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 Imexon

Description of Imexon: Imexon is a cyanoaziridine derivatives with potential anticancer activity.  Imexon belongs to a novel class of promising anticancer agents that induce tumor apoptosis through oxidative stress. Although its mechanism of action is not clearly known, imexon may induce apoptosis via a pathway involving cleaved caspase-3, caspase-9, and/or caspase-8. Other cytotoxic mechanisms of action of this agent may involve thiol depletion, generation of reactive oxygen species (ROS), and decreases in the mitochondrial membrane potential. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   Direct Therapeutics, Inc.

 Phase I study of Imexon: One hundred five patients received 340 treatment cycles (median 2, range 1-16). Patient characteristics: median age 63, 61% male, ECOG PS 0/1 50%/50%, 93% metastatic. DLT was abdominal cramping and pain, often with transient, acute diarrhea. Best response was confirmed partial response (PR) in 11.4%, 8.9% unconfirmed PR, and 48.1% with stable disease. There was a dose proportional increase in imexon AUC across the doses tested with terminal half life 69 min at the MTD and no alteration of gemcitabine pharmacokinetics. The recommended phase II dose of imexon is 875 mg/m(2) with gemcitabine 1,000 mg/m(2). DLT was acute abdominal pain and cramping. Encouraging antitumor responses support further evaluation of this combination in advanced pancreatic cancer. (source: Cancer Chemother Pharmacol. 2010 Jul;66(2):287-94.).

Combined Phase I/II study of Imexon: Imexon belongs to a novel class of promising anticancer agents that induce tumor apoptosis through oxidative stress. Clinical experience since the late 1960s has provided initial evidence for a clinical antitumor activity.  Preliminary antimyeloma efficacy of  Imexon was observed with 1 minimal response, 12 (36%) stable disease responses, and all other evaluable patients had progressive disease. Remarkably, the patient with minimal response also experienced a complete clinical resolution of myeloma-associated polyneuropathy. Overall, Imexon was safe and well tolerated in the dose range investigated. Imexon showed minor clinical activity as a single agent in heavily pretreated myeloma patients. On account of its unique mechanism of action, favorable toxicity profile, initial clinical evidence for antimyeloma activity, and its known synergistic activity in combination with approved agents for myeloma treatment, Imexon  is recommended for future clinical studies in combination regimens in multiple myeloma. (Anticancer Drugs. 2010 Aug;21(7):708-15.).

 1: Sheveleva EV, Landowski TH, Samulitis BK, Bartholomeusz G, Powis G, Dorr RT. Imexon Induces an Oxidative Endoplasmic Reticulum Stress Response in Pancreatic Cancer Cells. Mol Cancer Res. 2012 Jan 24. [Epub ahead of print] PubMed PMID: 22275514.

2: Samulitis BK, Dorr RT, Chow HH. Interaction of dacarbazine and imexon, in vitro and in vivo, in human A375 melanoma cells. Anticancer Res. 2011 Sep;31(9):2781-5. PubMed PMID: 21868520.

3: Moehler TM, Feneberg R, Ho AD, Golenkov AK, Ludwig H, Kropff M, Khuageva NK, Hajda J, von Broen I, Goldschmidt H. Combined phase I/II study of imexon (AOP99.0001) for treatment of relapsed or refractory multiple myeloma. Anticancer Drugs. 2010 Aug;21(7):708-15. PubMed PMID: 20571355.

4: Weber JS, Samlowski WE, Gonzalez R, Ribas A, Stephenson J, O'Day S, Sato T, Dorr R, Grenier K, Hersh E. A phase 1-2 study of imexon plus dacarbazine in patients with unresectable metastatic melanoma. Cancer. 2010 Aug 1;116(15):3683-91. PubMed PMID: 20564083.

5: Roman NO, Samulitis BK, Wisner L, Landowski TH, Dorr RT. Imexon enhances gemcitabine cytotoxicity by inhibition of ribonucleotide reductase. Cancer Chemother Pharmacol. 2011 Jan;67(1):183-92. Epub 2010 Mar 26. PubMed PMID: 20339847; PubMed Central PMCID: PMC2987536.

6: Cho H, Koto M, Riesterer O, Molkentine DP, Giri U, Milas L, Story MD, Ha CS, Raju U. Imexon augments sensitivity of human lymphoma cells to ionizing radiation: in vitro experimental study. Anticancer Res. 2009 Nov;29(11):4409-15. PubMed PMID: 20032386.

