ET-743.
ET-743 is a novel antineoplastic DNA-binding agent derived from the marine tunicate Ecteinascidia turbinata. It has significant cytotoxic activity against soft tissue sarcomas (STS). It also has in vitro activity against melanoma, breast, ovarian, colon, renal, non-small cell lung and prostate carcinomas. The drug has unique mechanism of action which includes in vitro inhibition of transcription-dependent nucleotide excision repair pathways and inhibition of cell cycle progression leading to p53-independent apoptosis. It also selectively inhibits transcriptional activation of multidrug-resistance (MDR1) gene in human sarcoma cells in vivo. The efficacy of ET-743 has been investigated in patients with advanced STS in three multicentre phase II clinical trials. Patients receiving ET-743 as second- or third-line treatment had partial tumour response rates of 6 to 8%. Patients receiving ET-743 as first-line chemotherapy had a partial response rate of 18%. Forty-two to 50% of all patients in these trials achieved stable disease. All responses were durable up to 14 months. A pooled analysis of the three multicentre phase II trials showed the following: median overall survival time of 10.2 months, 1-year survival rate of 40% and 6-month progression-free rate of 27.2%. ET-743 is generally well tolerated. The most common adverse events in clinical trials were non-cumulative haematological and hepatic toxicities. Transient and reversible elevation of hepatic transaminases, nausea, vomiting and asthenia were common but seldom severe and never treatment-limiting. Mucositis, alopecia and cardiac or neurotoxicities were not observed.
Cvetkovic
Risto S
RS
Adis International Limited, Auckland, New Zealand. demail@adis.co.nz
Figgitt
David P
DP
Plosker
Greg L
GL
D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D004149:Dioxoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy; D009503:Neutropenia / Q000139:chemically induced; D016019:Survival Analysis; D044005:Tetrahydroisoquinolines; D013921:Thrombocytopenia / Q000139:chemically induced; D000077606:Trabectedin
D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin