MedKoo product information:

ABT-751

Deacription of ABT-751: ABT-751 is an orally bioavailable antimitotic sulfonamide. ABT-751 binds to the colchicine-binding site on beta-tubulin and inhibits the polymerization of microtubules, thereby preventing tumor cell replication. This agent also disrupts tumor neovascularization, reducing tumor blood flow and so inducing a cytotoxic effect. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    Abbott Laboratories.

ABT-751 is an orally bioavailable tubulin-binding agent that is currently under clinical development for cancer treatment. In preclinical studies, ABT-751 showed antitumor activity against a broad spectrum of tumor lines including those resistant to conventional chemotherapies. In this study, we investigated the antivascular properties of ABT-751 in a rat subcutaneous tumor model using dynamic contrast-enhanced magnetic resonance imaging. A single dose of ABT-751 (30 mg/kg, intravenously) induced a rapid, transient reduction in tumor perfusion. After 1 h, tumor perfusion decreased by 57% before recovering to near pretreatment levels within 6 h. In contrast, ABT-751 produced little change in muscle perfusion at either time point. To further elucidate mechanisms of drug action at the cellular level, we examined the effects of ABT-751 on endothelial cells using an in-vitro assay. ABT-751, at concentrations corresponding to plasma levels achieved in vivo, caused endothelial cell retraction and significant loss of microtubules within 1 h. The severity of these morphological changes was dose-dependent but reversible within 6 h after the discontinuation of the drug. Taken together, these results show that ABT-751 is a tubulin-binding agent with antivascular properties. Microtubule disruption and morphological changes in vascular endothelial cells may be responsible, at least in part, for the dysfunction of tumor blood vessels after ABT-751 treatment. (source: Anticancer Drugs. 2009 Jul;20(6):483-92. or http://www.ncbi.nlm.nih.gov/pubmed/19398903).

 1: Fox E, Maris JM, Cohn SL, Goodspeed W, Goodwin A, Kromplewski M, Medina D, Xiong H, Krivoshik A, Widemann B, Adamson PC, Balis FM. Pharmacokinetics of orally administered ABT-751 in children with neuroblastoma and other solid tumors. Cancer Chemother Pharmacol. 2010 Sep;66(4):737-43. Epub 2010 Jan 1. PubMed PMID: 20044751.

2: Meany HJ, Sackett DL, Maris JM, Ward Y, Krivoshik A, Cohn SL, Steinberg SM, Balis FM, Fox E. Clinical outcome in children with recurrent neuroblastoma treated with ABT-751 and effect of ABT-751 on proliferation of neuroblastoma cell lines and on tubulin polymerization in vitro. Pediatr Blood Cancer. 2010 Jan;54(1):47-54. PubMed PMID: 19731320; PubMed Central PMCID: PMC2783914.

3: Michels J, Ellard SL, Le L, Kollmannsberger C, Murray N, Tomlinson Guns ES, Carr R, Chi KN. A phase IB study of ABT-751 in combination with docetaxel in patients with advanced castration-resistant prostate cancer. Ann Oncol. 2010 Feb;21(2):305-11. Epub 2009 Jul 24. PubMed PMID: 19633045.

4: Gridelli C, Rossi A, Maione P, Rossi E, Castaldo V, Sacco PC, Colantuoni G. Vascular disrupting agents: a novel mechanism of action in the battle against non-small cell lung cancer. Oncologist. 2009 Jun;14(6):612-20. Epub 2009 May 27. Review. PubMed PMID: 19474164.

5: Luo Y, Hradil VP, Frost DJ, Rosenberg SH, Gordon GB, Morgan SJ, Gagne GD, Cox BF, Tahir SK, Fox GB. ABT-751, a novel tubulin-binding agent, decreases tumor perfusion and disrupts tumor vasculature. Anticancer Drugs. 2009 Jul;20(6):483-92. PubMed PMID: 19398903.

6: Döme B, Magyar M. [Tumor vasculature as a therapeutic target in non-small cell lung cancer]. Magy Onkol. 2008 Sep;52(3):247-59. Review. Hungarian. PubMed PMID: 18845495.

7: Kuppens IE. Current state of the art of new tubulin inhibitors in the clinic. Curr Clin Pharmacol. 2006 Jan;1(1):57-70. Review. PubMed PMID: 18666378.

8: Mauer AM, Cohen EE, Ma PC, Kozloff MF, Schwartzberg L, Coates AI, Qian J, Hagey AE, Gordon GB. A phase II study of ABT-751 in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2008 Jun;3(6):631-6. PubMed PMID: 18520803.

