Yondelis® (trabectedin, ET-743): The development of an anticancer agent of marine origin

Anti-Cancer Drugs

Volumn 14, Issue 7, 2003, Pages 487-502

  Van Kesteren, Ch ^a   De Vooght, M M M ^a   Lopez Lazaro L ^b   Mathot R A A ^a   Schellens, J H M ^c   Jimeno, J M ^b   Beijnen, J H ^a,c  

^a SLOTERVAART HOSPITAL   (Netherlands)

^b PHARMAMAR S A   (Spain)

^c NETHERLANDS CANCER INSTITUTE   (Netherlands)

Author keywords

ET 743; Marine origin; Trabectedin; Yondelis

Indexed keywords

ANTINEOPLASTIC AGENT; DEXAMETHASONE; DNA; DNA BINDING PROTEIN; DNA TOPOISOMERASE; DOXORUBICIN; ETOPOSIDE; FOLINIC ACID; GLYCOPROTEIN P; METHOTREXATE; NAVELBINE; PACLITAXEL; TRABECTEDIN; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR MDR1; TRANSCRIPTION FACTOR NUCLEAR FACTOR Y; TRANSCRIPTION FACTOR SXR; TRASTUZUMAB; TRIMETREXATE; UNCLASSIFIED DRUG; 1,3 DIOXOLANE DERIVATIVE; ALKYLATING AGENT; ISOQUINOLINE DERIVATIVE; TETRAHYDROISOQUINOLINE DERIVATIVE;

ANEMIA; ANTINEOPLASTIC ACTIVITY; ASTHENIA; BLOOD TOXICITY; BONE MARROW SUPPRESSION; BONE MARROW TOXICITY; CANCER; CANCER CELL CULTURE; CANCER CHEMOTHERAPY; CANCER PATIENT; CARDIOTOXICITY; CELL CYCLE; CHEMOTHERAPY INDUCED EMESIS; CHILDHOOD CANCER; CLINICAL TRIAL; DNA REPAIR; DOSE RESPONSE; DRUG CLEARANCE; DRUG DNA BINDING; DRUG ELIMINATION; DRUG FORMULATION; DRUG HALF LIFE; DRUG INFUSION; DRUG MECHANISM; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TOLERABILITY; FATIGUE; FEBRILE NEUTROPENIA; FIBROSARCOMA; HUMAN; HYPERBILIRUBINEMIA; HYPOKALEMIA; KIDNEY FAILURE; LEIOMYOSARCOMA; LEUKOPENIA; LIPOSARCOMA; LIVER FAILURE; LIVER TOXICITY; MALIGNANT MESOTHELIOMA; MICROTUBULE ORGANIZING CENTER; MULTIPLE ORGAN FAILURE; NAUSEA; NEUROTOXICITY; NONHUMAN; OSTEOSARCOMA; OVARY CARCINOMA; PANCYTOPENIA; PRIORITY JOURNAL; REVIEW; RHABDOMYOLYSIS; SIDE EFFECT; STOMACH CARCINOMA; SYNOVIAL SARCOMA; THROMBOCYTOPENIA; ANIMAL; CHEMISTRY; DRUG EFFECT; FEMALE; METABOLISM; NEOPLASM;

ANIMALS; ANTINEOPLASTIC AGENTS, ALKYLATING; CELL CYCLE; CHEMISTRY, PHARMACEUTICAL; CLINICAL TRIALS; DIOXOLES; FEMALE; HUMANS; ISOQUINOLINES; NEOPLASMS; TETRAHYDROISOQUINOLINES;

EID: 0041330535     PISSN: 09594973     EISSN: None     Source Type: Journal    
DOI: 10.1097/00001813-200308000-00001     Document Type: Review

References (111)

