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 originati ng from the Caribbean tunicate Ecteinascidia turbinata. It has potent cytot oxic and antitumour activity and a potential new mechanism of action. The a im of the present study was to further explore the antitumour activity of E T743 in human tumour xenografts from melanoma, non-small-cell lung and ovar ian cancer. Design: As the antitumour profile of ET743 was largely unknown a chemo-sens itive and a marginal chemo-resistant human tumour xenograft were selected f or each tumour type. ET743 was administered intravenously using two adminis tration schedules (days 0, 4, 8 and 0-2, 13-15). Results: ET743 was very active at the maximum tolerated dose (MTD) in the c hemo-sensitive xenograft melanoma MEXF 989, non-small-cell lung cancer LXFL 529, and ovarian cancers HOC22 and (marginally resistant to cisplatin) HOC 18. Activity was also seen at 1/2 MTD. Apart from HOC18, ET743 caused compl ete remissions in the responding xenografts. The compound was inactive in t he chemo-resistant xenograft melanoma MEXF 514 and non-small-cell lung canc er 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 margina l chemo-resistant xenografts, but inactive in chemo-resistant tumour xenogr afts. The activity of ET743 in the marginally cisplatin-resistant ovarian c ancer HOC18 might indicate absence or incomplete cross-resistance against c isplatin. 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.