Ciomei Marina, Croci Valter, Stellari Fabio, Amboldi Nadia, Giavarini Rosa, Pesenti Enrico
Cell Biology/Oncology, Nerviano Medical Sciences, Viale Pasteur, 10, 20014 Nerviano (MI), Italy.
Cancer Chemother Pharmacol. 2007 Jul;60(2):229-35. doi: 10.1007/s00280-006-0365-8. Epub 2006 Nov 7.
Edotecarin (J-107088, formerly ED-749) is a potent indolocarbazole topoisomerase-I inhibitor that has the potential to treat solid tumors. The current studies evaluated the potency and antitumor activity of edotecarin, as a single agent and in combination with capecitabine or docetaxel.
Antiproliferative activity was tested in vitro in a panel of 13 mammary cell lines and antitumor efficacy was tested in vivo in various breast cancer models.
Edotecarin inhibited cellular proliferation in breast carcinoma cell lines: 50% inhibitory concentrations ranged from 8 nmol/L in SKBR-3 cells to approximately 30 micromol/L in BT20 cells. Single dose and weekly intravenous treatments with edotecarin 30 and 150 mg/kg produced significant antitumor activity in the SKBR-3 human breast carcinoma xenograft model, with no major toxicities, compared with vehicle solvent treatment. Daily administration of edotecarin 15 mg/kg for 10 days was not well tolerated, whereas the total dose of 150 mg/kg was safe when administered in a single injection. Edotecarin 3 and 30 mg/kg given after docetaxel in the nude mouse SKBR-3 xenograft model produced tumor growth delays that were greater than those observed with either agent alone and with no toxicity as evaluated on the basis of body weight reduction (<20%). Furthermore, edotecarin 3 mg/kg in combination with capecitabine produced more than additive effects and the combination was well tolerated. However, edotecarin at a dose of 30 mg/kg in combination with capecitabine was lethal. Edotecarin also exhibited potent antitumor activity against xenografted human MX-1 cells, MMTV-v-Ha-ras oncogene-driven mouse breast tumors, and chemically induced rat mammary tumors.
The data suggest that edotecarin may be useful as a single agent or a component of combination chemotherapy regimens for treating human breast cancer.
依多卡林（J-107088，原ED-749）是一种强效吲哚咔唑拓扑异构酶-I抑制剂，具有治疗实体瘤的潜力。目前的研究评估了依多卡林作为单一药物以及与卡培他滨或多西他赛联合使用时的效力和抗肿瘤活性。
在一组13种乳腺细胞系中进行体外抗增殖活性测试，并在多种乳腺癌模型中进行体内抗肿瘤疗效测试。
依多卡林抑制乳腺癌细胞系中的细胞增殖：50%抑制浓度范围从SKBR-3细胞中的8 nmol/L到BT20细胞中的约30 μmol/L。与赋形剂溶剂处理相比，在SKBR-3人乳腺癌异种移植模型中，30和150 mg/kg的依多卡林单剂量和每周静脉内治疗产生了显著的抗肿瘤活性，且无重大毒性。连续10天每日给予15 mg/kg依多卡林耐受性不佳，而单次注射给予150 mg/kg的总剂量是安全的。在裸鼠SKBR-3异种移植模型中，多西他赛后给予3和30 mg/kg依多卡林导致肿瘤生长延迟，大于单独使用任何一种药物时观察到的延迟，并且根据体重减轻（<20%）评估无毒性。此外，3 mg/kg依多卡林与卡培他滨联合使用产生了超过相加的效应，且该联合用药耐受性良好。然而，30 mg/kg依多卡林与卡培他滨联合使用是致命的。依多卡林还对异种移植的人MX-1细胞、MMTV-v-Ha-ras癌基因驱动的小鼠乳腺肿瘤和化学诱导的大鼠乳腺肿瘤表现出强效抗肿瘤活性。
数据表明依多卡林可能作为单一药物或联合化疗方案的组成部分用于治疗人类乳腺癌。
