摘要：

Trabectedin (Yondelis[R]; ET-743) is an antineoplastic agent that was originally derived from the Caribbean marine tunicate Ecteinascidia turbinata and is now produced synthetically. It binds to the minor groove of DNA, disrupting the cell cycle and inhibiting cell proliferation. Intravenous trabectedin administered once every 3 weeks is approved as monotherapy in Europe for use in patients with advanced soft tissue sarcoma (STS) after failure of standard therapy with anthracyclines or ifosfamide, or who are unsuited to receive these agents. It also has orphan drug status in STS in the US and in ovarian cancer in the US and Europe, and is under investigation as combination therapy in patients with recurrent ovarian cancer. In clinical trials, trabectedin showed efficacy in the treatment of patients with advanced or metastatic STS, especially those with leiomyosarcoma or liposarcoma, as well as in women with platinum-sensitive advanced or recurrent ovarian cancer. In addition, its tolerability profile was generally manageable. The introduction of trabectedin expands the currently limited range of effective treatment options for patients with advanced or metastatic STS; trabectedin also has the potential to be a beneficial treatment for advanced or recurrent ovarian cancer. Pharmacological Properties Trabectedin, an antineoplastic agent originally derived from the Caribbean marine tunicate Ecteinascidia turbinata that is now produced synthetically, binds to the minor groove of DNA. Unlike other minor-groove binders that bend DNA towards the site of interaction, trabectedin bends DNA towards the major groove. Although the exact mechanism of action is not clear, it is thought that interference with the transcription-coupled nucleotide excision repair pathway is an important component. In addition, trabectedin blocks the [G.sub.2]/M phase of the cell cycle and is a selective inhibitor of activated gene transcription. Trabectedin has demonstrated activity in vitro and in vivo against a range of solid tumour cell lines, human xenografts and human tumour explants, including STS, ovarian, breast, prostate and renal cancers, melanoma and non-small cell lung cancer. In vitro and in vivo studies indicated that trabectedin had an additive or synergistic effect when combined with other antineoplastic agents, such as cisplatin, doxorubicin or irinotecan. Unlike many other chemotherapeutic agents used in treatment of STS, trabectedin resistance does not appear to involve MDRI gene transcription. Trabectedin displayed linear pharmacokinetics over a wide dose range in patients with solid tumours (including STS). However, pharmacokinetic parameters showed a large interpatient variability. The mean maximum plasma concentration after intravenous administration of trabectedin 1.5 mg/[m.sup.2] as a 24-hour infusion in patients with STS was 1.04-1.34 ng/mL and the mean area under the plasma concentration-time curve was 39.9-15.5 ng x h/mL. Trabectedin is extensively distributed into tissues. Trabectedin is predominantly metabolised via the cytochrome P450 (CYP) pathway with a lesser contribution from phase II metabolism. The cytotoxicity of trabectedin is increased when it is coadministered with CYP inhibitors, but is unchanged when the drug is coadministered with CYP inducers or phase II enzyme inhibitors. Faecal excretion predominates. Impaired hepatic function is associated with reduced total body clearance of trabectedin and may require dosage reductions. Therapeutic Efficacy In a randomised, nonblind, multicentre trial in chemotherapy-experienced patients with advanced or metastatic leiomyosarcoma or liposarcoma, intravenous trabectedin 1.5 mg/[m.sup.2] administered over 24 hours every 3 weeks (3-weekly trabectedin) was significantly more effective than the weekly regimen in terms of the median time to disease progression (primary endpoint), as well as for the objective response rate, progression-free survival and overall survival duration. These efficacy outcomes were supported by the results of several noncomparative studies of trabected

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