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  OXi-4503

combretastatin A1 diphosphate OXi4503 is the diphosphate prodrug of the stilbenoid combretastatin A1, originally isolated from the plant Combretum caffrum, with vascular-disrupting and antineoplastic activities. Upon administration, combretastatin A1 diphosphate (CA1P) is dephosphorylated to the active metabolite combretastatin A1 (CA1), which promotes rapid microtubule depolymerization; endothelial cell mitotic arrest and apoptosis, destruction of the tumor vasculature, disruption of tumor blood flow and tumor cell necrosis may ensue. In addition, orthoquinone intermediates, metabolized from combretastatin A1 by oxidative enzymes found to be elevated levels in some tumor types, may bind to tumor cell thiol-specific antioxidant proteins and DNA, and stimulate oxidative stress by enhancing superoxide/hydrogen peroxide production. CA1 binds to tubulin at the same site as colchicine but with higher affinity. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    OXiGENE

1: Stratford MR, Folkes LK. Validation of a method for the determination of the anticancer agent Combretastatin A1 phosphate (CA1P, OXi4503) in human plasma by HPLC with post-column photolysis and fluorescence detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Sep 1;879(25):2673-6. Epub 2011 Jul 18. PubMed PMID: 21820978.

2: Rice L, Pampo C, Lepler S, Rojiani AM, Siemann DW. Support of a free radical mechanism for enhanced antitumor efficacy of the microtubule disruptor OXi4503. Microvasc Res. 2011 Jan;81(1):44-51. Epub 2010 Oct 23. PubMed PMID: 20974154; PubMed Central PMCID: PMC3021177.

3: Madlambayan GJ, Meacham AM, Hosaka K, Mir S, Jorgensen M, Scott EW, Siemann DW, Cogle CR. Leukemia regression by vascular disruption and antiangiogenic therapy. Blood. 2010 Sep 2;116(9):1539-47. Epub 2010 May 14. PubMed PMID: 20472832; PubMed Central PMCID: PMC2938842.

4: Wankhede M, Dedeugd C, Siemann DW, Sorg BS. In vivo functional differences in microvascular response of 4T1 and Caki-1 tumors after treatment with OXi4503. Oncol Rep. 2010 Mar;23(3):685-92. PubMed PMID: 20127007; PubMed Central PMCID: PMC2978044.

5: Daenen LG, Shaked Y, Man S, Xu P, Voest EE, Hoffman RM, Chaplin DJ, Kerbel RS. Low-dose metronomic cyclophosphamide combined with vascular disrupting therapy induces potent antitumor activity in preclinical human tumor xenograft models. Mol Cancer Ther. 2009 Oct;8(10):2872-81. PubMed PMID: 19825805; PubMed Central PMCID: PMC2782518.

6: Shaked Y, Tang T, Woloszynek J, Daenen LG, Man S, Xu P, Cai SR, Arbeit JM, Voest EE, Chaplin DJ, Smythe J, Harris A, Nathan P, Judson I, Rustin G, Bertolini F, Link DC, Kerbel RS. Contribution of granulocyte colony-stimulating factor to the acute mobilization of endothelial precursor cells by vascular disrupting agents. Cancer Res. 2009 Oct 1;69(19):7524-8. Epub 2009 Sep 8. PubMed PMID: 19738066; PubMed Central PMCID: PMC2758166.

7: Shirali A, Sriram M, Hall JJ, Nguyen BL, Guddneppanavar R, Hadimani MB, Ackley JF, Siles R, Jelinek CJ, Arthasery P, Brown RC, Murrell VL, McMordie A, Sharma S, Chaplin DJ, Pinney KG. Development of synthetic methodology suitable for the radiosynthesis of combretastatin A-1 (CA1) and its corresponding prodrug CA1P. J Nat Prod. 2009 Mar 27;72(3):414-21. PubMed PMID: 19161336.

8: Dalal S, Burchill SA. Preclinical evaluation of vascular-disrupting agents in Ewing's sarcoma family of tumours. Eur J Cancer. 2009 Mar;45(4):713-22. Epub 2009 Jan 10. PubMed PMID: 19136249.

9: Chan LS, Daruwalla J, Christophi C. Selective targeting of the tumour vasculature. ANZ J Surg. 2008 Nov;78(11):955-67. Review. PubMed PMID: 18959693.