1. Adams J, Elliott PJ. New agents in cancer clinical trials. Oncogene 2000; 19:6687-6692.
2. Schwartsmann G, da Rocha AB, Berlinck RGS, Jimeno J. Marine organisms as a source of new anticancer agents. Lancet Oncol 2001; 2:221-225.
3. Da Rocha AB, Lopes RM, Schwartsmann G. Natural products in anticancer therapy. Curr Opin Pharmacol 2001; 1:364-369.
4. Cragg GM, Newman DJ, Weiss RB. Coral reefs, forests, and thermal vents: the worldwide exploration of nature for novel antitumor agents. Semin Oncol 1997; 24:156-163.
5. D'Incalci MD. Some hope from marine natural products. Ann Oncol 1998; 9:937-938.
6. Scheuer PJ. From the rainforest to the reef. Med Res Rev 1994; 14:487-503.
7. Pettit GR, Day JF. Antineoplastic components of marine animals. Nature 1970; 277:962-963.
8. Jimeno J, Faircloth G, Guzmán C, Vega E, Fernández Sousa JM. Marine derived therapeutics. Conference Lecture: Medicines from Nature: Scientific, Legal and Ethical Aspects. The Royal Academy of Medicine, London, 9-10 June 1998.
9. Schellens JHM, Rademaker JL, Horenblas S, et al. Phase I and pharmacokinetic study of kahalalide F in patients with advanced androgen refractory prostate cancer. Proc AACR-NCI-EORTC 2001: #207.
10. Li LH, Timmins LG, Wallace TL, Joullié. Mechanism of action of didemnin B, a depsipeptide from the sea. Cancer Lett 1984; 23:279-288.
11. Depenbrock H, Peter R, Faircloth GT, Manzanares I, Jimeno J, Hanauske AR. In vitro activity of aplidine, a new marine-derived anti-cancer compound, on freshly explanted clonogenic human tumour cells and haematopoietic precursor cells. Br J Cancer 1998; 78:739-744.
12. Propper DJ, Macaulay V, O'Byrne KJ, et al. A phase II study of bryostatin 1 in metastatic malignant melanoma. Br J Cancer 1998; 78:1337-1341.
13. Rinehart KL. Antitumor compounds from tunicates. Med Res Rev 2000; 20:1-27.
14. 2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata. Biochemistry 1996; 35:13303-13309.
15. Jimeno JM, Faircloth G, Cameron L, et al. Progress in the acquisition of new marine-derived anticancer compounds: development of ecteinascidin-743 (ET-743). Drugs of the Future 1996; 21:1155-1165.
16. Cvetkovic RS, Figgitt DP, Plosker GL. Ecteinascidin-743. Drugs 2002; 62:1185-1192.
17. Rinehart KL, Holt TG, Fregeau NL, et al. Potent antitumor agents from the Caribbean tunicate Ecteinascidia turbinata. J Org Chem 1990; 55:4512-4515.
18. Sakai R, Rinehart KL, Guan Y, Wang AHJ. Additional antitumor ecteinascidins from a Caribbean tunicate: crystal structures and activities in vivo. Proc Natl Acad Sci USA 1992; 89:11456-11460.
19. Guan Y, Sakai R, Rinehart KL, Wang AHJ. Molecular and crystal structures of ecteinascidins: potent antitumor compounds from the Caribbean tunicate Ecteinascidia turbinata. J Biomol Struct Dyn 1993; 10:793-818.
20. Wright AE, Forleo DA, Gunawardana GP, Gunasekera SP, Koehn FE, McConnell OJ. Antitumor tetrahydroisoquinoline alkaloids from the colonial ascidian Ecteinascidia turbinata. J Org Chem 1990; 55:4508-4512.
21. Reid JM, Walker DL, Ames MM. Preclinical pharmacology of ecteinascidin 729, a marine natural product with potent antitumor activity. Cancer Chemother Pharmacol 1996; 38:329-334.
22. Corey EJ, Gin DY, Kania RS. Enantioselective total synthesis of ecteinascidin 743. J Am Chem Soc 1996; 118:9202-9203.
