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

Hendriks, H.R.; Fiebig, H. H.; Giavazzi, Raffaella; Langdon, Simon P.; Jimeno, J.; Faircloth, Glynn

doi:10.1023/a:1008364727071

Cited by 94 publications

(44 citation statements)

References 15 publications

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“…In a preclinical study, trabectedin showed significant antitumor activity in vitro and in vivo against a range of solid tumor cells, including soft-tissue sarcoma (STS), ovarian, breast, prostate, and renal cancers; melanoma; and non-small-cell lung cancer (8)(9)(10)(11). On the basis of the promising results of preclinical and clinical studies (10,12,13), trabectedin is now approved in Europe for the treatment of STS after anthracycline and ifosfamide failure and for treating patients who cannot receive these agents (14).…”

Section: Introductionmentioning

confidence: 99%

The Activity of Trabectedin As a Single Agent or in Combination with Everolimus for Clear Cell Carcinoma of the Ovary

Mabuchi

Hisamatsu

Kawase

et al. 2011

Clinical Cancer Research

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Purpose: The objective of this study was to evaluate the antitumor efficacy of trabectedin in clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histologic subtype.Experimental Design: Using 6 human ovarian cancer cell lines (3 CCC and 3 serous adenocarcinomas), the antitumor effects of trabectedin were examined in vitro, and we compared its activity according to histology. We next examined the antitumor activity of trabectedin in both cisplatin-resistant and paclitaxelresistant CCC cells in vitro. Then, the in vivo effects of trabectedin were evaluated using mice inoculated with CCC cell lines. Using 2 pairs of trabectedin-sensitive parental and trabectedin-resistant CCC sublines, we investigated the role of mTOR in the mechanism of acquired resistance to trabectedin. Finally, we determined the effect of mTOR inhibition by everolimus on the antitumor efficacy of trabectedin in vitro and in vivo.

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Section: Introductionmentioning

confidence: 99%

The Activity of Trabectedin As a Single Agent or in Combination with Everolimus for Clear Cell Carcinoma of the Ovary

Mabuchi

Hisamatsu

Kawase

et al. 2011

Clinical Cancer Research

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“…Trabectedin has a complex mechanism of action, involving DNA binding [25,27], interference with transcription factor binding [24], and activation of the transcription-coupled nucleotide excision repair (NER) system to create lethal single-strand breaks in DNA [4,35]. The cytotoxicity of trabectedin has been demonstrated in several in vitro and preclinical studies involving a variety of cancer types [12,14,18,29,37].…”

Section: Introductionmentioning

confidence: 99%

Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors

Messersmith

Jimeno

Ettinger

et al. 2008

Cancer Chemother Pharmacol

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Purpose-To determine the maximum tolerated dose (MTD) of trabectedin plus gemcitabine administered on a weekly schedule in patients with advanced solid tumors.Methods-Patients with ECOG performance status 0-1 and adequate organ function were enrolled. On days 1, 8, and 15 of a 28-day cycle, patients received gemcitabine (starting dose, 800 mg/m 2 ) followed by trabectedin (starting dose, 0.3 mg/m 2 ). Strict liver function test treatment criteria were employed to avoid hepatic toxicity seen in previous trabectedin studies. Plasma samples were collected during cycles 1 and 2 for pharmacokinetic analyses.Results-Fifteen patients received ≥1 dose, with a median of two treatment cycles (range 1-10). The most common drug-related toxicity was hepatic. Dose reductions were required for $watermark-text $watermark-text $watermark-text trabectedin in four (27%) patients and gemcitabine in six (40%) patients. Cycle delays/dose holds were required in 11 (73%) patients and doses above trabectedin 0.4 mg/m 2 and gemcitabine 1,000 mg/m 2 , which is the recommended phase II dose, were not feasible. Seven patients maintained stable disease after two cycles. Gemcitabine and trabectedin pharmacokinetics were not altered substantially with concomitant administration.Conclusions-Given the lack of pharmacokinetic interaction and potential efficacy of trabectedin and gemcitabine combination therapy, further study is warranted with alternate schedules.

