Koh Junichi, Kubota Tetsuro, Migita Tomofusa, Abe Sadanori, Hashimoto Mitsumasa, Hosoda Yoichiro, Kitajima Masaki
Department of Surgery, Saitama Social Insurance Hospital, 4-9-3, Kitaurawa, Saitama-shi, Japan.
Breast Cancer. 2002;9(1):50-4. doi: 10.1007/BF02967547.
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.
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.
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).
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.
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。
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。
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。
UCN-01似乎是一种有前景的乳腺癌治疗药物，其作用方式和抗肿瘤谱与目前可用的其他抗肿瘤药物不同。
