Trabectedin
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| Pronunciation | /trəˈbɛktɪdɪn/ trə-BEK-ti-din |
| Trade names | Yondelis |
| Other names | ecteinascidin 743, ET-743 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a615059 |
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| Routes of administration | Intravenous |
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| Pharmacokineticdata | |
| Bioavailability | Not applicable (IV only) |
| Protein binding | 94 to 98% |
| Metabolism | Liver(mostlyCYP3A4-mediated) |
| Eliminationhalf-life | 180 hours (mean) |
| Excretion | Mostly fecal |
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| ECHA InfoCard | 100.223.368 |
| Chemical and physical data | |
| Formula | C39H43N3O11S |
| Molar mass | 761.84g·mol−1 |
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Trabectedin,sold under the brand nameYondelis,is an antitumor chemotherapy medication for the treatment of advancedsoft-tissue sarcomaandovarian cancer.[3][4]
The most common adverse reactions include nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache.[3][4]
It is sold by Pharma Mar S.A. and Johnson and Johnson. It is approved for use in the European Union, Russia, South Korea and the United States. The European Commission and the U.S.Food and Drug Administration(FDA) grantedorphan drugstatus to trabectedin for soft-tissue sarcomas andovarian cancer.
Discovery and production
[edit]During the 1950s and 1960s, theNational Cancer Institutecarried out a wide-ranging program of screening plant and marine organism material. As part of that program, extract from thesea squirtEcteinascidia turbinatawas found to have anticancer activity in 1969.[5] Separation and characterization of the active molecules had to wait many years for the development of sufficiently sensitive techniques, and the structure of one of them, Ecteinascidin 743, was determined by KL Rinehart at the University of Illinois in 1984.[6]Rinehart had collected his sea squirts by scuba diving in the reefs of the West Indies.[7]The biosynthetic pathway responsible for producing the drug has been determined to come fromCandidatusEndoecteinascidia frumentensis, a microbial symbiont of the tunicate.[8] The Spanish companyPharmaMarlicensed the compound from the University of Illinois before 1994[citation needed]and attempted to farm the sea squirt with limited success.[7]Yields from the sea squirt are extremely low as around 1,000 kilograms of animals is needed to isolate 1 gram of trabectedin - and about 5 grams were believed to be needed for a clinical trial[9]so Rinehart asked the Harvard chemistE. J. Coreyto search for a synthetic method of preparation. His group developed such a method and published it in 1996.[10]This was later followed by a simpler and more tractable method which was patented by Harvard and subsequently licensed to PharmaMar.[7]The current[when?]supply is based on a semisynthetic process developed by PharmaMar starting from safracin B, a chemical obtained by fermentation of the bacteriumPseudomonas fluorescens.[11]PharmaMar entered into an agreement with Johnson & Johnson to market the compound outside Europe.[citation needed]
Approvals and indications
[edit]Trabectedin was first trialed in humans in 1996.[citation needed]
Soft tissue sarcoma
[edit]In 2007, the European Commission gave authorization for the marketing of trabectedin, under the trade name Yondelis, "for the treatment of patients with advanced soft tissue sarcoma, after failure ofanthracyclinesandifosfamide,or who are unsuited to receive these agents ".[12][4]The European Medicine Agency's evaluating committee, theCommittee for Medicinal Products for Human Use(CHMP), observed that trabectedin had not been evaluated in an adequately designed and analyzed randomized controlled trial against current best care, and that the clinical efficacy data were mainly based on patients withliposarcomaandleiomyosarcoma.However, the pivotal study did show a significant difference between two different trabectedin treatment regimens, and due to the rarity of the disease, the CHMP considered that marketing authorization could be granted under exceptional circumstances.[13]As part of the approval PharmaMar agreed to conduct a further trial to identify whether any specific chromosomaltranslocationscould be used to predict responsiveness to trabectedin.[14]
Trabectedin is also approved in South Korea[15]and Russia.[citation needed]
In 2015, (after a phase III study comparing trabectedin withdacarbazine[16]), theUS FDAapproved trabectedin (Yondelis) for the treatment of liposarcoma and leiomyosarcoma that is either unresectable or has metastasized. Patients must have received prior chemotherapy with an anthracycline.[17]
Ovarian cancer and other
