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Exatecan Mesylate

Description of Exatecan mesylate: Exatecan mesylate is a semisynthetic, water-soluble derivative of camptothecin with antineoplastic activity. Exatecan mesylate inhibits topoisomerase I activity by stabilizing the cleavable complex between topoisomerase I and DNA and inhibiting religation of DNA breaks, thereby inhibiting DNA replication and triggering apoptotic cell death. This agent does not require enzymatic activation and exhibits greater potency than camptothecin and other camptothecin analogues. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

 Current developer:   Daiichi Sankyo, Inc.

 1: Wethington SL, Wright JD, Herzog TJ. Key role of topoisomerase I inhibitors in the treatment of recurrent and refractory epithelial ovarian carcinoma. Expert Rev Anticancer Ther. 2008 May;8(5):819-31. Review. PubMed PMID: 18471053.

2: Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C. Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer. 2008 Mar 28;8:82. PubMed PMID: 18373843; PubMed Central PMCID: PMC2292732.

3: Shiose Y, Ochi Y, Kuga H, Yamashita F, Hashida M. Relationship between drug release of DE-310, macromolecular prodrug of DX-8951f, and cathepsins activity in several tumors. Biol Pharm Bull. 2007 Dec;30(12):2365-70. PubMed PMID: 18057727.

4: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Jul-Aug;29(6):427-37. PubMed PMID: 17922073.

5: Reichardt P, Nielsen OS, Bauer S, Hartmann JT, Schöffski P, Christensen TB, Pink D, Daugaard S, Marreaud S, Van Glabbeke M, Blay JY; EORTC Soft Tissue and Bone Sarcoma Group. Exatecan in pretreated adult patients with advanced soft tissue sarcoma: results of a phase II--study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2007 Apr;43(6):1017-22. Epub 2007 Mar 1. PubMed PMID: 17336054.

6: Al-Faris N, Al Harbi T, Goia C, Pappo A, Doyle J, Gassas A. Does consolidation with autologous stem cell transplantation improve the outcome of children with metastatic or relapsed Ewing sarcoma? Pediatr Blood Cancer. 2007 Aug;49(2):190-5. PubMed PMID: 17262797.

7: Shiose Y, Kuga H, Yamashita F, Hashida M. Quantitative acid hydrolysis of DE-310, a macromolecular carrier system for the camptothecin analog DX-8951f. J Pharm Biomed Anal. 2007 Mar 12;43(4):1290-6. Epub 2006 Nov 28. PubMed PMID: 17127025.

8: Owen OG. Exatecan and gemcitabine: no better than gemcitabine only. Lancet Oncol. 2006 Nov;7(11):891. PubMed PMID: 17106952.

9: Abou-Alfa GK, Letourneau R, Harker G, Modiano M, Hurwitz H, Tchekmedyian NS, Feit K, Ackerman J, De Jager RL, Eckhardt SG, O'Reilly EM. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol. 2006 Sep 20;24(27):4441-7. PubMed PMID: 16983112.

10: Chua YJ, Cunningham D. Chemotherapy for advanced pancreatic cancer. Best Pract Res Clin Gastroenterol. 2006 Apr;20(2):327-48. Review. PubMed PMID: 16549331.

11: Takimoto CH. Are there any better camptothecins than the ones we have? Clin Adv Hematol Oncol. 2003 Oct;1(10):578-9, 600. PubMed PMID: 16258452.

12: Richards DA. Chemotherapeutic gemcitabine doublets in pancreatic carcinoma. Semin Oncol. 2005 Aug;32(4 Suppl 6):S9-13. Review. PubMed PMID: 16143162.

13: Ajani JA, Takimoto C, Becerra CR, Silva A, Baez L, Cohn A, Major P, Kamida M, Feit K, De Jager R. A phase II clinical and pharmacokinetic study of intravenous exatecan mesylate (DX-8951f) in patients with untreated metastatic gastric cancer. Invest New Drugs. 2005 Oct;23(5):479-84. PubMed PMID: 16133799.