7: Cohen SJ, Zalupski MM, Modiano MR, Conkling P, Patt YZ, Davis P, Dorr RT, Boytim ML, Hersh EM. A phase I study of imexon plus gemcitabine as first-line therapy for advanced pancreatic cancer. Cancer Chemother Pharmacol. 2010 Jul;66(2):287-94. Epub 2009 Oct 24. PubMed PMID: 19855966; PubMed Central PMCID: PMC2873145.

8: Moulder S, Dhillon N, Ng C, Hong D, Wheler J, Naing A, Tse S, La Paglia A, Dorr R, Hersh E, Boytim M, Kurzrock R. A phase I trial of imexon, a pro-oxidant, in combination with docetaxel for the treatment of patients with advanced breast, non-small cell lung and prostate cancer. Invest New Drugs. 2010 Oct;28(5):634-40. Epub 2009 Jun 6. PubMed PMID: 19499186.

9: Samulitis BK, Landowski TH, Dorr RT. Inhibition of protein synthesis by imexon reduces HIF-1alpha expression in normoxic and hypoxic pancreatic cancer cells. Invest New Drugs. 2009 Feb;27(1):89-98. Epub 2008 Jul 8. PubMed PMID: 18607542; PubMed Central PMCID: PMC2607477.

10: Baker AF, Landowski T, Dorr R, Tate WR, Gard JM, Tavenner BE, Dragovich T, Coon A, Powis G. The antitumor agent imexon activates antioxidant gene expression: evidence for an oxidative stress response. Clin Cancer Res. 2007 Jun 1;13(11):3388-94. PubMed PMID: 17545547.

11: Dragovich T, Gordon M, Mendelson D, Wong L, Modiano M, Chow HH, Samulitis B, O'Day S, Grenier K, Hersh E, Dorr R. Phase I trial of imexon in patients with advanced malignancy. J Clin Oncol. 2007 May 1;25(13):1779-84. PubMed PMID: 17470869.

12: Scott J, Dorr RT, Samulitis B, Landowski TH. Imexon-based combination chemotherapy in A375 human melanoma and RPMI 8226 human myeloma cell lines. Cancer Chemother Pharmacol. 2007 May;59(6):749-57. Epub 2007 Feb 28. PubMed PMID: 17333195.

13: Pourpak A, Meyers RO, Samulitis BK, Sherry Chow HH, Kepler CY, Raymond MA, Hersh E, Dorr RT. Preclinical antitumor activity, pharmacokinetics and pharmacodynamics of imexon in mice. Anticancer Drugs. 2006 Nov;17(10):1179-84. PubMed PMID: 17075317.

14: Kuehl PJ, Hoye WL, Myrdal PB. Preformulation studies on imexon. Drug Dev Ind Pharm. 2006 Jul;32(6):687-97. PubMed PMID: 16885124.

15: Samulitis BK, Landowski TH, Dorr RT. Correlates of imexon sensitivity in human multiple myeloma cell lines. Leuk Lymphoma. 2006 Jan;47(1):97-109. PubMed PMID: 16321833.

16: Ashley RA. Rob Ashley of AmpliMed discusses the discovery and development of Imexon. Interview by Steve Carney. Drug Discov Today. 2005 Oct 15;10(20):1339-42. PubMed PMID: 16253868.

17: Dorr RT, Raymond MA, Landowski TH, Roman NO, Fukushima S. Induction of apoptosis and cell cycle arrest by imexon in human pancreatic cancer cell lines. Int J Gastrointest Cancer. 2005;36(1):15-28. PubMed PMID: 16227632.

18: den Brok MW, Nuijen B, Challa EE, Lutz C, Opitz HG, Beijnen JH. Compatibility and stability of Imexon in infusion devices and its in vitro biocompatibility. Anticancer Drugs. 2005 Aug;16(7):727-32. PubMed PMID: 16027520.

19: den Brok MW, Nuijen B, Hillebrand MJ, Lutz C, Opitz HG, Beijnen JH. LC-UV method development and validation for the investigational anticancer agent imexon and identification of its degradation products. J Pharm Biomed Anal. 2005 Jul 15;38(4):686-94. Epub 2005 Mar 19. PubMed PMID: 15967296.

20: den Brok MW, Nuijen B, Lutz C, Opitz HG, Beijnen JH. Pharmaceutical development of a lyophilised dosage form for the investigational anticancer agent Imexon using dimethyl sulfoxide as solubilising and stabilising agent. J Pharm Sci. 2005 May;94(5):1101-14. PubMed PMID: 15793808.

21: Evens AM, Prachand S, Shi B, Paniaqua M, Gordon LI, Gartenhaus RB. Imexon-induced apoptosis in multiple myeloma tumor cells is caspase-8 dependent. Clin Cancer Res. 2004 Feb 15;10(4):1481-91. PubMed PMID: 14977852.