[edit]In 2008, the submission was announced of a registration dossier to theEuropean Medicines Agencyand the FDA for Yondelis when administered in combination withpegylated liposomal doxorubicin(Doxil, Caelyx) for the treatment of women with relapsedovarian cancer.In 2011, Johnson & Johnson voluntarily withdrew the submission in the United States following a request by the FDA for an additional phase III study to be done in support of the submission.[18]
Trabectedin is[when?]also in phase II trials for prostate, breast, and paediatric cancers.[19]
Structure
[edit]Trabectedin is composed of threetetrahydroisoquinolinemoieties,eight rings including one 10-membered heterocyclic ring containing acysteineresidue, and seven chiral centers.[20][21]
Biosynthesis
[edit]
The biosynthesis of trabectedin in the tunicatesymbiotic bacteriaCandidatusEndoecteinascidia frumentensisstarts with a fatty acid loading onto the acyl-ligase domain of the EtuA3 module. A cysteine and glycine are then loaded as canonical NRPS amino acids. A tyrosine residue is modified by the enzymes EtuH, EtuM1, and EtuM2 to add a hydroxyl at the meta position of the phenol, and adding two methyl groups at the para-hydroxyl and the meta carbon position. This modified tyrosine reacts with the original substrate via aPictet-Spengler reaction,where the amine group is converted to an imine by deprotonation, then attacks the free aldehyde to form a carbocation that is quenched by electrons from the methyl-phenol ring. This is done in the EtuA2 T-domain. This reaction is done a second time to yield a dimer of modified tyrosine residues that have been further cyclized via Pictet-Spengler reaction, yielding a bicyclic ring moiety. The EtuO and EtuF3 enzymes continue to post-translationally modify the molecule, adding several functional groups and making a sulfide bridge between the original cysteine residue and the beta-carbon of the first tyrosine to form ET-583, ET-597, ET-596, and ET-594 which have been previously isolated.[8]A thirdO-methylated tyrosine is added and cyclized via Pictet-Spengler to yield the final product.[8]
Total synthesis
[edit]Thetotal synthesisby E.J. Corey[10]used this proposed biosynthesis to guide their synthetic strategy. The synthesis uses such reactions as theMannich reaction,Pictet-Spengler reaction,theCurtius rearrangement,andchiralrhodium-baseddiphosphine-catalyzedenantioselectivehydrogenation.A separate synthetic process also involved theUgi reactionto assist in the formation of the pentacyclic core. This reaction was unprecedented for using such a one pot multicomponent reaction in the synthesis of such a complex molecule.
Mechanism of action
[edit]Recently,[when?]it has been shown that trabectedin blocks DNA binding of the oncogenictranscription factorFUS-CHOPand reverses the transcriptional program inmyxoid liposarcoma.By reversing the genetic program created by this transcription factor, trabectedin promotes differentiation and reverses the oncogenic phenotype in these cells.[22]
Other than transcriptional interference, the mechanism of action of trabectedin is complex and not completely understood. The compound is known to bind and alkylate DNA at the N2 position of guanine. It is known fromin vitrowork that this binding occurs in the minor groove, spans approximately three to five base pairs and is most efficient with CGG sequences. Additional favorable binding sequences are TGG, AGC, or GGC. Once bound, this reversible covalent adduct bends DNA toward the major groove, interferes directly with activated transcription, poisons thetranscription-coupled nucleotide excision repaircomplex, promotes degradation of RNA polymerase II, and generates DNA double-strand breaks.[22]
In 2024, researchers fromETH ZürichandUNISTdetermined that abortivetranscription-coupled nucleotide excision repairof trabectedin-DNA adducts forms persistent single-strand breaks (SSBs) as the adducts block the second of the two sequentialNERincisions. The researchers mapped the 3’-hydroxyl groups of SSBs originating from the firstNERincision at trabectedin lesions, recording TC-NER on a genome-wide scale, which resulted in a TC-NER-profiling assay TRABI-Seq.[23]
Society and culture
[edit]Legal status
[edit]In September 2020, the European Medicines Agency recommended that the use of trabectedin in treating ovarian cancer remain unchanged.[24]
References
[edit]- ^ab"Yondelis".Therapeutic Goods Administration (TGA).3 May 2021.Retrieved6 September2021.
- ^"Yondelis 1 mg powder for concentrate for solution for infusion - Summary of Product Characteristics (SmPC)".(emc).21 September 2020.Retrieved30 September2020.
- ^abc"Yondelis- trabectedin injection, powder, lyophilized, for solution".DailyMed.22 September 2020.Retrieved30 September2020.
- ^abcd"Yondelis EPAR".European Medicines Agency(EMA).17 September 2018.Retrieved30 September2020.
