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  Amonafide L-malate

Description of amonafide: Amonafide L-malate is the malate salt of amonafide, an imide derivative of naphthalic acid, with potential antineoplastic activity. Amonafide intercalates into DNA and inhibits topoisomerase II, resulting in DNA double-strand breaks (DSB) and inhibition of DNA replication and RNA synthesis. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:  Antisoma Research Limited (formerly by Xanthus Pharmaceuticals, Inc.)

According to http://en.wikipedia.org/wiki/Amonafide, Amonafide (originally AS1413) (INN, trade name Quinamed) is a drug that is being studied in the treatment of cancer. It belongs to the families of drugs called topoisomerase inhibitors and DNA intercalators. It is being developed as an anti-cancer therapy by Antisoma. As of 2008, it is in Phase III clinical trials. eg In March 2010 it is Phase III trial against secondary acute myeloid leukaemia (AML). (also see Antisoma's webpage: http://www.antisoma.com/asm/products/as1413/).

1: Chen Z, Liang X, Zhang H, Xie H, Liu J, Xu Y, Zhu W, Wang Y, Wang X, Tan S, Kuang D, Qian X. A new class of naphthalimide-based antitumor agents that inhibit topoisomerase II and induce lysosomal membrane permeabilization and apoptosis. J  Med Chem. 2010 Mar 25;53(6):2589-600. PubMed PMID: 20170164.

2: Lv M, Xu H. Overview of naphthalimide analogs as anticancer agents. Curr Med Chem. 2009;16(36):4797-813. Review. PubMed PMID: 19929786.

3: Zhu H, Miao ZH, Huang M, Feng JM, Zhang ZX, Lu JJ, Cai YJ, Tong LJ, Xu YF, Qian XH, Ding J. Naphthalimides induce G(2) arrest through the ATM-activated Chk2-executed pathway in HCT116 cells. Neoplasia. 2009 Nov;11(11):1226-34. PubMed PMID: 19881958; PubMed Central PMCID: PMC2767224.

4: Wu A, Xu Y, Qian X, Wang J, Liu J. Novel naphthalimide derivatives as potential apoptosis-inducing agents: design, synthesis and biological evaluation. Eur J Med Chem. 2009 Nov;44(11):4674-80. Epub 2009 Jul 16. PubMed PMID: 19643513.

5: Ingrassia L, Lefranc F, Kiss R, Mijatovic T. Naphthalimides and azonafides as  promising anti-cancer agents. Curr Med Chem. 2009;16(10):1192-213. Review. PubMed PMID: 19355879.

6: Xie L, Xu Y, Wang F, Liu J, Qian X, Cui J. Synthesis of new amonafide analogues via coupling reaction and their cytotoxic evaluation and DNA-binding studies. Bioorg Med Chem. 2009 Jan 15;17(2):804-10. Epub 2008 Nov 27. PubMed PMID: 19070496.

7: Burcu M, O'Loughlin KL, Ford LA, Baer MR. Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia.  Leukemia. 2008 Nov;22(11):2110-5. Epub 2008 Apr 17. PubMed PMID: 18418409.

8: Chau M, Christensen JL, Ajami AM, Capizzi RL. Amonafide, a topoisomerase II inhibitor, is unaffected by P-glycoprotein-mediated efflux. Leuk Res. 2008 Mar;32(3):465-73. Epub 2007 Sep 10. PubMed PMID: 17826829.

9: Alami N, Paterson J, Belanger S, Juste S, Grieshaber CK, Leyland-Jones B. Comparative analysis of xanafide cytotoxicity in breast cancer cell lines. Br J Cancer. 2007 Jul 2;97(1):58-64. Epub 2007 Jun 5. PubMed PMID: 17551498; PubMed Central PMCID: PMC2359668.

10: Zhu H, Huang M, Yang F, Chen Y, Miao ZH, Qian XH, Xu YF, Qin YX, Luo HB, Shen X, Geng MY, Cai YJ, Ding J. R16, a novel amonafide analogue, induces apoptosis and G2-M arrest via poisoning topoisomerase II. Mol Cancer Ther. 2007 Feb;6(2):484-95. PubMed PMID: 17308047.

11: Braña MF, Cacho M, García MA, de Pascual-Teresa B, Ramos A, Domínguez MT, Pozuelo JM, Abradelo C, Rey-Stolle MF, Yuste M, Báñez-Coronel M, Lacal JC. New analogues of amonafide and elinafide, containing aromatic heterocycles: synthesis, antitumor activity, molecular modeling, and DNA binding properties. J  Med Chem. 2004 Mar 11;47(6):1391-9. PubMed PMID: 14998328.

12: Braña MF, Ramos A. Naphthalimides as anti-cancer agents: synthesis and biological activity. Curr Med Chem Anticancer Agents. 2001 Nov;1(3):237-55. Review. PubMed PMID: 12678756.

