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 Tanomastat

Tanomastat is a biphenyl matrix metalloproteinase (MMP) inhibitor (MMPI) with potential antineoplastic activity. Tanomastat inhibits MMP-2, MMP-3, and MMP-9, inhibiting extracellular matrix degradation and potentially inhibiting angiogenesis, tumor growth and invasion, and metastasis. MMPs consist of at least 18 zinc-containing endo-proteinases that are capable of degrading collagen and proteoglycan. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Results of phase III clinical trials:  This drug, developed by Bayer, was entered into Phase III human clinical trials. However, Bayer decided to stop the trials due to negative results from other phase III trials in pancreatic and small cell lung cancer. It was concluded that BAY 12-9566 was generally well tolerated and at the time of the final analysis, there was no evidence of an impact of BAY 12-9566 on progression-free survival  or overall survival .   (source: Gynecol Oncol. 2006 Aug;102(2):300-8. Epub 2006 Jan 25.).

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2: Cosgrove D, Meehan DT, Delimont D, Pozzi A, Chen X, Rodgers KD, Tempero RM, Zallocchi M, Rao VH. Integrin alpha1beta1 regulates matrix metalloproteinases via P38 mitogen-activated protein kinase in mesangial cells: implications for Alport syndrome. Am J Pathol. 2008 Mar;172(3):761-73. Epub 2008 Feb 7. PubMed PMID: 18258846; PubMed Central PMCID: PMC2258247.

3: Moore AS, Dernell WS, Ogilvie GK, Kristal O, Elmslie R, Kitchell B, Susaneck S, Rosenthal R, Klein MK, Obradovich J, Legendre A, Haddad T, Hahn K, Powers BE, Warren D. Doxorubicin and BAY 12-9566 for the treatment of osteosarcoma in dogs: a randomized, double-blind, placebo-controlled study. J Vet Intern Med. 2007 Jul-Aug;21(4):783-90. PubMed PMID: 17708400.

4: Howes JM, Theakston RD, Laing GD. Neutralization of the haemorrhagic activities of viperine snake venoms and venom metalloproteinases using synthetic peptide inhibitors and chelators. Toxicon. 2007 Apr;49(5):734-9. Epub 2006 Nov 30. PubMed PMID: 17196631.

5: Narazaki M, Tosato G. Conflicting results from clinical observations and murine models: what is the role of plasminogen activators in tumor growth? J Natl Cancer Inst. 2006 Jun 7;98(11):726-7. PubMed PMID: 16757692.

6: Saif MW. Anti-angiogenesis therapy in pancreatic carcinoma. JOP. 2006 Mar 9;7(2):163-73. Review. PubMed PMID: 16525200.

7: Hirte H, Vergote IB, Jeffrey JR, Grimshaw RN, Coppieters S, Schwartz B, Tu D, Sadura A, Brundage M, Seymour L. A phase III randomized trial of BAY 12-9566 (tanomastat) as maintenance therapy in patients with advanced ovarian cancer responsive to primary surgery and paclitaxel/platinum containing chemotherapy: a National Cancer Institute of Canada Clinical Trials Group Study. Gynecol Oncol. 2006 Aug;102(2):300-8. Epub 2006 Jan 25. PubMed PMID: 16442153.

8: Molina JR, Reid JM, Erlichman C, Sloan JA, Furth A, Safgren SL, Lathia CD, Alberts SR. A phase I and pharmacokinetic study of the selective, non-peptidic inhibitor of matrix metalloproteinase BAY 12-9566 in combination with etoposide and carboplatin. Anticancer Drugs. 2005 Oct;16(9):997-1002. PubMed PMID: 16162976.

9: Hirte H, Stewart D, Goel R, Chouinard E, Huan S, Stafford S, Waterfield B, Matthews S, Lathia C, Schwartz B, Agarwal V, Humphrey R, Seymour AL. An NCIC-CTG phase I dose escalation pharmacokinetic study of the matrix metalloproteinase inhibitor BAY 12-9566 in combination with doxorubicin. Invest New Drugs. 2005 Oct;23(5):437-43. PubMed PMID: 16133795.

10: Lutz J, Yao Y, Song E, Antus B, Hamar P, Liu S, Heemann U. Inhibition of matrix metalloproteinases during chronic allograft nephropathy in rats. Transplantation. 2005 Mar 27;79(6):655-61. PubMed PMID: 15785371.

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12: Molecule of the month: Bay-12-9566. Drug News Perspect. 1998 Dec;11(10):646. PubMed PMID: 15616633.

13: Goel R, Chouinard E, Stewart DJ, Huan S, Hirte H, Stafford S, Waterfield B, Roach J, Lathia C, Agarwal V, Humphrey R, Walsh W, Matthews S, Seymour L. An NCIC CTG phase I/pharmacokinetic study of the matrix metalloproteinase and angiogenesis inhibitor BAY 12-9566 in combination with 5-fluorouracil/leucovorin. Invest New Drugs. 2005 Jan;23(1):63-71. PubMed PMID: 15528982.

14: Buckland-Wright JC, Ward RJ, Peterfy C, Mojcik CF, Leff RL. Reproducibility of the semiflexed (metatarsophalangeal) radiographic knee position and automated measurements of medial tibiofemoral joint space width in a multicenter clinical trial of knee osteoarthritis. J Rheumatol. 2004 Aug;31(8):1588-97. PubMed PMID: 15290740.