- ^Lichter W, Wallham LL, Van Der Worf BA, Middle Brook RE, Sigal MM, Weinheimer AJ (August 1972). Worthen LW (ed.). "Food Drugs from the Sea".Proceedings.173.Marine Tech Soc: 117–127.
- ^Rinehart KL (January 2000). "Antitumor compounds from tunicates".Medicinal Research Reviews.20(1): 1–27.doi:10.1002/(SICI)1098-1128(200001)20:1<1::AID-MED1>3.0.CO;2-A.PMID10608919.S2CID25117225.
- ^abcCromie WJ (4 May 2000)."Potent cancer drugs made -- Sea squirts provide recipe".Harvard University Gazette.Archived fromthe originalon 3 June 2006.
- ^abcRath CM, Janto B, Earl J, Ahmed A, Hu FZ, Hiller L, et al. (November 2011)."Meta-omic characterization of the marine invertebrate microbial consortium that produces the chemotherapeutic natural product ET-743".ACS Chemical Biology.6(11): 1244–1256.doi:10.1021/cb200244t.PMC3220770.PMID21875091.
- ^Pain S (14 September 1996)."Hostages of the deep - Prospectors are taking to the seas in search of new and promising chemicals. But the better the drugs turn out to be, the greater the threat to the animals that produce them".New Scientist.
- ^abCorey EJ, Gin DY, Kania RS (1996). "Enantioselective Total Synthesis of Ecteinascidin 743".Journal of the American Chemical Society.118(38): 9202–9203.doi:10.1021/ja962480t.
- ^Cuevas C, Pérez M, Martín MJ, Chicharro JL, Fernández-Rivas C, Flores M, et al. (August 2000). "Synthesis of ecteinascidin ET-743 and phthalascidin Pt-650 from cyanosafracin B".Organic Letters.2(16): 2545–2548.doi:10.1021/ol0062502.PMID10956543.
- ^"YONDELIS (trabectedin)"(PDF).Post-Authorization Summary of Positive Opinion.European Medicines Agency. 24 September 2009.Retrieved12 November2019.
- ^"CHMP evaluation"(PDF).
- ^"PharmaMar website".Archived fromthe originalon September 18, 2008.
- ^"S.Korea approves Zeltia cancer drug Yondelis".Reuters.8 May 2008.Retrieved30 September2020.
- ^"Trabectedin Superior to Dacarbazine for Leiomyosarcoma, Liposarcoma".Cancer Network.21 September 2015. Archived fromthe originalon 5 March 2016.
- ^"FDA Approves Trabectedin (Yondelis) for Advanced Soft-Tissue Sarcoma".Cancer Network.26 October 2015. Archived fromthe originalon 17 March 2016.
- ^Grogan K (3 May 2011)."J&J pulls submission for Zeltia's Yondelis".PharmaTimes Magazine.London, England. Online PharmaTimes.Archivedfrom the original on 2 October 2011.Retrieved7 May2011.
- ^"Yondelis (trabectedin)".PharmaMar.Archived fromthe originalon 13 February 2012.
- ^D'Incalci M, Galmarini CM (August 2010). "A review of trabectedin (ET-743): a unique mechanism of action".Molecular Cancer Therapeutics.9(8): 2157–2163.doi:10.1158/1535-7163.MCT-10-0263.PMID20647340.S2CID6723817.
- ^Chukwueke UN, Wen PY (2020). "Medical management of meningiomas". In McDermott MW (ed.).Meningiomas, Part II.Handbook of Clinical Neurology. Vol. 170. Elsevier. pp. 291–302.doi:10.1016/B978-0-12-822198-3.00048-3.ISBN978-0-12-822198-3.PMC6169485.PMID32586501.
- ^abGrohar PJ, Griffin LB, Yeung C, Chen QR, Pommier Y, Khanna C, et al. (February 2011)."Ecteinascidin 743 interferes with the activity of EWS-FLI1 in Ewing sarcoma cells".Neoplasia.13(2): 145–153.doi:10.1593/neo.101202.PMC3033593.PMID21403840.and works cited therein.
- ^Son K, Takhaveev V, Mor V, Yu H, Dillier E, Zilio N, et al. (February 2024). "Trabectedin derails transcription-coupled nucleotide excision repair to induce DNA breaks in highly transcribed genes".Nature Communications.15(1): 1388.doi:10.1038/s41467-024-45664-7.hdl:20.500.11850/661709.PMID38360910.
- ^"Yondelis".European Medicines Agency(EMA).27 February 2020.Retrieved30 September2020.