14: Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2005 May;27(4):265-84. PubMed PMID: 16082427.

15: Abou-Alfa GK, Rowinsky EK, Patt YZ, Schwartz GK, Kelsen DP, Sharma S, Siegel E, Becerra CR, Eckhardt SG, Feit K, De Jager R, O'Reilly EM. A Phase II study of intravenous exatecan administered daily for 5 days, every 3 weeks to patients with biliary tract cancers. Am J Clin Oncol. 2005 Aug;28(4):334-9. PubMed PMID: 16062073.

16: Lopes G, Rocha Lima CM. Docetaxel in the management of advanced pancreatic cancer. Semin Oncol. 2005 Apr;32(2 Suppl 4):S10-23. Review. PubMed PMID: 16015551.

17: Wente MN, Kleeff J, Büchler MW, Wanders J, Cheverton P, Langman S, Friess H. DE-310, a macromolecular prodrug of the topoisomerase-I-inhibitor exatecan (DX-8951), in patients with operable solid tumors. Invest New Drugs. 2005 Aug;23(4):339-47. PubMed PMID: 16012793.

18: Kato M, Matsuhashi K, Shimomura K, Shimada M, Hagiwara M, Fujikawa K, Furuhama K. Examination of meningocele induced by the antitumor agent DE-310 in rat fetuses. Reprod Toxicol. 2005 Nov-Dec;20(4):495-502. PubMed PMID: 15869860.

19: Friberg G, Kindler HL. Chemotherapy for advanced pancreatic cancer: past, present, and future. Curr Oncol Rep. 2005 May;7(3):186-95. Review. PubMed PMID: 15847709.

20: Oguma T, Cicci D, Gaudette F, Gauthier-Dubois G, Guilbaud R, Atsumi R. Validation study of a method for assaying DE-310, a macromolecular carrier conjugate containing an anti-tumor camptothecin derivative, and the free drug in human plasma by HPLC and LC/MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Apr 25;818(2):249-56. PubMed PMID: 15734166.

21: Soepenberg O, de Jonge MJ, Sparreboom A, de Bruin P, Eskens FA, de Heus G, Wanders J, Cheverton P, Ducharme MP, Verweij J. Phase I and pharmacokinetic study of DE-310 in patients with advanced solid tumors. Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):703-11. PubMed PMID: 15701859.

22: Becker RC, Alexander J, Li YF, Bovill E, Spencer FA, Robertson TL, Kunitada S, Dyke CK, Harrington RA. Combined coagulation phase-directed factor Xa inhibition with heparin compounds and DX-9065a - a direct and selective antagonist. Thromb Haemost. 2004 Dec;92(6):1229-31. PubMed PMID: 15622616.

23: Ochi Y, Shiose Y, Kuga H, Kumazawa E. A possible mechanism for the long-lasting antitumor effect of the macromolecular conjugate DE-310: mediation by cellular uptake and drug release of its active camptothecin analog DX-8951. Cancer Chemother Pharmacol. 2005 Apr;55(4):323-32. Epub 2004 Oct 26. PubMed PMID: 15517271.

24: Oguma T, Morikawa H, Iwasaki D, Atsumi R. Validation study of a method for assaying DE-310, a macromolecular carrier conjugate containing an anti-tumor camptothecin derivative, and the free drug in tumor tissue by high performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry. Biomed Chromatogr. 2005 Jan;19(1):19-26. PubMed PMID: 15484225.

25: Masubuchi N, May RD, Atsumi R. A predictive model of human myelotoxicity using five camptothecin derivatives and the in vitro colony-forming unit granulocyte/macrophage assay. Clin Cancer Res. 2004 Oct 1;10(19):6722-31. PubMed PMID: 15475463.

26: Clamp A, Adams M, Atkinson R, Boven E, Calvert AH, Cervantes A, Ganesan T, Lotz J, Vasey P, Cheverton P, Jayson GC. A phase IIA study of the topoisomerase I inhibitor, exatecan mesylate (DX-8951f), administered at two different dose schedules in patients with platinum- and taxane-resistant/refractory ovarian cancer. Gynecol Oncol. 2004 Oct;95(1):114-9. PubMed PMID: 15385119.

27: Kuppens IE, Beijnen J, Schellens JH. Topoisomerase I inhibitors in the treatment of gastrointestinal cancer: from intravenous to oral administration. Clin Colorectal Cancer. 2004 Sep;4(3):163-80. Review. PubMed PMID: 15377400.

28: Masubuchi N. Pharmacokinetics of DE-310, a novel macromolecular carrier system for the camptothecin analog DX-8951f, in tumor-bearing mice. Pharmazie. 2004 May;59(5):374-7. PubMed PMID: 15212304.

29: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2004 Apr;26(3):211-44. PubMed PMID: 15148527.

30: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2004 Mar;26(2):129-61. PubMed PMID: 15071612.

31: Kumazawa E, Ochi Y. DE-310, a novel macromolecular carrier system for the camptothecin analog DX-8951f: potent antitumor activities in various murine tumor models. Cancer Sci. 2004 Feb;95(2):168-75. PubMed PMID: 14965368.

32: Oguma T, Konno T, Nakaoka M. Validation study of assay method for DE-310, a novel polymer-bound camptothecin derivative, and the free drug in mouse plasma by liquid chromatography with fluorimetric detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2004 Mar 5;801(2):157-64. PubMed PMID: 14751783.

33: Royce ME, Rowinsky EK, Hoff PM, Coyle J, DeJager R, Pazdur R, Saltz LB. A phase II study of intravenous exatecan mesylate (DX-8951f) administered daily for five days every three weeks to patients with metastatic adenocarcinoma of the colon or rectum. Invest New Drugs. 2004 Jan;22(1):53-61. PubMed PMID: 14707494.

34: Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2003 Nov;25(9):747-71. PubMed PMID: 14685303.

35: Soepenberg O, de Bruijn P, Verweij J, Atsumi R, Sparreboom A. Liquid chromatographic assays for DE-310, a novel camptothecin analog, and two major enzymatic products in human matrices. J Chromatogr B Analyt Technol Biomed Life Sci. 2004 Jan 5;799(1):15-22. PubMed PMID: 14659432.

36: Verschraegen CF, Kudelka AP, Hu W, Vincent M, Kavanagh JJ, Loyer E, Bastien L, Duggal A, De Jager R. A phase II study of intravenous exatecan mesylate (DX-8951f) administered daily for 5 days every 3 weeks to patients with advanced ovarian, tubal or peritoneal cancer resistant to platinum, taxane and topotecan. Cancer Chemother Pharmacol. 2004 Jan;53(1):1-7. Epub 2003 Oct 28. PubMed PMID: 14586557.

37: Esteva FJ, Rivera E, Cristofanilli M, Valero V, Royce M, Duggal A, Colucci P, DeJager R, Hortobagyi GN. A Phase II study of intravenous exatecan mesylate (DX-8951f) administered daily for 5 days every 3 weeks to patients with metastatic breast carcinoma. Cancer. 2003 Sep 1;98(5):900-7. PubMed PMID: 12942555.

38: Braybrooke JP, Ranson M, Manegold C, Mattson K, Thatcher N, Cheverton P, Sekiguchi M, Suzuki M, Oyama R, Talbot DC. Phase II study of exatecan mesylate (DX-8951f) as first line therapy for advanced non-small cell lung cancer. Lung Cancer. 2003 Aug;41(2):215-9. PubMed PMID: 12871785.

39: Garrison MA, Hammond LA, Geyer CE Jr, Schwartz G, Tolcher AW, Smetzer L, Figueroa JA, Ducharme M, Coyle J, Takimoto CH, De Jager RL, Rowinsky EK. A Phase I and pharmocokinetic study of exatecan mesylate administered as a protracted 21-day infusion in patients with advanced solid malignancies. Clin Cancer Res. 2003 Jul;9(7):2527-37. PubMed PMID: 12855627.

40: Lansiaux A, Bailly C. [A symphony for the camptothecins]. Bull Cancer. 2003 Mar;90(3):239-45. French. PubMed PMID: 12801826.

41: Braybrooke JP, Boven E, Bates NP, Ruijter R, Dobbs N, Cheverton PD, Pinedo HM, Talbot DC. Phase I and pharmacokinetic study of the topoisomerase I inhibitor, exatecan mesylate (DX-8951f), using a weekly 30-minute intravenous infusion, in patients with advanced solid malignancies. Ann Oncol. 2003 Jun;14(6):913-21. PubMed PMID: 12796030.

42: Sun FX, Tohgo A, Bouvet M, Yagi S, Nassirpour R, Moossa AR, Hoffman RM. Efficacy of camptothecin analog DX-8951f (Exatecan Mesylate) on human pancreatic cancer in an orthotopic metastatic model. Cancer Res. 2003 Jan 1;63(1):80-5. PubMed PMID: 12517781.

43: Ulukan H, Swaan PW. Camptothecins: a review of their chemotherapeutic potential. Drugs. 2002;62(14):2039-57. Review. PubMed PMID: 12269849.

44: van Hattum AH, Hoogsteen IJ, Schlüper HM, Maliepaard M, Scheffer GL, Scheper RJ, Kohlhagen G, Pommier Y, Pinedo HM, Boven E. Induction of breast cancer resistance protein by the camptothecin derivative DX-8951f is associated with minor reduction of antitumour activity. Br J Cancer. 2002 Sep 9;87(6):665-72. PubMed PMID: 12237778; PubMed Central PMCID: PMC2364245.

45: van Hattum AH, Pinedo HM, Schlüper HM, Erkelens CA, Tohgo A, Boven E. The activity profile of the hexacyclic camptothecin derivative DX-8951f in experimental human colon cancer and ovarian cancer. Biochem Pharmacol. 2002 Oct 15;64(8):1267-77. PubMed PMID: 12234607.

46: Giles FJ, Cortes JE, Thomas DA, Garcia-Manero G, Faderl S, Jeha S, De Jager RL, Kantarjian HM. Phase I and pharmacokinetic study of DX-8951f (exatecan mesylate), a hexacyclic camptothecin, on a daily-times-five schedule in patients with advanced leukemia. Clin Cancer Res. 2002 Jul;8(7):2134-41. PubMed PMID: 12114413.

47: Inoue K. [Drug delivery systems for cancer chemotherapy]. Nippon Geka Gakkai Zasshi. 2002 Feb;103(2):224-8. Review. Japanese. PubMed PMID: 11904984.

48: Garcia-Carbonero R, Supko JG. Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. Clin Cancer Res. 2002 Mar;8(3):641-61. Review. PubMed PMID: 11895891.

49: Okamoto R, Takano H, Okamura T, Park JS, Tanimoto K, Sekikawa T, Yamamoto W, Sparreboom A, Verweij J, Nishiyama M. O(6)-methylguanine-DNA methyltransferase (MGMT) as a determinant of resistance to camptothecin derivatives. Jpn J Cancer Res. 2002 Jan;93(1):93-102. PubMed PMID: 11802813.

50: Sharma S, Kemeny N, Schwartz GK, Kelsen D, O'Reilly E, Ilson D, Coyle J, De Jager RL, Ducharme MP, Kleban S, Hollywood E, Saltz LB. Phase I study of topoisomerase I inhibitor exatecan mesylate (DX-8951f) given as weekly 24-hour infusions three of every four weeks. Clin Cancer Res. 2001 Dec;7(12):3963-70. PubMed PMID: 11751488.