9: Fox E, Maris JM, Widemann BC, Goodspeed W, Goodwin A, Kromplewski M, Fouts ME, Medina D, Cohn SL, Krivoshik A, Hagey AE, Adamson PC, Balis FM. A phase I study of ABT-751, an orally bioavailable tubulin inhibitor, administered daily for 21 days every 28 days in pediatric patients with solid tumors. Clin Cancer Res. 2008 Feb 15;14(4):1111-5. PubMed PMID: 18281544.

10: Apostolidou E, Swords R, Alvarado Y, Giles FJ. Treatment of acute lymphoblastic leukaemia : a new era. Drugs. 2007;67(15):2153-71. Review. PubMed PMID: 17927282.

11: Edelman MJ. Novel cytotoxic agents for non-small cell lung cancer. J Thorac Oncol. 2006 Sep;1(7):752-5. Review. PubMed PMID: 17409954.

12: Morton CL, Favours EG, Mercer KS, Boltz CR, Crumpton JC, Tucker C, Billups CA, Houghton PJ. Evaluation of ABT-751 against childhood cancer models in vivo. Invest New Drugs. 2007 Aug;25(4):285-95. Epub 2007 Mar 24. PubMed PMID: 17384918.

13: Alvarado Y, Apostolidou E, Swords R, Giles FJ. Emerging therapeutic options for Philadelphia-positive acute lymphocytic leukemia. Expert Opin Emerg Drugs. 2007 Mar;12(1):165-79. Review. PubMed PMID: 17355221.

14: Cho SY, Fox E, McCully C, Bauch J, Marsh K, Balis FM. Plasma and cerebrospinal fluid pharmacokinetics of intravenously administered ABT-751 in non-human primates. Cancer Chemother Pharmacol. 2007 Sep;60(4):563-7. Epub 2006 Dec 23. PubMed PMID: 17187251.

15: Jorgensen TJ, Tian H, Joseph IB, Menon K, Frost D. Chemosensitization and radiosensitization of human lung and colon cancers by antimitotic agent, ABT-751, in athymic murine xenograft models of subcutaneous tumor growth. Cancer Chemother Pharmacol. 2007 May;59(6):725-32. Epub 2006 Sep 12. PubMed PMID: 16967299.

16: Fox E, Maris JM, Widemann BC, Meek K, Goodwin A, Goodspeed W, Kromplewski M, Fouts ME, Medina D, Cho SY, Cohn SL, Krivoshik A, Hagey AE, Adamson PC, Balis FM. A phase 1 study of ABT-751, an orally bioavailable tubulin inhibitor, administered daily for 7 days every 21 days in pediatric patients with solid tumors. Clin Cancer Res. 2006 Aug 15;12(16):4882-7. PubMed PMID: 16914576.

17: Rudek MA, Zhao M, He P, Messersmith WA, Baker SD. Validation and implementation of a liquid chromatography/tandem mass spectrometry assay to quantitate ABT-751, ABT-751 glucuronide, and ABT-751 sulfate in human plasma for clinical pharmacology studies. J Pharm Biomed Anal. 2006 Sep 18;42(2):253-60. Epub 2006 Jun 9. PubMed PMID: 16765012.

18: Hande KR, Hagey A, Berlin J, Cai Y, Meek K, Kobayashi H, Lockhart AC, Medina D, Sosman J, Gordon GB, Rothenberg ML. The pharmacokinetics and safety of ABT-751, a novel, orally bioavailable sulfonamide antimitotic agent: results of a phase 1 study. Clin Cancer Res. 2006 May 1;12(9):2834-40. PubMed PMID: 16675578.

19: Carlson DM, Steinberg JL, Gordon G. Targeting the unmet medical need: the Abbott Laboratories oncology approach. Clin Adv Hematol Oncol. 2005 Sep;3(9):703-10. PubMed PMID: 16224444.

20: Yee KW, Hagey A, Verstovsek S, Cortes J, Garcia-Manero G, O'Brien SM, Faderl S, Thomas D, Wierda W, Kornblau S, Ferrajoli A, Albitar M, McKeegan E, Grimm DR, Mueller T, Holley-Shanks RR, Sahelijo L, Gordon GB, Kantarjian HM, Giles FJ. Phase 1 study of ABT-751, a novel microtubule inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res. 2005 Sep 15;11(18):6615-24. PubMed PMID: 16166440.

21: Galmarini CM. ABT-751 (Abbott). Curr Opin Investig Drugs. 2005 Jun;6(6):623-30. Review. PubMed PMID: 15988914.

22: Segreti JA, Polakowski JS, Koch KA, Marsh KC, Bauch JL, Rosenberg SH, Sham HL, Cox BF, Reinhart GA. Tumor selective antivascular effects of the novel antimitotic compound ABT-751: an in vivo rat regional hemodynamic study. Cancer Chemother Pharmacol. 2004 Sep;54(3):273-81. Epub 2004 Jun 2. PubMed PMID: 15173957.