Ghielmini M, Colli E, Erba E, Bergamaschi D, Pampallona S, Jimeno J, Faircloth G, Sessa C
Division of Oncology, Ospedale S. Giovanni, Bellinzona, Switzerland.
Ann Oncol. 1998 Sep;9(9):989-93. doi: 10.1023/A:1008430827281.
Ecteinascidin (ET-743) is a marine derived compound with an interesting preclinical profile currently completing phase I clinical trials. The present study was undertaken to compare the toxicity of different schedules of ET-743 against human hemopoietic progenitors and tumour cell lines.
Human hemopoietic progenitors and solid tumour cell lines were incubated with ET-743 for one hour, 24 hours and one hour daily for five consecutive days to define by comparison an 'in vitro therapeutic index'. Additional experiments were set up to assess whether incubation for 24 hours or five days could change either the sensitivity of cells or the activity of ET-743.
Prolonged or repeated exposures were more toxic than a single one hour exposure (P < 0.001), but due to the higher sensitivity to prolonged exposure of several tumor cell lines, prolonged treatment yielded a more favorable in vitro therapeutic index. After incubation for 24 hours, ET-743 showed a significantly (P < 0.01) lower inhibiting capacity. Incubation before treatment rendered progenitors more resistant, but incubation after treatment increased their sensitivity, so that overall the toxicity of ET-743 on hemopoietic cells appears to be close to AUC dependency.
Despite the possible effect of some experimental artefacts, prolonged exposure could represent the best schedule of administration of ET-743.
埃博霉素（ET - 743）是一种源自海洋的化合物，其临床前研究表现令人关注，目前正处于I期临床试验阶段。本研究旨在比较不同给药方案的ET - 743对人类造血祖细胞和肿瘤细胞系的毒性。
将人类造血祖细胞和实体瘤细胞系与ET - 743分别孵育1小时、24小时以及连续5天每天孵育1小时，通过比较来确定“体外治疗指数”。另外还进行了实验，以评估24小时或5天的孵育是否会改变细胞的敏感性或ET - 743的活性。
延长暴露时间或重复暴露比单次1小时暴露毒性更大（P < 0.001），但由于几种肿瘤细胞系对延长暴露更敏感，延长治疗产生了更有利的体外治疗指数。孵育24小时后，ET - 743的抑制能力显著降低（P < 0.01）。治疗前孵育使祖细胞更具抗性，但治疗后孵育增加了它们的敏感性，因此总体而言，ET - 743对造血细胞的毒性似乎接近AUC依赖性。
尽管可能存在一些实验假象的影响，但延长暴露可能是ET - 743的最佳给药方案。
