High antitumour activity of ET743 against human tumour xenografts from melanoma, non-small-cell lung and ovarian cancer

• Published in: Annals of oncology Vol. 10; no. 10; pp. 1233 - 1240
• Main Authors: Hendriks, H. R., Fiebig, H. H., Giavazzi, R., Langdon, S. P., Jimeno, J. M., Faircloth, G. T.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-10-1999
• Subjects: Adult; Animals; Antineoplastic agents; Antineoplastic Agents, Alkylating - adverse effects; Antineoplastic Agents, Alkylating - therapeutic use; antitumour activity; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Chemotherapy; Dioxoles - adverse effects; Dioxoles - therapeutic use; ET743; Female; human tumour xenografts; Humans; Isoquinolines - adverse effects; Isoquinolines - therapeutic use; Lung Neoplasms - drug therapy; Male; Medical sciences; melanoma; Melanoma - drug therapy; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; non-small-cell lung cancer; ovarian cancer; Ovarian Neoplasms - drug therapy; Pharmacology. Drug treatments; Tetrahydroisoquinolines; Trabectedin; Antineoplastic agent; Lung disease; Animal model; Intravenous administration; Respiratory disease; Toxicity; Treatment efficiency; Rodentia; Malignant tumor; Bronchopulmonary; Female genital diseases; Ovarian diseases; Ovary; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Malignant melanoma; Bronchus disease; Mechanism of action; Non small cell carcinoma
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1023/A:1008364727071

Background: 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. Design: 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). Results: 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 ½ 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. Conclusions: 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.