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


METHODS
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 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.


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.
Hendriks
H R
HR
NDDO Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands. hr.hendriks@planet.nl
Fiebig
H H
HH
Giavazzi
R
R
Langdon
S P
SP
Jimeno
J M
JM
Faircloth
G T
GT
D000328:Adult; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D004149:Dioxoles / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000009:adverse effects / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin