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Gimatecan

Description of gimatecan: Gimatecan  is an orally bioavailable, semi-synthetic lipophilic analogue of camptothecin, a quinoline alkaloid extracted from the Asian tree Camptotheca acuminate, with potential antineoplastic and antiangiogenic activities. Gimatecan binds to and inhibits the activity of topoisomerase I, stabilizing the cleavable complex of topoisomerase I-DNA, which inhibits the religation of single-stranded DNA breaks generated by topoisomerase I; lethal double-stranded DNA breaks occur when the topoisomerase I-DNA complex is encountered by the DNA replication machinery, DNA replication is disrupted, and the tumor cell undergoes apoptosis. Although the mechanism of its antiangiogenic activity has yet to be full elucidated, this agent may inhibit endothelial cell migration, tumor neovascularization, and the expression of proangiogenic basic fibroblast growth factor (bFGF). Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    Novartis Pharmaceuticals and Sigma-Tau Research

Phase II study of Gimatecan: From June 2005 to December 2005, 69 assessable patients were enrolled. The best overall response to study treatment by combined CA-125 and RECIST criteria was partial response in 17 patients (24.6%) and disease stabilization in 22 patients (31.9%). The median time to progression and overall survival were 3.8 and 16.2 months, respectively. A total of 312 cycles were administered. Neutropenia grade 4 and thrombocytopenia grade 4 occurred in 17.4% and 7.2% of patients, respectively. Diarrhea grade 4 was never observed. Asthenia and fatigue were reported by 36.2% and 18.8% of patients, but were all grade 2 or less. CONCLUSION: Gimatecan is a new active agent in previously treated ovarian cancer with myelosuppression as main toxicity.   (source: Ann Oncol. 2010 Apr;21(4):759-65.).

 1: Zucchetti M, Meco D, Di Francesco AM, Servidei T, Patriarca V, Cusano G, D'Incalci M, Forestieri D, Pisano C, Riccardi R. Antitumor activity and pharmacokinetics of oral gimatecan on pediatric cancer xenografts. Cancer Chemother Pharmacol. 2010 Sep;66(4):635-41. Epub 2009 Dec 20. PubMed PMID: 20091168.

2: Frapolli R, Zucchetti M, Sessa C, Marsoni S, Viganò L, Locatelli A, Rulli E, Compagnoni A, Bello E, Pisano C, Carminati P, D'Incalci M. Clinical pharmacokinetics of the new oral camptothecin gimatecan: the inter-patient variability is related to alpha1-acid glycoprotein plasma levels. Eur J Cancer. 2010 Feb;46(3):505-16. Epub 2009 Dec 16. PubMed PMID: 20007015.

3: Pecorelli S, Ray-Coquard I, Tredan O, Colombo N, Parma G, Tisi G, Katsaròs D, Lhommé C, Lissoni AA, Vermorken JB, du Bois A, Poveda A, Frigerio L, Barbieri P, Carminati P, Brienza S, Guastalla JP. Phase II of oral gimatecan in patients with recurrent epithelial ovarian, fallopian tube or peritoneal cancer, previously treated with platinum and taxanes. Ann Oncol. 2010 Apr;21(4):759-65. Epub 2009 Nov 11. PubMed PMID: 19906760; PubMed Central PMCID: PMC2844948.

4: Pace S, Capocasa F, Tallarico C, Frapolli R, Zucchetti M, Longo A. Determination of total and lactone form of a new camptothecin derivative gimatecan (ST1481) and its metabolite ST1698 in human plasma by high-performance liquid chromatography with fluorimetric detection. J Pharm Biomed Anal. 2009 Oct 15;50(3):507-14. Epub 2009 May 27. PubMed PMID: 19553057.

5: Vekhoff P, Halby L, Oussedik K, Dallavalle S, Merlini L, Mahieu C, Lansiaux A, Bailly C, Boutorine A, Pisano C, Giannini G, Alloatti D, Arimondo PB. Optimized synthesis and enhanced efficacy of novel triplex-forming camptothecin derivatives based on gimatecan. Bioconjug Chem. 2009 Apr;20(4):666-72. PubMed PMID: 19309124.

6: Oostendorp RL, van de Steeg E, van der Kruijssen CM, Beijnen JH, Kenworthy KE, Schinkel AH, Schellens JH. Organic anion-transporting polypeptide 1B1 mediates transport of Gimatecan and BNP1350 and can be inhibited by several classic ATP-binding cassette (ABC) B1 and/or ABCG2 inhibitors. Drug Metab Dispos. 2009 Apr;37(4):917-23. Epub 2009 Jan 12. PubMed PMID: 19139163.

7: Zhu AX, Ready N, Clark JW, Safran H, Amato A, Salem N, Pace S, He X, Zvereva N, Lynch TJ, Ryan DP, Supko JG. Phase I and pharmacokinetic study of gimatecan given orally once a week for 3 of 4 weeks in patients with advanced solid tumors. Clin Cancer Res. 2009 Jan 1;15(1):374-81. PubMed PMID: 19118068.

8: Petrangolini G, Tortoreto M, Perego P, Carenini N, De Cesare M, Balsari A, Zunino F, Pratesi G. Combination of metronomic gimatecan and CpG-oligodeoxynucleotides against an orthotopic pancreatic cancer xenograft. Cancer Biol Ther. 2008 Apr;7(4):596-601. Epub 2008 Jan 9. PubMed PMID: 18364568.

9: Marchetti S, Oostendorp RL, Pluim D, van Eijndhoven M, van Tellingen O, Schinkel AH, Versace R, Beijnen JH, Mazzanti R, Schellens JH. In vitro transport of gimatecan (7-t-butoxyiminomethylcamptothecin) by breast cancer resistance protein, P-glycoprotein, and multidrug resistance protein 2. Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3307-13. PubMed PMID: 18089724.

10: Gounder MK, Nazar AS, Saleem A, Pungaliya P, Kulkarni D, Versace R, Rubin EH. Effects of drug efflux proteins and topoisomerase I mutations on the camptothecin analogue gimatecan. Invest New Drugs. 2008 Jun;26(3):205-13. Epub 2007 Oct 18. PubMed PMID: 17943230.

11: Sessa C, Cresta S, Cerny T, Baselga J, Rota Caremoli E, Malossi A, Hess D, Trigo J, Zucchetti M, D'Incalci M, Zaniboni A, Capri G, Gatti B, Carminati P, Zanna C, Marsoni S, Gianni L. Concerted escalation of dose and dosing duration in a phase I study of the oral camptothecin gimatecan (ST1481) in patients with advanced solid tumors. Ann Oncol. 2007 Mar;18(3):561-8. Epub 2006 Dec 5. PubMed PMID: 17150998.

12: Perego P, Ciusani E, Gatti L, Carenini N, Corna E, Zunino F. Sensitization to gimatecan-induced apoptosis by tumor necrosis factor-related apoptosis inducing ligand in prostate carcinoma cells. Biochem Pharmacol. 2006 Mar 14;71(6):791-8. Epub 2006 Jan 24. PubMed PMID: 16438941.

13: Di Francesco AM, Riccardi A, Barone G, Rutella S, Meco D, Frapolli R, Zucchetti M, D'Incalci M, Pisano C, Carminati P, Riccardi R. The novel lipophilic camptothecin analogue gimatecan is very active in vitro in human neuroblastoma: a comparative study with SN38 and topotecan. Biochem Pharmacol. 2005 Oct 15;70(8):1125-36. Erratum in: Biochem Pharmacol. 2005 Dec 5;70(12):1891. Riccardi, Anna Shirley [corrected to Riccardi, Anna]. PubMed PMID: 16139802.

14: Nitiss JL, Nitiss KC. Gimatecan (sigma-tau industrie farmaceutiche riunite/novartis). IDrugs. 2005 Jul;8(7):578-88. Review. PubMed PMID: 15973567.

15: De Cesare M, Perego P, Righetti SC, Pratesi G, Carenini N, Rivoltini L, Zupi G, Del Bufalo D, Balsari A, Zunino F. Enhanced antitumour efficacy of gimatecan in combination with Bcl-2 antisense oligonucleotide in human melanoma xenografts. Eur J Cancer. 2005 May;41(8):1213-22. PubMed PMID: 15911246.

16: Ulivi P, Zoli W, Fabbri F, Brigliadori G, Ricotti L, Tesei A, Rosetti M, De Cesare M, Beretta GL, Corna E, Supino R, Zunino F. Cellular basis of antiproliferative and antitumor activity of the novel camptothecin derivative, gimatecan, in bladder carcinoma models. Neoplasia. 2005 Feb;7(2):152-61. PubMed PMID: 15802020; PubMed Central PMCID: PMC1501124.

17: De Cesare M, Pratesi G, Veneroni S, Bergottini R, Zunino F. Efficacy of the novel camptothecin gimatecan against orthotopic and metastatic human tumor xenograft models. Clin Cancer Res. 2004 Nov 1;10(21):7357-64. PubMed PMID: 15534112.

18: Stano P, Bufali S, Pisano C, Bucci F, Barbarino M, Santaniello M, Carminati P, Luisi PL. Novel camptothecin analogue (gimatecan)-containing liposomes prepared by the ethanol injection method. J Liposome Res. 2004;14(1-2):87-109. PubMed PMID: 15461935.

19: Pratesi G, Beretta GL, Zunino F. Gimatecan, a novel camptothecin with a promising preclinical profile. Anticancer Drugs. 2004 Jul;15(6):545-52. Review. PubMed PMID: 15205595.

20: Croce AC, Bottiroli G, Supino R, Favini E, Zuco V, Zunino F. Subcellular localization of the camptothecin analogues, topotecan and gimatecan. Biochem Pharmacol. 2004 Mar 15;67(6):1035-45. PubMed PMID: 15006540.

21: Petrangolini G, Pratesi G, De Cesare M, Supino R, Pisano C, Marcellini M, Giordano V, Laccabue D, Lanzi C, Zunino F. Antiangiogenic effects of the novel camptothecin ST1481 (gimatecan) in human tumor xenografts. Mol Cancer Res. 2003 Oct;1(12):863-70. PubMed PMID: 14573787.