23. Martinez EJ, Corey EJ. A new, more efficient, and effective process for the synthesis of a key pentacyclic intermediate for production of ecteinascidin and phthalascidin antitumor agents. Org Lett 2000; 2:993-996.
24. Cuevas C, Pérez M, Martin MJ, et al. Synthesis of ecteinascidin ET-743 and phthalascidin Pt-650 from cyanosafracin B. Org Lett 2000; 2:2545-2548.
25. Saito N, Tachi M, Seki R, Kamayachi H, Kubo A. A practical synthesis of the ABC ring model of ecteinascidins. Chem Pharm Bull 2000; 48:1549-1557.
26. Zhou B, Guo J, Danishefsky SJ. Studies directed to the total synthesis of ET-743 and analogues thereof: an expeditious route to the ABFGH subunit. Org Lett 2002; 4:43-46.
27. Martinez EJ, Owa T, Schreiber SL, Corey EJ. Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743. Proc Natl Acad Sci USA 1999; 96:3496-3501.
28. Martinez EJ, Corey EJ, Owa T. Antitumor activity- and gene expression-based profiling of ecteinascidin Et 743 and phthalascidin Pt 650. Chem Biol 2001; 8:1151-1160.
29. 2. J Am Chem Soc 1998; 120:2490-2491.
30. Nuijen B, Bouma M, Manada C, et al. Pharmaceutical development of anticancer agents derived from marine sources. Anticancer Drugs 2000; 11:793-811.
31. Marco E, García-Nieto R, Mendieta J, Manzanares I, Cuevas C, Gago F. A 3*(ET743)-DNA complex that both resembles an RNA-DNA hybrid and mimics zinc finger-induced DNA structural distortions. J Med Chem 2002; 45:871-880.
32. Moore BM, Seaman FC, Hurley LH. NMR-based model of an ecteinascidin 743-DNA adduct. J Am Chem Soc 1997; 119:5475-5476.
33. Seaman FC, Hurley H. Molecular basis for the DNA sequence selectivity of ecteinascidin 736 and 743: evidence for the dominant role of direct readout via hydrogen bonding. J Am Chem Soc 1998; 120:13028-13041.
34. García-Nieto R, Manzanares I, Cuevas C, Gago F. Bending of DNA upon binding of Ecteinascidin 743 and phthalascidin 650 studies by unrestrained molecular dynamics simulations. J Am Chem Soc 2000; 122:7172-7182.
35. García-Nieto R, Manzanares I, Cuevas C, Gago F. Increased DNA binding specificity for antitumor Ecteinascidin 743 through protein-DNA interactions? J Med Chem 2000; 43:4367-4369.
36. Zewail-Foote M, Hurley LH. Differential rates of reversibility of ecteinascidin 743-DNA covalent adducts from different sequences lead to migration to favored bonding sites. J Am Chem Soc 2001; 123:6485-6495.
37. Hurley LH, Zewail-Foote M. The antitumor agent ecteinascidin 743: characterization of its covalent DNA adducts and chemical stability. Adv Exp Med Biol 2001; 500:289-299.
38. Zewail-Foote M, Hurley LH. Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove. J Med Chem 1999; 42:2493-2497.
39. Bonfanti M, La Valle E, Fernandez Sousa Faro J, et al. Effect of ecteinascidin-743 on the interaction between DNA binding proteins and DNA. Anticancer Drug Des 1999; 14:179-186.
40. Minuzzo M, Marchini S, Broggini M, Faircloth G, D'Incalci M, Mantovani R. Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. Proc Natl Acad Sci 2000; 97:6780-6784.
41. Jin S, Gorfajn B, Faircloth G, Scotto KW. Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation. Proc Natl Acad Sci 2000; 97:6775-6779.
42. Markenson D, Hu Z, Scotto KW. ET-743 inhibits SP1-mediated transcriptional activation of the p21 promoter. Proc Am Ass Cancer Res 2001; 42:203.
43. Erba E, Bergamaschi D, Bassano L, et al. Isolation and characterisation of an IGROV-1 human ovarian cancer cell line made resistant to ecteinascidin-743 (ET-743). Br J Cancer 2000; 82:1732-1739.