22: Iyengar BS, Dorr RT, Remers WA. Chemical basis for the biological activity of imexon and related cyanoaziridines. J Med Chem. 2004 Jan 1;47(1):218-23. PubMed PMID: 14695835.

23: Dvorakova K, Payne CM, Tome ME, Briehl MM, Vasquez MA, Waltmire CN, Coon A, Dorr RT. Molecular and cellular characterization of imexon-resistant RPMI8226/I myeloma cells. Mol Cancer Ther. 2002 Jan;1(3):185-95. PubMed PMID: 12467213.

24: Dvorakova K, Payne CM, Landowski TH, Tome ME, Halperin DS, Dorr RT. Imexon activates an intrinsic apoptosis pathway in RPMI8226 myeloma cells. Anticancer Drugs. 2002 Nov;13(10):1031-42. PubMed PMID: 12439337.

25: Dvorakova K, Waltmire CN, Payne CM, Tome ME, Briehl MM, Dorr RT. Induction of mitochondrial changes in myeloma cells by imexon. Blood. 2001 Jun 1;97(11):3544-51. PubMed PMID: 11369649.

26: Dvorakova K, Payne CM, Tome ME, Briehl MM, McClure T, Dorr RT. Induction of oxidative stress and apoptosis in myeloma cells by the aziridine-containing agent imexon. Biochem Pharmacol. 2000 Sep 15;60(6):749-58. PubMed PMID: 10930529.

27: Sagaster P, Kokoschka EM, Kokron O, Micksche M. Antitumor activity of imexon. J Natl Cancer Inst. 1995 Jun 21;87(12):935-6. PubMed PMID: 7666487.

28: Dorr RT, Liddil JD, Klein MK, Hersh EM. Preclinical pharmacokinetics and antitumor activity of imexon. Invest New Drugs. 1995;13(2):113-6. PubMed PMID: 8617572.

29: Salmon SE, Hersh EM. Sensitivity of multiple myeloma to imexon in the human tumor cloning assay. J Natl Cancer Inst. 1994 Feb 2;86(3):228-30. PubMed PMID: 8283495.

30: Hersh EM, Grogan TM, Funk CY, Taylor CW. Suppression of human lymphoma development in the severe combined immune-deficient mouse by imexon therapy. J Immunother Emphasis Tumor Immunol. 1993 Feb;13(2):77-83. PubMed PMID: 8391308.

31: Hersh EM, Gschwind CR, Taylor CW, Dorr RT, Taetle R, Salmon SE. Antiproliferative and antitumor activity of the 2-cyanoaziridine compound imexon on tumor cell lines and fresh tumor cells in vitro. J Natl Cancer Inst. 1992 Aug 19;84(16):1238-44. PubMed PMID: 1640482.

32: Funk CY, Eisman J, Hersh EM. Treatment of the murine, retrovirus-induced lymphoproliferative immunodeficiency disease (LP-BM5) in C57BL/10 mice with the immunomodulator Imexon. AIDS Res Hum Retroviruses. 1992 May;8(5):633-8. PubMed PMID: 1515214.

33: Morrey JD, Mead JR, Warren RP, Okleberry KM, Burger RA, Sidwell RW. Elucidation of mode of retroviral-inhibitory effects of imexon through use of immune competent and severe combined immune deficiency (SCID) mice. Antiviral Res. 1992 Mar;17(3):223-33. PubMed PMID: 1314537.

34: Morrey JD, Warren RP, Okleberry KM, Burger RA, Chirigos MA, Sidwell RW. Effect of imexon treatment on Friend virus complex infection using genetically defined mice as a model for HIV-1 infection. Antiviral Res. 1991 Jan;15(1):51-65. PubMed PMID: 2036000.

35: Chirigos MA, Ussery MA, Black PL. Imexon and biological response modifiers in murine models of AIDS. Int J Immunopharmacol. 1991;13 Suppl 1:33-41. PubMed PMID: 1823906.

36: Chirigos MA, Ussery MA, Rankin JT Jr, Herrmann D, Bicker U, Black PL. Antiviral efficacy of Imexon in the Rauscher murine retrovirus AIDS model. Immunopharmacol Immunotoxicol. 1990;12(1):1-21. PubMed PMID: 1693633.

37: Ziegler AE, Bicker U, Hebold G. Experimental investigations on increased resistance to infections with Candida albicans and Staphylococcus aureus Smith by 4-imino-1,4-diazobicyclo-(3.1.0)-hexane-2-on BM 06.002 (prop. INN imexon) in mice. Exp Pathol (Jena). 1977;14(6):321-7. PubMed PMID: 598463.