family, and phosphorylated and dephosphorylated Rb protein was detected by Western blotting using treated and control tumors.

RESULTS

UCN-01 had activity against MCF-7 and Br-10, with the lowest T/C ratios of 25.0% and 27.0%, respectively, while MX-1 was resistant to UCN-01 with a T/C ratio of 65.9%. The antitumor spectrum of UCN-01 was different from that of other conventional agents such as doxorubicin and cyclophosphamide which were ineffective against Br-10 but were active against MX-1. Although p21 was induced in three tested strains by UCN-01, little dephosphorylated Rb protein was expressed in MX-1 compared with Br-10 and MCF-7 (in vitro).

CONCLUSION

UCN-01 appeared to be a promising agent for the treatment of breast cancer, with a different mode of action and antitumor spectrum from other currently available antitumor drugs.

摘要

背景

7-羟基星孢菌素（UCN-01）最初作为一种磷脂依赖性蛋白激酶C抑制剂被分离出来，已显示出对多种人类癌细胞系具有抗肿瘤活性。UCN-01通过抑制细胞周期蛋白依赖性激酶（CDK）活性和诱导内源性CDK抑制蛋白，抑制细胞从G1期到S期的进程，导致视网膜母细胞瘤（Rb）蛋白去磷酸化。

材料与方法

研究了UCN-01对三种连续移植到裸鼠体内的人乳腺癌细胞系的抗肿瘤活性，包括雌激素依赖性的MCF-7、Br-10和雌激素非依赖性的MX-1。当接种的肿瘤开始呈指数生长时，每周连续5天腹腔注射UCN-01（7.5mg/kg），共2周。抗肿瘤效果以实验期间最低的T/C比值（%）来评估，其中T为治疗组的相对平均肿瘤重量，C为对照组的相对平均肿瘤重量。在UCN-01给药结束时，使用处理过的和对照肿瘤通过蛋白质印迹法检测CDK抑制蛋白家族的一种蛋白p21以及磷酸化和去磷酸化的Rb蛋白的表达。

结果

UCN-01对MCF-7和Br-10有活性，最低T/C比值分别为25.0%和27.0%，而MX-1对UCN-01耐药，T/C比值为65.9%。UCN-01的抗肿瘤谱与其他传统药物如阿霉素和环磷酰胺不同，阿霉素和环磷酰胺对Br-10无效，但对MX-1有活性。尽管UCN-01在三种受试细胞系中均诱导了p21的表达，但与Br-10和MCF-7（体外）相比，MX-1中几乎没有去磷酸化的Rb蛋白表达。