44. Kanzaki A, Takebayashi Y, Fukumoto M, Uchida T, Pommier Y. Activity of Ecteinascidin 743 and synergism with doxorubicin and vincristine in P-glycoprotein/MDR1 over-expression cell lines. Proc Am Ass Cancer Res 2001; 42:811.
45. Fontaniere C, Terrier-Lacombe M, Santos A, et al. Antitumor activity of ET-743 (ecteinascidin-743) in neuroblastoma and medulloblastoma xenografts. Proc Am Ass Cancer Res 2001; 42:477.
46. Shao L, Weissbach L, Faircloth GT, Horniceh FJ. In vitro invasiveness of chondrosarcoma altered by ecteinascidin-743. Proc Am Ass Cancer Res 2002; abstr 2676.
47. Kim H, Healey J, Sowers R, et al. Expression of drug resistance related genes and drug cytotoxicity is discordant in human osteosarcoma. Proc Am Ass Cancer Res 2002; abstr 5486.
48. Maliepaard M, Van Gastelen M, Faircloth GT, Jimneo JM, Beijnen JH, Schellens JHM. Novel marine derived anticancer agents ET-743, Aplidine, Spisulosine (ES-285) and Kahalalide F are not transported by the Breast Cancer Resistance Protein. Proc Am Ass Cancer Res 2001; 42:4352.
49. Synold TW, Dussault I, Forman BM. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 2001; 7:584-590.
50. Izbicka E, Lawrence R, Raymond E, et al. In vitro antitumor activity of the novel marine agent, ecteinascidin-743 (ET-743, NSC-648766) against human tumors explanted from patients. Ann Oncol 1998; 9:981-987.
51. García-Rocha M, García-Gravalos MD, Avila J. Characterisation of antimitotic products from marine organisms that disorganise the microtubule network: ecteinascidin 743, isohomohalichondrin-B and LL-15. Br J Cancer 1996; 73:875-883.
52. Takebayashi Y, Pommier Y. DNA minor groove alkylation by ecteinascidin 743 (ET743) induces sequence specific topoisomerase I-mediated DNA damage. Proc Am Ass Cancer Res 1999; 40:108.
53. Takebayashi Y, Pourquier P, Yoshida A, Kohlhagen G, Pommier Y. Poisoning of human DNA topoisomerase I by ecteinascidin 743, an anticancer drug that selectively alkylates DNA in the minor groove. Proc Natl Acad Sci 1999; 96:7196-7201.
54. Takebayashi Y, Goldwasser F, Urasaki Y, Kohlhagen G, Pommier Y. Ecteinascidin 743 induces protein-linked DNA breaks in human colon carcinoma HCT116 cells and is cytotoxic independently of topoisomerase I expression. Clin Cancer Res 2001; 7:185-191.
55. Erba E, Bergamaschi D, Bassano L, et al. Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action. Eur J Cancer 2001; 37:97-105.
56. Simoens C, Korst AEC, Pattyn GGO, et al. Cell cycle effects of ET-743. Proc Am Ass Cancer Res 2002; abstr 324.
57. Takebayashi Y, Pouqier P, Zimonjic DB, et al. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med 2001; 7:961-966.
58. Damia G, Silvestri S, Carrassa L, et al. Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways. Int J Cancer 2001; 92:583-588.
59. Zewail-Foote M, Li VS, Kohn H, Bearss D, Guzman M, Hurley LH. The inefficiency of incisions of ecteinascidin 743-DNA adducts by the UvrABC nuclease and the unique structural feature of the DNA adducts can be used to explain the repair-dependent toxicities of this antitumor agent. Chem Biol 2001; 8:1033-1049.
60. Rinehart KL, Gravalos LG, Faircloth G, Jimeno J. ET-743: preclinical antitumor development of a marine derived natural product. Proc Am Ass Cancer Res 1995; 36:2322.