51: Minami H, Fujii H, Igarashi T, Itoh K, Tamanoi K, Oguma T, Sasaki Y. Phase I and pharmacological study of a new camptothecin derivative, exatecan mesylate (DX-8951f), infused over 30 minutes every three weeks. Clin Cancer Res. 2001 Oct;7(10):3056-64. PubMed PMID: 11595695.

52: Satoh H, Uesugi Y, Kawabata T, Mori K, Fujii F, Kashimoto Y, Kajimura T, Furuhama K. Morphological classification of dental lesions induced by various antitumor drugs in mice. Toxicol Pathol. 2001 May-Jun;29(3):292-9. PubMed PMID: 11442015.

53: Atsumi R, Oguma T, Yoshioka N, Konno T, Okazaki O, Fujimaki Y. Urinary metabolites of DX-8951, a novel camptothecin analog, in rats and humans. Arzneimittelforschung. 2001;51(3):253-7. PubMed PMID: 11304942.

54: Oguma T, Konno T, Inaba A, Nakaoka M. Validation study of assay method for DX-8951 and its metabolite in human plasma and urine by high-performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry. Biomed Chromatogr. 2001 Apr;15(2):108-15. PubMed PMID: 11268051.

55: Royce ME, Hoff PM, Dumas P, Lassere Y, Lee JJ, Coyle J, Ducharme MP, De Jager R, Pazdur R. Phase I and pharmacokinetic study of exatecan mesylate (DX-8951f): a novel camptothecin analog. J Clin Oncol. 2001 Mar 1;19(5):1493-500. PubMed PMID: 11230496.

56: Oguma T, Yamada M, Konno T, Inukai K, Nakaoka M. High-Performance liquid chromatographic analysis of lactone and hydroxy acid of new antitumor drug, DX-8951 (exatecan), in mouse plasma. Biol Pharm Bull. 2001 Feb;24(2):176-80. PubMed PMID: 11217088.

57: Saijo N. Preclinical and clinical trials of topoisomerase inhibitors. Ann N Y Acad Sci. 2000;922:92-9. Review. PubMed PMID: 11193928.

58: Verschraegen CF, Levenback C, Vincent M, Wolf J, Bevers M, Loyer E, Kudelka AP, Kavanagh JJ. Phase II study of intravenous DX-8951f in patients with advanced ovarian, tubal, or peritoneal cancer refractory to platinum, taxane, and topotecan. Ann N Y Acad Sci. 2000;922:349-51. PubMed PMID: 11193920.

59: De Jager R, Cheverton P, Tamanoi K, Coyle J, Ducharme M, Sakamoto N, Satomi M, Suzuki M; DX-8931f Investigators. DX-8951f: summary of phase I clinical trials. Ann N Y Acad Sci. 2000;922:260-73. Review. PubMed PMID: 11193901.

60: Boven E, Van Hattum AH, Hoogsteen I, Schlüper HM, Pinedo HM. New analogues of camptothecins. Activity and resistance. Ann N Y Acad Sci. 2000;922:175-7. PubMed PMID: 11193892.

61: Boige V, Raymond E, Faivre S, Gatineau M, Meely K, Mekhaldi S, Pautier P, Ducreux M, Rixe O, Armand JP. Phase I and pharmacokinetic study of the camptothecin analog DX-8951f administered as a 30-minute infusion every 3 weeks in patients with advanced cancer. J Clin Oncol. 2000 Dec 1;18(23):3986-92. PubMed PMID: 11099328.

62: Rowinsky EK, Johnson TR, Geyer CE Jr, Hammond LA, Eckhardt SG, Drengler R, Smetzer L, Coyle J, Rizzo J, Schwartz G, Tolcher A, Von Hoff DD, De Jager RL. DX-8951f, a hexacyclic camptothecin analog, on a daily-times-five schedule: a phase I and pharmacokinetic study in patients with advanced solid malignancies. J Clin Oncol. 2000 Sep;18(17):3151-63. PubMed PMID: 10963644.