10: Siemann DW, Shi W. Dual targeting of tumor vasculature: combining Avastin and vascular disrupting agents (CA4P or OXi4503). Anticancer Res. 2008 Jul-Aug;28(4B):2027-31. PubMed PMID: 18751370; PubMed Central PMCID: PMC2788501.

11: Musumeci ML, Schlecht K, Perrotta R, Schwartz RA, Micali G. Management of cutaneous hemangiomas in pediatric patients. Cutis. 2008 Apr;81(4):315-22. Review. PubMed PMID: 18491478.

12: Cai SX. Small molecule vascular disrupting agents: potential new drugs for cancer treatment. Recent Pat Anticancer Drug Discov. 2007 Jan;2(1):79-101. Review. PubMed PMID: 18221055.

13: Chan LS, Malcontenti-Wilson C, Muralidharan V, Christophi C. Alterations in vascular architecture and permeability following OXi4503 treatment. Anticancer Drugs. 2008 Jan;19(1):17-22. PubMed PMID: 18043126.

14: Hokland SL, Horsman MR. The new vascular disrupting agent combretastatin-A1-disodium-phosphate (OXi4503) enhances tumour response to mild hyperthermia and thermoradiosensitization. Int J Hyperthermia. 2007 Nov;23(7):599-606. PubMed PMID: 18038290.

15: Folkes LK, Christlieb M, Madej E, Stratford MR, Wardman P. Oxidative metabolism of combretastatin A-1 produces quinone intermediates with the potential to bind to nucleophiles and to enhance oxidative stress via free radicals. Chem Res Toxicol. 2007 Dec;20(12):1885-94. Epub 2007 Oct 18. PubMed PMID: 17941699.

16: Chan LS, Malcontenti-Wilson C, Muralidharan V, Christophi C. Effect of vascular targeting agent Oxi4503 on tumor cell kinetics in a mouse model of colorectal liver metastasis. Anticancer Res. 2007 Jul-Aug;27(4B):2317-23. PubMed PMID: 17695520.

17: Malcontenti-Wilson C, Chan L, Nikfarjam M, Muralidharan V, Christophi C. Vascular targeting agent Oxi4503 inhibits tumor growth in a colorectal liver metastases model. J Gastroenterol Hepatol. 2008 Jul;23(7 Pt 2):e96-e104. Epub 2007 Jun 7. PubMed PMID: 17559382.

18: Lippert JW 3rd. Vascular disrupting agents. Bioorg Med Chem. 2007 Jan 15;15(2):605-15. Epub 2006 Oct 27. PubMed PMID: 17070061.

19: Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM, Hicklin DJ, Chaplin D, Foster FS, Benezra R, Kerbel RS. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science. 2006 Sep 22;313(5794):1785-7. PubMed PMID: 16990548.

20: Salmon HW, Mladinich C, Siemann DW. Evaluations of vascular disrupting agents CA4P and OXi4503 in renal cell carcinoma (Caki-1) using a silicon based microvascular casting technique. Eur J Cancer. 2006 Nov;42(17):3073-8. Epub 2006 Sep 7. PubMed PMID: 16956760.

21: Salmon HW, Siemann DW. Effect of the second-generation vascular disrupting agent OXi4503 on tumor vascularity. Clin Cancer Res. 2006 Jul 1;12(13):4090-4. PubMed PMID: 16818709.

22: Sheng Y, Hua J, Pinney KG, Garner CM, Kane RR, Prezioso JA, Chaplin DJ, Edvardsen K. Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis. Int J Cancer. 2004 Sep 10;111(4):604-10. PubMed PMID: 15239140.

23: Thorpe PE. Vascular targeting agents as cancer therapeutics. Clin Cancer Res. 2004 Jan 15;10(2):415-27. Review. PubMed PMID: 14760060.

24: Hua J, Sheng Y, Pinney KG, Garner CM, Kane RR, Prezioso JA, Pettit GR, Chaplin DJ, Edvardsen K. Oxi4503, a novel vascular targeting agent: effects on blood flow and antitumor activity in comparison to combretastatin A-4 phosphate. Anticancer Res. 2003 Mar-Apr;23(2B):1433-40. PubMed PMID: 12820406.

25: Hill SA, Toze GM, Pettit GR, Chaplin DJ. Preclinical evaluation of the antitumour activity of the novel vascular targeting agent Oxi 4503. Anticancer Res. 2002 May-Jun;22(3):1453-8. Erratum in: Anticancer Res. 2003;23:5369. PubMed PMID: 12168822.