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Triapine

Description of Triapine: Triapine is a synthetic heterocyclic carboxaldehyde thiosemicarbazone with potential antineoplastic activity. Triapine inhibits the enzyme ribonucleotide reductase, resulting in the inhibition of the conversion of ribonucleoside diphosphates to deoxyribonucleotides necessary for DNA synthesis. This agent has been shown to inhibit tumor growth in vitro. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:     Vion Pharmaceuticals Inc。

Triapine is a substance that is being studied in the treatment of cancer. It belongs to the family of drugs called ribonucleotide reductase inhibitors.  Triapine  is a potent inhibitor of ribonucleotide reductase, the rate determining enzyme in the supply of deoxynucleotides (DNA building blocks) for DNA synthesis. DNA synthesis is required for cellular proliferation and DNA repair. It is therefore not surprising that it has broad spectrum antitumor activity and synergizes with antitumor drugs that target DNA. It is a very strong iron chelator and in the body it is likely that the iron chelate is the active species that quenches the active site tyrosyl radical required by ribonucleotide reductase for its enzymatic activity. The Triapine iron chelate is redox active and there have been several reports in the literature ascribing this property to some of the biological activities of Triapine.   (source: http://en.wikipedia.org/wiki/3-Aminopyridine-2-carboxaldehyde_thiosemicarbazone).

According to Wikipedia.com, Triapine  is a product of the laboratory of Dr Alan C. Sartorelli, a renowned cancer researcher in the Yale University School of Medicine Pharmacology Department. Dr. Sartorelli has a long standing interest in ribonucleotide reductase inhibitors as anticancer agents, and in collaboration with the late Dr. Tai-Shun Lin, and Dr. Mao-Chin Liu, a large number of thiosemicarbazone based ribonucleotide reductase inhibitors were synthesized over several decades. Triapine  was chosen, based on the results of studying and the screening these products, as the candidate inhibitor most likely to express activity in the setting of human neoplastic disease. As of 2006, Triapine  is being developed by Vion Pharmaceuticals. It has undergone Phase 1 and Phase 2 clinical trials. Vion Pharmaceuticals has also filed several use patents concerning the antiviral and antifungal activity of Triapine. (source: http://en.wikipedia.org/wiki/3-Aminopyridine-2-carboxaldehyde_thiosemicarbazone).

1: Kunos CA, Radivoyevitch T, Ingalls ST, Hoppel CL. Management of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone-induced methemoglobinemia. Future Oncol. 2012 Feb;8(2):145-50. PubMed PMID: 22335579; PubMed Central PMCID: PMC3292053.

2: Chao J, Synold TW, Morgan RJ Jr, Kunos C, Longmate J, Lenz HJ, Lim D, Shibata S, Chung V, Stoller RG, Belani CP, Gandara DR, McNamara M, Gitlitz BJ, Lau DH, Ramalingam SS, Davies A, Espinoza-Delgado I, Newman EM, Yen Y. A phase I and pharmacokinetic study of oral 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of advanced-stage solid cancers: a California Cancer Consortium Study. Cancer Chemother Pharmacol. 2012 Mar;69(3):835-43. Epub 2011 Nov 22. PubMed PMID: 22105720; PubMed Central PMCID: PMC3288125.

3: Popović-Bijelić A, Kowol CR, Lind ME, Luo J, Himo F, Enyedy EA, Arion VB, Gräslund A. Ribonucleotide reductase inhibition by metal complexes of Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone): a combined experimental and theoretical study. J Inorg Biochem. 2011 Nov;105(11):1422-31. Epub 2011 Jul 31. PubMed PMID: 21955844.

4: Kolesar JM, Sachidanandam K, Schelman WR, Eickhoff J, Holen KD, Traynor AM, Alberti DB, Thomas JP, Chitambar CR, Wilding G, Antholine WE. Cytotoxic Evaluation of 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone, 3-AP, in Peripheral Blood Lymphocytes of Patients with Refractory Solid Tumors using Electron Paramagnetic Resonance. Exp Ther Med. 2011 Jan;2(1):119-123. PubMed PMID: 21373381; PubMed Central PMCID: PMC3046871.

5: Kolesar J, Brundage RC, Pomplun M, Alberti D, Holen K, Traynor A, Ivy P, Wilding G. Population pharmacokinetics of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine®) in cancer patients. Cancer Chemother Pharmacol. 2011 Feb;67(2):393-400. Epub 2010 May 4. PubMed PMID: 20440618; PubMed Central PMCID: PMC3059107.

6: Kunos CA, Waggoner S, von Gruenigen V, Eldermire E, Pink J, Dowlati A, Kinsella TJ. Phase I trial of pelvic radiation, weekly cisplatin, and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) for locally advanced cervical cancer. Clin Cancer Res. 2010 Feb 15;16(4):1298-306. Epub 2010 Feb 9. PubMed PMID: 20145183; PubMed Central PMCID: PMC2822897.

7: Choi BS, Alberti DB, Schelman WR, Kolesar JM, Thomas JP, Marnocha R, Eickhoff JC, Ivy SP, Wilding G, Holen KD. The maximum tolerated dose and biologic effects of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) in combination with irinotecan for patients with refractory solid tumors. Cancer Chemother Pharmacol. 2010 Oct;66(5):973-80. Epub 2010 Feb 2. PubMed PMID: 20127092; PubMed Central PMCID: PMC2921466.

8: Kowol CR, Trondl R, Arion VB, Jakupec MA, Lichtscheidl I, Keppler BK. Fluorescence properties and cellular distribution of the investigational anticancer drug triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) and its zinc(II) complex. Dalton Trans. 2010 Jan 21;39(3):704-6. Epub 2009 Oct 22. PubMed PMID: 20066211.