61. Ghielmini M, Colli E, Erba E, et al. In vitro schedule-dependency of myelotoxicity and cytotoxicity of ecteinascidin 743 (ET-743). Ann Oncol 1998; 9:989-993.
62. Shtil AA, Kolb EA, Faircloth G, LaQuaglia M, Scotto KW. Ecteinascidin 743, a novel natural cytotoxic compound, is potent for human neuroblastoma and rhabdomyosarcoma cell lines: multiple mechanisms of cell kill. Proc Am Ass Cancer Res 2001; 42:4353.
63. Li WW, Takahashi N, Jhanwar S, et al. Sensitivity of soft tissue sarcoma cell lines to chemotherapeutic agents: identification of Ecteinsacidin-743 as a potent cytotoxic agent. Clin Cancer Res 2001; 7:2908-2911.
64. Eckhardt SG, Degen D, Ortiz V, Faircloth GT, Jimeno JM, Von Hoff DD. In vitro studies of a novel marine cytotoxic, ecteinascidin (ET-743). Ann Oncol 1996; 7(suppl 5):632P.
65. Takahashi N, Li W, Faircloth G, Jimeno J, et al. Ecetinascidin-743 (ET-743) and doxorubicin produce synergistic cytotoxic effects in soft tissue sarcoma lines HT-1080 and HS-18. Proc Am Ass Cancer Res 2000; abstr 208.
66. Takahashi N, Li WW, Banerjee D, Scotto KW, Bertino JR. Sequence dependent enhancement of cytotoxicity produced by Ecteinascidin 743 (ET-743) with doxorubicin or paclitaxel in soft tissue sarcoma cells. Clin Cancer Res 2001; 7:3251-3257.
67. Riccardi R, Colombo T, Meco D, et al. Effective combinations of ET-743 and doxorubicin for tumor growth inhibitions against murine and human sarcomas in athymic mice. Proc Am Ass Cancer Res 2001; 42:1132.
68. Moore R, Revilla M, Jimeno J, Faircloth G, Weitman S. Sequencing evaluation of ET-743 combinations with standard chemotherapy agents against a panel of human tumor cell lines. Proc NCI-EORTC-AACR 2000; abstr 504.
69. D'Incalci M, Erba E, Damia G, et al. The combination of ET-743 and cisplatin (DDP): from a molecular pharmacology study to a phase I clinical trial. Proc Am Ass Cancer Res 2002; abstr 404.
70. Valoti G, Nicoletti MI, Pellegrino A, et al. Ecteinascidin-743, a new marine natural product with potent antitumor activity on human ovarian carcinoma xenografts. Clin Cancer Res 1998; 4:1977-1983.
71. Hendriks HR, Fiebig HH, Giavazzi R, Langdon SP, Jimeno JM, Faircloth GT. High antitumour activity of ET743 against human tumour xenografts from melanoma, non-small-cell lung and ovarian cancer. Ann Oncol 1999; 10:1233-1240.
72. Mazza BD, Yang R, Sowers RS, et al. The establishment of xenograft models from osteosarcoma samples and their growth inhibition by ET-743. Proc Am Ass Cancer Res 2002; abstr 4575.
73. Faircloth GT, Grant W, Jimeno J, et al. Dexamethasone potentiates the activity of Ecteinascidin 743 in preclinical melanoma and osteosarcoma models. Proc Am Ass Cancer Res 2002; abstr 379.
74. Gomez SG, Bueren JA, Faircloth GT, Jimeno J, Albella B. Toxicity of ET-743, aplidine and kahalalide F on hemopoietic stem cell function. Proc Am Ass Cancer Res 2002; abstr 5419.
75. Dorr RT, Shipp NG, Lee KM. Comparison of cytotoxicity in heart cells and tumor cells exposed to DNA intercalating agents in vitro. Anticancer Drugs 1991; 2:27-33.
76. Luber-Narod J, Smith B, Grant W, Jimeno J, Lopez-Lazaro L, Faircloth GT. In vitro safety toxicology of ecteinascidin 743, a marine natural product with chemotherapeutic potential against solid tumors. Proc Am Ass Cancer Res 2001; 42:1133.
77. Mirsalis JC, Schindler-Horvat JE, Tomaszewski JE, et al. Preclinical toxicology studies of ecteinascidin 743. Proc Am Soc Clin Oncol 1996; 37:2556.
