Shakuto Shuji, Noguchi Keiko, Bissery Marie-Christine
Drug Safety Evaluation, Preclinical Development, Scientific Affairs, Aventis Pharma Ltd., sanofi-aventis Group.
Gan To Kagaku Ryoho. 2005 Oct;32(10):1437-42.
The antitumor effect of docetaxel against human endometrial tumor cell lines was investigated in vitro and in vivo. In the in vitro study,docetaxel showed concentration-dependent inhibition of the growth of 4 tumor cell lines having different degrees of differentiation (AN3 CA, KLE, HEC-1-A and HEC-1-B), with IC(50) values ranging from 2.48 to 82.40 ng/ml. These values represent ca. 1/900-1/30 of the mean maximum plasma concentration of 2.27 microg/ml attained when the recommended dose of 70 mg/m(2) for patients with endometrial cancer was administered to patients with various types of cancer in phase I trial. In addition, the activity was nearly equal to paclitaxel, and much more potent than fluorouracil, cisplatin and doxorubicin. Docetaxel also showed strong antitumor activity against xenografts of the AN3 CA human endometrial adenocarcinoma cell line in nude mice. In the docetaxel treated group at its MTD (33 mg/kg/dose, q 6 d x 3, iv), all of the animals were tumor-free survivors on Day 62 after xenografting. The antitumor effect in the MTD-administered group was the strongest of all of the tested anticancer drug groups (cyclophosphamide, mitomycin C, fluorouracil, cisplatin, doxorubicin). Even at two docetaxel dosages below its MTD (20.5 and 12.5 mg/kg/day), the drug showed a marked cytotoxic activity. These results demonstrated that docetaxel shows potent antitumor efficacy against human endometrial tumor cell lines, leading to the expectation that it will be useful as a therapeutic agent for endometrial cancer.
在体外和体内研究了多西他赛对人子宫内膜肿瘤细胞系的抗肿瘤作用。在体外研究中,多西他赛对4种具有不同分化程度的肿瘤细胞系(AN3 CA、KLE、HEC-1-A和HEC-1-B)的生长表现出浓度依赖性抑制,IC(50)值范围为2.48至82.40 ng/ml。这些值约为在I期试验中对各种类型癌症患者给予子宫内膜癌患者推荐剂量70 mg/m(2)时所达到的平均最大血浆浓度2.27 μg/ml的1/900 - 1/30。此外,其活性与紫杉醇几乎相当,且比氟尿嘧啶、顺铂和多柔比星强得多。多西他赛对裸鼠体内AN3 CA人子宫内膜腺癌细胞系的异种移植瘤也显示出强大的抗肿瘤活性。在多西他赛以其最大耐受剂量(33 mg/kg/剂量,每6天一次,共3次,静脉注射)治疗的组中,所有动物在异种移植后第62天均无瘤存活。在所有测试的抗癌药物组(环磷酰胺、丝裂霉素C、氟尿嘧啶、顺铂、多柔比星)中,最大耐受剂量给药组的抗肿瘤效果最强。即使在低于其最大耐受剂量的两个多西他赛剂量(20.5和12.5 mg/kg/天)下,该药物也显示出显著的细胞毒性活性。这些结果表明,多西他赛对人子宫内膜肿瘤细胞系显示出强大的抗肿瘤功效,有望成为治疗子宫内膜癌的有效药物。