63: Ishii M, Iwahana M, Mitsui I, Minami M, Imagawa S, Tohgo A, Ejima A. Growth inhibitory effect of a new camptothecin analog, DX-8951f, on various drug-resistant sublines including BCRP-mediated camptothecin derivative-resistant variants derived from the human lung cancer cell line PC-6. Anticancer Drugs. 2000 Jun;11(5):353-62. PubMed PMID: 10912951.

64: Oguma T, Ohshima Y, Nakaoka M. Sensitive high-performance liquid chromatographic method for the determination of the lactone form and the lactone plus hydroxy-acid forms of the new camptothecin derivative DX-8951 in human plasma using fluorescence detection. J Chromatogr B Biomed Sci Appl. 2000 Apr 14;740(2):237-45. PubMed PMID: 10821410.

65: Vey N, Giles FJ, Kantarjian H, Smith TL, Beran M, Jeha S. The topoisomerase I inhibitor DX-8951f is active in a severe combined immunodeficient mouse model of human acute myelogenous leukemia. Clin Cancer Res. 2000 Feb;6(2):731-6. PubMed PMID: 10690560.

66: Lawrence RA, Izbicka E, De Jager RL, Tohgo A, Clark GM, Weitman SD, Rowinsky EK, Von Hoff DD. Comparison of DX-8951f and topotecan effects on tumor colony formation from freshly explanted adult and pediatric human tumor cells. Anticancer Drugs. 1999 Aug;10(7):655-61. PubMed PMID: 10507315.

67: Lavergne O, Bigg DC. [The other camptothecins: recent advances with camptothecin analogues other than irinotecan and topotecan]. Bull Cancer. 1998 Dec;Spec No:51-8. Review. French. PubMed PMID: 9932086.

68: Nomoto T, Nishio K, Ishida T, Mori M, Saijo N. Characterization of a human small-cell lung cancer cell line resistant to a new water-soluble camptothecin derivative, DX-8951f. Jpn J Cancer Res. 1998 Nov;89(11):1179-86. PubMed PMID: 9914787.

69: Kumazawa E, Jimbo T, Ochi Y, Tohgo A. Potent and broad antitumor effects of DX-8951f, a water-soluble camptothecin derivative, against various human tumors xenografted in nude mice. Cancer Chemother Pharmacol. 1998;42(3):210-20. PubMed PMID: 9685056.

70: Saijo N. New chemotherapeutic agents for the treatment of non-small cell lung cancer: the Japanese experience. Chest. 1998 Jan;113(1 Suppl):17S-23S. Review. PubMed PMID: 9438685.

71: Joto N, Ishii M, Minami M, Kuga H, Mitsui I, Tohgo A. DX-8951f, a water-soluble camptothecin analog, exhibits potent antitumor activity against a human lung cancer cell line and its SN-38-resistant variant. Int J Cancer. 1997 Aug 7;72(4):680-6. PubMed PMID: 9259410.

72: Takiguchi S, Kumazawa E, Shimazoe T, Tohgo A, Kono A. Antitumor effect of DX-8951, a novel camptothecin analog, on human pancreatic tumor cells and their CPT-11-resistant variants cultured in vitro and xenografted into nude mice. Jpn J Cancer Res. 1997 Aug;88(8):760-9. Erratum in: Jpn J Cancer Res 1997 Sep;88(9):919. PubMed PMID: 9330608.

73: Mitsui I, Kumazawa E, Hirota Y, Aonuma M, Sugimori M, Ohsuki S, Uoto K, Ejima A, Terasawa H, Sato K. A new water-soluble camptothecin derivative, DX-8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. Jpn J Cancer Res. 1995 Aug;86(8):776-82. PubMed PMID: 7559102.