78. Tomaszewski JE, Donohue SJ, et al. Preclinical toxicity of ecteinascidin 743. Proc PAMM/EORTC 1995.
79. Kuffel MJ, Reid JM, Ames MM. Cytochrome P450 catalyzed metabolism of ecteinascidin 743 by rat and human liver microsomes. Proc Am Ass Cancer Res 1997; 38:4003.
80. Rosing H, Hillebrand MJX, Jimeno JM, et al. Quantitative determination of ecteinascidin 743 in human plasma by miniaturized high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. J Mass Spectr 1998; 33:1134-1140.
81. Sparidans RW, Rosing H, Hillebrand MJX, et al. Search for metabolites of ecteinascidin-743, a novel marine derived anti-cancer agent. Anticancer Drugs 2001; 12:653-666.
82. Adachi Y, Yamamoto T. Hepatic bilirubin-conjugating enzymes of man in the normal state and in liver disease. Gastroenterol Jpn 1982; 17:235-240.
83. Black M, Billing BH. Hepatic bilirubin UDP-glucuronyl transferase in liver disease and Gilbert's syndrome. N Engl J Med 1969; 280:1266-1271.
84. Rosing H, Hillebrand MJX, Jimeno JM, et al. Analysis of ecteinascidin 743, a new potent marine-derived anticancer drug, in human plasma by high-performance liquid chromatography in combination with solid-phase extraction. J Chrom B 1998; 710:183-189.
85. van Kesteren Ch, Twelves C, Bowman A, et al. Clinical pharmacology of the novel marine-derived anti-cancer agent Ecteinascidin 743 administered as a 1- and 3-h infusion in a phase I study. Anticancer Drugs 2002; 13:381-393.
86. van Kesteren Ch, Cvitkovic E, Taamma A, et al. Pharmacokinetics and pharmacodynamics of the novel marine-derived anti-cancer agent Ecteinascidin 743 in a phase I dose-finding study. Clin Cancer Res 2000; 6:4725-4732.
87. Ryan DP, Supko JG, Eder JP, et al. Phase I and pharmacokinetic study of ecteinascidin 743 administered as a 72-hour continuous intravenous infusion in patients with solid malignancies. Clin Cancer Res 2001; 7:231-242.
88. Villalona-Calero M, Eckhardt SG, Weiss G, et al. A phase I and pharmacokinetic study of Ecteinscidin-743 on a daily x 5 schedule in patients with solid malignancies. Clin Cancer Res 2002; 8:75-85.
89. Bowman A, Twelves C, Hoekman K, et al. Phase I clinical and pharmacokinetic (PK) study of ecteinascidin-743 (ET-743) given as a one hour infusion every 21 days. Ann Oncol 1998; 9(suppl 2):452.
90. Twelves C, Hoeckman H, Bowman A, et al. A phase I and pharmacokinetic study of ET-743 evaluating a 3-hour intravenous infusion in patients with solid tumors. Clin Cancer Res 1999; 5:307.
91. Taamma A, Misset JL, Riofrio M, et al. Phase I and pharmacokinetic study of ecteinascidin-743, a new marine compound, administered as a 24-hour continuous infusion in patients with solid tumors. J Clin Oncol 2001; 19:1256-1265.
92. Delaloge S, Yovine A, Taama A, et al. Ecteinascidin-743: a marine-derived compound in advanced, pretreated sarcoma patients - preliminary evidence of activity. J Clin Oncol 2001; 19:1248-1255.
93. Forouzesh B, Hidalgo M, Denis L, et al. Phase I and pharmacokinetic study of the marine-derived DNA minor groove binder on a weekly x 3 every 4 weeks schedule in patients with advanced solid malignancies. Proc AACR-NCI-EORTC 2001; abstr 209.
94. Baruchel S, Blaney S, Hershon L, et al. A phase I study of ET-743 in pediatric refractory solid tumors: a Children's Oncology Groups Study. Proc Am Soc Clin Oncol 2002; 21:96a.