9: Kowol CR, Trondl R, Heffeter P, Arion VB, Jakupec MA, Roller A, Galanski M, Berger W, Keppler BK. Impact of metal coordination on cytotoxicity of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (triapine) and novel insights into terminal dimethylation. J Med Chem. 2009 Aug 27;52(16):5032-43. PubMed PMID: 19637923.

10: Attia S, Kolesar J, Mahoney MR, Pitot HC, Laheru D, Heun J, Huang W, Eickhoff J, Erlichman C, Holen KD. A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas. Invest New Drugs. 2008 Aug;26(4):369-79. Epub 2008 Feb 16. PubMed PMID: 18278438.

11: Odenike OM, Larson RA, Gajria D, Dolan ME, Delaney SM, Karrison TG, Ratain MJ, Stock W. Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia. Invest New Drugs. 2008 Jun;26(3):233-9. Epub 2008 Jan 24. PubMed PMID: 18217206.

12: Ma B, Goh BC, Tan EH, Lam KC, Soo R, Leong SS, Wang LZ, Mo F, Chan AT, Zee B, Mok T. A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells. Invest New Drugs. 2008 Apr;26(2):169-73. Epub 2007 Sep 12. PubMed PMID: 17851637.

13: Karp JE, Giles FJ, Gojo I, Morris L, Greer J, Johnson B, Thein M, Sznol M, Low J. A phase I study of the novel ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) in combination with the nucleoside analog fludarabine for patients with refractory acute leukemias and aggressive myeloproliferative disorders. Leuk Res. 2008 Jan;32(1):71-7. Epub 2007 Jul 20. PubMed PMID: 17640728; PubMed Central PMCID: PMC2726775.

14: Mackenzie MJ, Saltman D, Hirte H, Low J, Johnson C, Pond G, Moore MJ. A Phase II study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) and gemcitabine in advanced pancreatic carcinoma. A trial of the Princess Margaret hospital Phase II consortium. Invest New Drugs. 2007 Dec;25(6):553-8. Epub 2007 Jun 22. PubMed PMID: 17585372.

15: Jiang ZG, Lebowitz MS, Ghanbari HA. Neuroprotective activity of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (PAN-811), a cancer therapeutic agent. CNS Drug Rev. 2006 Spring;12(1):77-90. Review. PubMed PMID: 16834759.

16: Barker CA, Burgan WE, Carter DJ, Cerna D, Gius D, Hollingshead MG, Camphausen K, Tofilon PJ. In vitro and in vivo radiosensitization induced by the ribonucleotide reductase inhibitor Triapine (3-aminopyridine-2-carboxaldehyde-thiosemicarbazone). Clin Cancer Res. 2006 May 1;12(9):2912-8. PubMed PMID: 16675588.

17: Alvero AB, Chen W, Sartorelli AC, Schwartz P, Rutherford T, Mor G. Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) induces apoptosis in ovarian cancer cells. J Soc Gynecol Investig. 2006 Feb;13(2):145-52. PubMed PMID: 16443509.

18: Chen RW, Yao C, Lu XC, Jiang ZG, Whipple R, Liao Z, Ghanbari HA, Almassian B, Tortella FC, Dave JR. PAN-811 (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a novel neuroprotectant, elicits its function in primary neuronal cultures by up-regulating Bcl-2 expression. Neuroscience. 2005;135(1):191-201. PubMed PMID: 16084648.

19: Yen Y, Margolin K, Doroshow J, Fishman M, Johnson B, Clairmont C, Sullivan D, Sznol M. A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer. Cancer Chemother Pharmacol. 2004 Oct;54(4):331-42. Epub 2004 May 18. PubMed PMID: 15148626.

20: Wadler S, Makower D, Clairmont C, Lambert P, Fehn K, Sznol M. Phase I and pharmacokinetic study of the ribonucleotide reductase inhibitor, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, administered by 96-hour intravenous continuous infusion. J Clin Oncol. 2004 May 1;22(9):1553-63. PubMed PMID: 15117978.

21: Feun L, Modiano M, Lee K, Mao J, Marini A, Savaraj N, Plezia P, Almassian B, Colacino E, Fischer J, MacDonald S. Phase I and pharmacokinetic study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) using a single intravenous dose schedule. Cancer Chemother Pharmacol. 2002 Sep;50(3):223-9. Epub 2002 Aug 1. PubMed PMID: 12203104.

22: Finch RA, Liu M, Grill SP, Rose WC, Loomis R, Vasquez KM, Cheng Y, Sartorelli AC. Triapine (3-aminopyridine-2-carboxaldehyde- thiosemicarbazone): A potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. Biochem Pharmacol. 2000 Apr 15;59(8):983-91. PubMed PMID: 10692563.

23: Finch RA, Liu MC, Cory AH, Cory JG, Sartorelli AC. Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone; 3-AP): an inhibitor of ribonucleotide reductase with antineoplastic activity. Adv Enzyme Regul. 1999;39:3-12. Review. PubMed PMID: 10470363.

24: Krishna G, Mao J, Almassian B, Lang W. Development of a parenteral formulation of an investigational anticancer drug, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. Pharm Dev Technol. 1999 Jan;4(1):71-80. Erratum in: Pharm Dev Technol 1999 Aug;4(3):461. PubMed PMID: 10027215.

25: Li J, Luo X, Wang Q, Zheng LM, King I, Doyle TW, Chen SH. Synthesis and biological evaluation of a water soluble phosphate prodrug of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP). Bioorg Med Chem Lett. 1998 Nov 17;8(22):3159-64. PubMed PMID: 9873695.