Izbicka E, Lawrence R, Raymond E, Eckhardt G, Faircloth G, Jimeno J, Clark G, Von Hoff D D
Institute for Drug Development-Cancer Therapy and Research Center, San Antonio, TX, USA.
Ann Oncol. 1998 Sep;9(9):981-7. doi: 10.1023/A:1008224322396.
Ecteinascidin-743 (ET-743), a member of the ecteinascidin family selected for clinical development, is a tetrahydroisoquinolone alkaloid isolated from the marine ascidian, Ecteinascidia turbinata. This novel compound is a minor groove binding, guanine-specific alkylating agent which also interacts with the microtubule network and blocks cell cycle progression at late S/G2.
A soft agar cloning assay was used to determine the in vitro effects of ET-743 against primary human tumor specimens taken directly from patients. A total of 93 evaluable specimens were exposed to ET-743 for one-hour (n = 25) and/or 14-day continuous exposure (n = 92) at concentrations ranging from 0.1 nM to 1 microM. In vitro responses were defined as an inhibition > or = 50% of human tumor colony forming units at a given concentration.
One-hour exposure to ET-743 at concentrations of 0.1 nM, 1 nM, 10 nM, 100 nM and 1 microM induced in vitro responses in 0% (0/17), 6% (1/17), 16% (4/25), 13% (1/8), and 25% (2/8) of specimens, respectively. Continuous exposure to ET-743 at concentrations of 0.1 nM, 1 nM, 10 nM, 100 nM and 1 microM, inhibited 0% (0/16), 13% (2/16), 49% (44/90), 62% (47/76), and 77% (58/75) of tumor specimens, respectively. Tumor-specific responses and concentration-dependent relationships were observed with a continuous exposure to ET-743. At 100 nM, the compound inhibited 79% (11/14) breast, 69% (9/13) non-small-cell lung, 58% (7/12) ovary, and 88% (7/8) melanoma specimens. At 1 microM, ET-743 inhibited 100% (14/14) breast specimens, 85% (11/13) non-small-cell lung, 67% (8/12) ovary and 86% (6/7) melanoma specimens. Activity of ET-743 at and above 10 nM was also observed against sarcoma and kidney tumors. At 10 nM concentration and continuous exposure ET-743 demonstrated incomplete cross-resistance with paclitaxel, alkylating agents, doxorubicin and cisplatin.
Our data from the cloning assay indicate that the duration of exposure to ET-743 is an important factor in human tumors. Therefore, long-term exposure to ET-743 may be preferred in future clinical trials. The activity of ET-743 in breast, non-small-cell lung, and ovarian cancers as well as in melanoma may deserve further clinical evaluations. The potential of ET-743 in sarcoma and renal tumors might also be considered. In addition, our data indicate that a plasma concentration of 100 nM of ET-743 must be considered as a target during the clinical development of the compound; also the concept of continuous/protracted exposure in clinical trials with ET-743 has to be taken into account.
埃博霉素-743（ET-743）是从海洋被囊动物（Turbinaria turbinata）中分离出的一种四氢异喹啉生物碱，属于被选用于临床开发的埃博霉素家族成员。这种新型化合物是一种小沟结合、鸟嘌呤特异性烷基化剂，它还与微管网络相互作用，并在S/G2晚期阻断细胞周期进程。
采用软琼脂克隆试验来确定ET-743对直接取自患者的原发性人类肿瘤标本的体外作用。总共93个可评估标本在浓度范围为0.1 nM至1 μM的条件下，接受ET-743 1小时（n = 25）和/或14天连续暴露（n = 92）。体外反应定义为在给定浓度下人类肿瘤集落形成单位的抑制率≥50%。
在浓度为0.1 nM、1 nM、10 nM、100 nM和1 μM的条件下，ET-743 1小时暴露分别在0%（0/17）、6%（1/17）、16%（4/25）、13%（1/8）和25%（2/8）的标本中诱导出体外反应。在浓度为0.1 nM、1 nM、10 nM、100 nM和1 μM的条件下，ET-743连续暴露分别抑制0%（0/16）、13%（2/16）、49%（44/90）、62%（47/76）和77%（58/75）的肿瘤标本。连续暴露于ET-743时观察到肿瘤特异性反应和浓度依赖性关系。在100 nM时，该化合物抑制79%（11/14）的乳腺、69%（9/13）的非小细胞肺癌、58%（7/12）的卵巢和88%（7/8）的黑色素瘤标本。在1 μM时，ET-743抑制100%（14/14）的乳腺标本、85%（11/13）的非小细胞肺癌、67%（8/12）的卵巢和86%（6/7）的黑色素瘤标本。在10 nM及以上浓度时，还观察到ET-743对肉瘤和肾肿瘤有活性。在10 nM浓度和连续暴露条件下，ET-743与紫杉醇、烷基化剂、阿霉素和顺铂表现出不完全交叉耐药性。
我们克隆试验的数据表明，ET-743的暴露持续时间是人类肿瘤中的一个重要因素。因此，在未来的临床试验中，长期暴露于ET-743可能更可取。ET-743在乳腺癌、非小细胞肺癌、卵巢癌以及黑色素瘤中的活性可能值得进一步的临床评估。也可考虑ET-743在肉瘤和肾肿瘤中的潜力。此外，我们的数据表明，在该化合物的临床开发过程中，必须将血浆浓度100 nM的ET-743视为一个目标；同时，在ET-743的临床试验中，连续/延长暴露的概念也必须予以考虑。