95. Sessa N, Colombo N, Bauer J, et al. Phase II study of salvage ET-743 given as 3-hr infusion in ovarian cancer patients. Ann Oncol 2002; 13(suppl 5):397a.
96. Dileo P, Casali PG, Bacci G, et al. Phase II evaluation of 3-hr infusion ET-743 in patients with recurrent sarcomas. Proc Am Soc Clin Oncol 2002; 21:408a.
97. Le Cesne A, Blay J, Judson I, et al. ET-743 is an active drug in soft-tissue sarcoma (sts): a STBSG-EORTC phase II trial. Proc Am Soc Clin Oncol 2001; 20:1407.
98. George S, Maki RG, Harmon D, et al. Phase II study of ecteinscidin-743 (ET-743) given by 3-hour IV infusion in patients with soft tissue sarcomas failing prior chemotherapies. Proc Am Soc Clin Oncol 2002; 21:408a.
99. Ruiz-Casado A, Lopez-Martin J, Nieto A, et al. Ecteinascidin in heavily pretreated advanced sarcoma patients as a compassionate basis. Proc Am Soc Clin Oncol 2002; 21:408a.
100. Lopez-Martin JA, Nieto A, Demetri GD, et al. Safety profile of ecteinscidin-743 (ET-743) in phase II clinical trials in adult patients with solid tumors. Proc Am Soc Clin Oncol 2002; 21:96a.
101. Yovine A, Riofrío M, Brain E, et al. Ecteinascidin (ET-743) given as a 24-hour (h) intravenous continuous infusion (ivci) every 3 weeks: results of a phase II trial in patients (pts) with pretreated soft tissue sarcomas (ptsts). Proc Am Soc Clin Oncol 2001;21:1449.
102. Demetri GD, Seiden M, Garcia-Carbonero R, et al. Ecteinascidin (ET-743) shows promising activity in distinct populations of sarcoma patients: summary of 3 U.S.-based phase II trials. Proc Am Soc Clin Oncol 2000; 19:2177.
103. Laverdiere C, Kolb A, Meyers P, et al. Phase II study of ET-743 in recurrent osteosarcoma. Proc Am Soc Clin Oncol 2002; 21:96a.
104. Zelek L, Yovine A, Brain E, et al. Preliminary results of phase II study of ecteinascidin-743 (ET-743) with the 24 hour (h) continuous infusion (cl) q3week schedule in pretreated advanced/metastatic breast cancer (A/MBC) patients (pts). Proc NCI-EORTC-AACR 2000; abstr 212
105. van Kesteren Ch, Mathôt RAA, Lópeza-Lázaro L, et al. A comparison of limited sampling strategies for prediction of Ecteinascidin 743 clearance when administered as a 24-hour infusion. Cancer Chemother Pharmacol 2001; 48:459-466.
106. Mathôt R, van Kesteren C, le Cesne A, et al. Population pharmacokinetics of the novel marine derived anti-cancer agent ecteinascidin 743 in two phase II studies using non-linear mixed effects modeling (NONMEM). Proc Am Soc Clin Oncol 2001; 20:372.
107. Garcia-Carbonero R, Demetri G, Ryan D, et al. Population pharmacokinetics of ecteinascidin-743 in patients with advanced soft tissue sarcoma. Proc NCI-EORTC-AACR 2000; abstr 211.
108. Gómez J, López-Lázaro L, Guzman C, et al. Identification of safety parameters that predict the onset of severe toxicities in patients treated with ET-743. Proc Am Soc Clin Oncol 2000; 19:187a.
109. Le Cesne A. Phase II study of ET-743 advanced in soft-tissue sarcoma in adult: a STBSG-EORTC phase II trial. Proc Am Soc Clin Oncol 2002; 21:554a.
110. Le Cesne A, Judson J, Crowther D, et al. Is obtention of partial response (PR) in from line chemotherapy critical to improve outcome of metastatic soft tissue sarcoma (MSTS) patients (PTS). Proc Eur Soc Med Oncol 1998: #556.
111. Van Glabbeke M, Verweij J, Judson I, Nielsen OS. Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas. Eur J Cancer 2002; 38:543-549.