13: Taylor SA, Rankin C, Townsend JJ, Craig JB, Vance RB, Solank DL, Brown TD, Jaeckle K; Southwest Oncology Group. Phase II trial of amonafide in central nervous system tumors: a Southwest Oncology Group study. Invest New Drugs. 2002 Feb;20(1):113-5. PubMed PMID: 12003186.

14: Asbury R, Blessing JA, Reid GC, McGuire WP. A phase II trial of amonafide in  patients with endometrial cancer: a Gynecologic Oncology Group Study. Am J Clin Oncol. 1998 Aug;21(4):406-7. PubMed PMID: 9708643.

15: Asbury R, Blessing JA, Podczaski E, Ball H. A phase II trial of amonafide in  patients with mixed mesodermal tumors of the uterus: a Gynecologic Oncology Group study. Am J Clin Oncol. 1998 Jun;21(3):306-7. PubMed PMID: 9626805.

16: Asbury R, Blessing JA, Look KY, Buller R, Lucci JA 3rd. A phase II trial of amonafide in patients with nonsquamous cell carcinoma of the cervix. A Gynecologic Oncology Group study. Am J Clin Oncol. 1997 Dec;20(6):626-7. PubMed PMID: 9391554.

17: Leaf AN, Neuberg D, Schwartz EL, Wadler S, Ritch PS, Dutcher JP, Adams GL. An ECOG phase II study of amonafide in unresectable or recurrent carcinoma of the head and neck (PB390). Eastern Cooperative Oncology Group. Invest New Drugs. 1997;15(2):165-72. PubMed PMID: 9220297.

18: Witte RS, Hsieh P, Elson P, Oken MM, Trump DL. A phase II trial of amonafide, caracemide, and homoharringtonine in the treatment of patients with advanced renal cell cancer. Invest New Drugs. 1996;14(4):409-13. PubMed PMID: 9157078.

19: Kreis W, Chan K, Budman DR, Allen SL, Fusco D, Mittelman A, Hock K, Akerman S, Calabro A, Puccio C, Spigelman M. Clinical pharmacokinetics of amonafide (NSC  308847) in 62 patients. Cancer Invest. 1996;14(4):320-7. PubMed PMID: 8689426.

20: Costanza ME, Berry D, Henderson IC, Ratain MJ, Wu K, Shapiro C, Duggan D, Kalra J, Berkowitz I, Lyss AP. Amonafide: An active agent in the treatment of previously untreated advanced breast cancer--a cancer and leukemia group B study  (CALGB 8642). Clin Cancer Res. 1995 Jul;1(7):699-704. PubMed PMID: 9816035.

21: Ratain MJ, Rosner G, Allen SL, Costanza M, Van Echo DA, Henderson IC, Schilsky RL. Population pharmacodynamic study of amonafide: a Cancer and Leukemia Group B study. J Clin Oncol. 1995 Mar;13(3):741-7. PubMed PMID: 7884434.

22: Rosen F, Vokes EE, Lad T, Kies M, Wade J 3rd, Kilton LJ, Blough R, French S,  Mullane M, Benson AB 3rd. Phase II study of amonafide in the treatment of patients with advanced squamous cell carcinoma of the head and the neck. An Illinois Cancer Center study. Invest New Drugs. 1995;13(3):249-52. PubMed PMID: 8729954.

23: Chang AY, Tu ZN, Smith JL, Bonomi P, Smith TJ, Wiernik PH, Blum R. Phase II trial of gallium nitrate, amonafide and teniposide in metastatic non-small cell lung cancer. An Eastern Cooperative Oncology Group study (E2588). Invest New Drugs. 1995;13(2):137-41. PubMed PMID: 8617576.

24: Levitt R, Buckner JC, Cascino TL, Burch PA, Morton RF, Westberg MW, Goldberg  RM, Gallagher JG, O'Fallon JR, Scheithauer BW. Phase II study of amonafide in patients with recurrent glioma. J Neurooncol. 1995;23(1):87-93. PubMed PMID: 7623074.

25: Marshall ME, Blumenstein B, Crawford ED, Thompson IM, Craig JB, Eisenberger M, Ahmann F. Phase II trial of amonafide for the treatment of advanced, hormonally refractory carcinoma of the prostate. A Southwest Oncology Group study. Am J Clin Oncol. 1994 Dec;17(6):514-5. PubMed PMID: 7977172.

26: Asbury RF, Blessing JA, Soper JT. A Gynecologic Oncology Group phase II study of amonafide (NSC #308847) in squamous cell carcinoma of the cervix. Am J Clin Oncol. 1994 Apr;17(2):125-8. PubMed PMID: 8141104.

