Hendriks H R, Fiebig H H, Giavazzi R, Langdon S P, Jimeno J M, Faircloth G T
NDDO Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
Ann Oncol. 1999 Oct;10(10):1233-40. doi: 10.1023/a:1008364727071.
Ecteinascidin-743 (ET743) is a novel antitumour agent originating from the Caribbean tunicate Ecteinascidia turbinata. It has potent cytotoxic and antitumour activity and a potential new mechanism of action. The aim of the present study was to further explore the antitumour activity of ET743 in human tumour xenografts from melanoma, non-small-cell lung and ovarian cancer.
As the antitumour profile of ET743 was largely unknown a chemo-sensitive and a marginal chemo-resistant human tumour xenograft were selected for each tumour type. ET743 was administered intravenously using two administration schedules (days 0, 4, 8 and 0-2, 13-15).
ET743 was very active at the maximum tolerated dose (MTD) in the chemo-sensitive xenograft melanoma MEXF 989, non-small-cell lung cancer LXFL 529, and ovarian cancers HOC22 and (marginally resistant to cisplatin) HOC18. Activity was also seen at 1/2 MTD. Apart from HOC18, ET743 caused complete remissions in the responding xenografts. The compound was inactive in the chemo-resistant xenograft melanoma MEXF 514 and non-small-cell lung cancer LXFA 629. In terms of antitumour activity the days 0, 4, 8 schedule had advantages over the days 0-2, 13-15 schedule.
ET743 is a very effective agent in chemo-sensitive and marginal chemo-resistant xenografts, but inactive in chemo-resistant tumour xenografts. The activity of ET743 in the marginally cisplatin-resistant ovarian cancer HOC18 might indicate absence or incomplete cross-resistance against cisplatin. It is recommended to include melanoma, non-small-cell lung cancer, and ovarian cancer in phase II clinical trials and to use an intermittent schedule.
埃博霉素-743（ET743）是一种源自加勒比海被囊动物瘤囊海鞘的新型抗肿瘤药物。它具有强大的细胞毒性和抗肿瘤活性以及潜在的新作用机制。本研究的目的是进一步探索ET743在源自黑色素瘤、非小细胞肺癌和卵巢癌的人肿瘤异种移植模型中的抗肿瘤活性。
由于ET743的抗肿瘤谱在很大程度上未知，因此为每种肿瘤类型选择了一个化疗敏感和一个边缘化疗耐药的人肿瘤异种移植模型。ET743采用两种给药方案（第0、4、8天和第0 - 2、13 - 15天）静脉给药。
ET743在化疗敏感的异种移植黑色素瘤MEXF 989、非小细胞肺癌LXFL 529以及卵巢癌HOC22和（对顺铂有边缘耐药性的）HOC18中，在最大耐受剂量（MTD）时非常有效。在1/2 MTD时也观察到活性。除了HOC18，ET743在有反应的异种移植模型中导致完全缓解。该化合物在化疗耐药的异种移植黑色素瘤MEXF 514和非小细胞肺癌LXFA 629中无活性。就抗肿瘤活性而言，第0、4、8天的给药方案优于第0 - 2、13 - 15天的给药方案。
ET743在化疗敏感和边缘化疗耐药的异种移植模型中是一种非常有效的药物，但在化疗耐药的肿瘤异种移植模型中无活性。ET743在对顺铂有边缘耐药性的卵巢癌HOC18中的活性可能表明对顺铂不存在或不完全存在交叉耐药性。建议在II期临床试验中纳入黑色素瘤、非小细胞肺癌和卵巢癌，并采用间歇给药方案。