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“…It possesses potent antineoplastic activity against a variety of human tumor xenografts grown in athymic mice, including melanoma and ovarian and breast carcinoma. [1][2][3] In clinical phase 1 studies of ET-743, promising responses were observed in patients with sarcoma, as well as breast and ovarian carcinoma, 4,5 and the drug is currently under intense investigation in a variety of phase 2 trials in cancer patients. However, myelotoxicity is dose-limiting.…”

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confidence: 99%

Dietary agent indole‐3‐carbinol protects female rats against the hepatotoxicity of the antitumor drug ET‐743 (trabectidin) without compromising efficacy in a rat mammary carcinoma

Donald

Verschoyle

Greaves

et al. 2004

Intl Journal of Cancer

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ET-743, an experimental antitumor drug with promising activity in sarcoma, breast and ovarian carcinoma, is currently under phase 2 clinical evaluation. It is hepatotoxic in animals and patients. We tested the hypothesis that indole-3-carbinol (I3C), the hydrolysis product of glucosinolates occurring in cruciferous vegetables, may protect against ET-743-induced hepatotoxicity in the female Wistar rat, the animal species with the highest sensitivity toward the adverse hepatic effect of this drug. Hepatotoxicity was adjudged by measurement of plasma levels of bilirubin, alkaline phosphatase (ALP) and aspartate aminotransferase ( Key words: indole-3-carbinol; chemoprevention; ET-743; hepatotoxicityET-743 (ecteinascidin 743, trabectidin, Yondelis) is a tetrahydroisoquinoline alkaloid isolated from the marine tunicate Ecteinascidia turbinata. It possesses potent antineoplastic activity against a variety of human tumor xenografts grown in athymic mice, including melanoma and ovarian and breast carcinoma. [1][2][3] In clinical phase 1 studies of ET-743, promising responses were observed in patients with sarcoma, as well as breast and ovarian carcinoma, 4,5 and the drug is currently under intense investigation in a variety of phase 2 trials in cancer patients. However, myelotoxicity is dose-limiting. Furthermore, hepatotoxicity is frequently observed in the clinic, as reflected by reversible transaminitis and subclinical cholangitis, characterized by increases in alkaline phosphatase (ALP) and/or bilirubin. Treatment with ET-743 caused an increase in plasma levels of liver-specific enzymes and pathologic manifestations of cholangitis in most animal species in which it has been tested. 6,7 We recently showed that high-dose dexamethasone protects rats from ET-743-induced hepatotoxicity without compromising its antitumor activity. 8 Hepatoprotection was probably the consequence of a dramatic reduction by dexamethasone of hepatic levels of ET-743, which in turn was reasoned to be related to the ability of dexamethasone to increase the rate of metabolic detoxification of ET-743 via induction of the cytochrome P450 enzyme CYP3A in the liver. The potential use of high-dose dexamethasone as a hepatoprotectant in humans might be confounded by adverse effects, including diabetes mellitus, hypertension, arrhythmias, hypokalemia, psychosis, peptic ulceration and susceptibility to infection. 9,10 Indole-3-carbinol (I3C) is the aglycone of glucobrassicin, a microconstituent of cruciferous vegetables such as broccoli and Brussels sprouts. I3C, which is generated by glycoside-hydrolyzing enzymes when plant cells are disrupted by processing, cooking or mastication, possesses chemopreventive properties against chemically induced tumors in rodents at a variety of sites. [11][12][13][14] Clinical pilot studies of I3C have been conducted in patients with recurrent respiratory papillomatosis 15 and cervical intraepithelial neoplasia. 16 There has also been a dose-finding study to prepare for its evaluation as a breast cancer preventive agen...

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

Cited by 94 publications

References 15 publications

The Activity of Trabectedin As a Single Agent or in Combination with Everolimus for Clear Cell Carcinoma of the Ovary

The Activity of Trabectedin As a Single Agent or in Combination with Everolimus for Clear Cell Carcinoma of the Ovary

Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors

Dietary agent indole‐3‐carbinol protects female rats against the hepatotoxicity of the antitumor drug ET‐743 (trabectidin) without compromising efficacy in a rat mammary carcinoma

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