27: Kornek G, Raderer M, Depisch D, Haider K, Fazeny B, Dittrich C, Scheithauer W. Amonafide as first-line chemotherapy for metastatic breast cancer. Eur J Cancer. 1994;30A(3):398-400. PubMed PMID: 8204367.

28: Malviya VK, Liu PY, O'Toole R, Alberts DS, Surwit E, Rosenoff S, Ward JH, Yu  A, O'Sullivan J, Craig JB. Phase II trial of amonafide in patients with advanced  metastatic or recurrent endometrial adenocarcinoma. A Southwest Oncology Group study. Am J Clin Oncol. 1994 Feb;17(1):37-40. PubMed PMID: 8311005.

29: Buys SS, Metch B, Balcerzak SP, Neefe JR, Stuckey WJ. Phase II evaluation of  amonafide in advanced sarcoma: a Southwest Oncology Group study. Cancer Invest. 1994;12(4):399-402. PubMed PMID: 8032960.

30: Mullane MR, Schilsky RL, Carroll RB, Wade JL 3rd, Kilton LJ, Blough RR, Bauman A, French SL, Benson AB 3rd. Phase II study of amonafide in gastric adenocarcinoma. An Illinois Cancer Center trial. Invest New Drugs. 1994;12(3):267-70. PubMed PMID: 7896548.

31: Asbury RF, Blessing JA, Look KY, Clarke-Pearson D, Homesley HD. A Gynecologic Oncology Group phase II study of amonafide (NSC 308847) in epithelial ovarian cancer. Am J Clin Oncol. 1993 Dec;16(6):529-31. PubMed PMID: 8256772.

32: Ratain MJ, Mick R, Berezin F, Janisch L, Schilsky RL, Vogelzang NJ, Lane LB.  Phase I study of amonafide dosing based on acetylator phenotype. Cancer Res. 1993 May 15;53(10 Suppl):2304-8. PubMed PMID: 8485716.

33: Gesme DH Jr, Jett JR, Schreffler DD, Su JQ, Mailliard JA, Foley JF, Krook JE, Maksymiuk AW, Hatfield AK, Ebbert LP, et al. A randomized phase II trial of amonafide or trimetrexate in patients with advanced non-small cell lung cancer. A trial of the North Central Cancer Treatment Group. Cancer. 1993 May 1;71(9):2723-6. PubMed PMID: 8385564.

34: Leichman CG, Tangen C, Macdonald JS, Leimert T, Fleming TR. Phase II trial of amonafide in advanced pancreas cancer. A Southwest Oncology Group study. Invest New Drugs. 1993 May-Aug;11(2-3):219-21. PubMed PMID: 8262735.

35: Brown TD, Goodman PJ, Fleming T, Macdonald JS, Craig JB, Einstein AB. Phase II trial of amonafide in advanced colorectal cancer: a SouthWest Oncology Group study. Anticancer Drugs. 1993 Feb;4(1):49-50. PubMed PMID: 8457714.

36: Perez RP, Nash SL, Ozols RF, Comis RL, O'Dwyer PJ. Phase II study of amonafide in advanced and recurrent sarcoma patients. Invest New Drugs. 1992 Jul;10(2):99-101. PubMed PMID: 1500272.

37: Malviya VK, Liu PY, Alberts DS, Surwit EA, Craig JB, Hannigan EV. Evaluation  of amonafide in cervical cancer, phase II. A SWOG study. Am J Clin Oncol. 1992 Feb;15(1):41-4. PubMed PMID: 1550078.

38: Higano CS, Goodman P, Craig JB, Kish JA, Rivkin SE, Wolf M, Crawford ED. Phase II evaluation of amonafide in renal cell carcinoma. A Southwest Oncology Group study. Invest New Drugs. 1991 Nov;9(4):361-3. PubMed PMID: 1804814.

39: Linke K, Pazdur R, Abbruzzese JL, Ajani JA, Winn R, Bradof JE, Daugherty K, Levin B. Phase II study of amonafide in advanced pancreatic adenocarcinoma. Invest New Drugs. 1991 Nov;9(4):353-6. PubMed PMID: 1804812.

40: Berger MZ, Kris MG, Gralla RJ, Marks LD, Potanovich LM, Dimaggio JJ, Heelan RT. Phase II trial of amonafide in patients with stage III and IV non-small-cell  lung cancer. Am J Clin Oncol. 1991 Apr;14(2):124-6. PubMed PMID: 1851387.

41: O'Dwyer PJ, Paul AR, Hudes GR, Walczak J, Ozols RF, Comis RL. Phase II study  of amonafide (nafidamide, NSC 308847) in advanced colorectal cancer. Invest New Drugs. 1991 Feb;9(1):65-7. PubMed PMID: 2026485.

42: Scheithauer W, Kornek G, Haider K, Depisch D. Amonafide in metastatic colorectal carcinoma. Eur J Cancer. 1990;26(8):923-4. PubMed PMID: 2145944.