15: Cappuzzo F, Bartolini S, Crinò L. Emerging drugs for non-small cell lung cancer. Expert Opin Emerg Drugs. 2003 May;8(1):179-92. Review. PubMed PMID: 14610920.

16: Nozaki S, Sissons S, Chien DS, Sledge GW Jr. Activity of biphenyl matrix metalloproteinase inhibitor BAY 12-9566 in a human breast cancer orthotopic model. Clin Exp Metastasis. 2003;20(5):407-12. PubMed PMID: 14524529.

17: Moore MJ, Hamm J, Dancey J, Eisenberg PD, Dagenais M, Fields A, Hagan K, Greenberg B, Colwell B, Zee B, Tu D, Ottaway J, Humphrey R, Seymour L; National Cancer Institute of Canada Clinical Trials Group. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003 Sep 1;21(17):3296-302. PubMed PMID: 12947065.

18: Oettle H. [Adjuvant treatment of pancreatic cancer]. Zentralbl Chir. 2003 May;128(5):411-8. Review. German. PubMed PMID: 12813641.

19: Leff RL, Elias I, Ionescu M, Reiner A, Poole AR. Molecular changes in human osteoarthritic cartilage after 3 weeks of oral administration of BAY 12-9566, a matrix metalloproteinase inhibitor. J Rheumatol. 2003 Mar;30(3):544-9. PubMed PMID: 12610815.

20: Heinemann V. Gemcitabine in the treatment of advanced pancreatic cancer: a comparative analysis of randomized trials. Semin Oncol. 2002 Dec;29(6 Suppl 20):9-16. Review. PubMed PMID: 12577228.

21: Ma BB, Britten CD, Siu LL. Clinical trial designs for targeted agents. Hematol Oncol Clin North Am. 2002 Oct;16(5):1287-305. Review. PubMed PMID: 12512393.

22: Gupta MK, Tseng YC, Goldman D, Bogner RH. Hydrogen bonding with adsorbent during storage governs drug dissolution from solid-dispersion granules. Pharm Res. 2002 Nov;19(11):1663-72. PubMed PMID: 12458672.

23: Rupnick MA, Panigrahy D, Zhang CY, Dallabrida SM, Lowell BB, Langer R, Folkman MJ. Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10730-5. Epub 2002 Jul 29. PubMed PMID: 12149466; PubMed Central PMCID: PMC125027.

24: Gupta MK, Bogner RH, Goldman D, Tseng YC. Mechanism for further enhancement in drug dissolution from solid-dispersion granules upon storage. Pharm Dev Technol. 2002 Jan;7(1):103-12. PubMed PMID: 11852693.

25: Gupta MK, Goldman D, Bogner RH, Tseng YC. Enhanced drug dissolution and bulk properties of solid dispersions granulated with a surface adsorbent. Pharm Dev Technol. 2001 Nov;6(4):563-72. PubMed PMID: 11775957.

26: Heath EI, O'Reilly S, Humphrey R, Sundaresan P, Donehower RC, Sartorius S, Kennedy MJ, Armstrong DK, Carducci MA, Sorensen JM, Kumor K, Kennedy S, Grochow LB. Phase I trial of the matrix metalloproteinase inhibitor BAY12-9566 in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2001 Oct;48(4):269-74. PubMed PMID: 11710626.

27: Billinghurst RC, Buxton EM, Edwards MG, McGraw MS, McIlwraith CW. Use of an antineoepitope antibody for identification of type-II collagen degradation in equine articular cartilage. Am J Vet Res. 2001 Jul;62(7):1031-9. PubMed PMID: 11453476.

28: Lathia C, Shah A, Sundaresan P. Effect of age and gender on the safety, tolerability, and pharmacokinetics of BAY 12-9566 in healthy subjects. J Clin Pharmacol. 2001 Jul;41(7):764-9. PubMed PMID: 11452709.

29: Zucker S, Cao J, Chen WT. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene. 2000 Dec 27;19(56):6642-50. Review. PubMed PMID: 11426650.

30: Erlichman C, Adjei AA, Alberts SR, Sloan JA, Goldberg RM, Pitot HC, Rubin J, Atherton PJ, Klee GG, Humphrey R. Phase I study of the matrix metalloproteinase inhibitor, BAY 12-9566. Ann Oncol. 2001 Mar;12(3):389-95. PubMed PMID: 11332153.

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32: Duivenvoorden WC, Hirte HW, Singh G. Quantification of matrix metalloproteinase activity in plasma of patients enrolled in a BAY 12-9566 phase I study. Int J Cancer. 2001 Mar 15;91(6):857-62. PubMed PMID: 11275992.

33: Shah A, Woodruff M, Agarwal V, Liu P, Sundaresan P. Pharmacokinetics, safety, and tolerability of BAY 12-9566 and nonsteroidal anti-inflammatory agents (naproxen, ibuprofen) during coadministration in patients with osteoarthritis. J Clin Pharmacol. 2001 Mar;41(3):330-9. PubMed PMID: 11269574.

34: Hirte H, Goel R, Major P, Seymour L, Huan S, Stewart D, Yau J, Arnold A, Holohan S, Waterfield B, Bates S, Bennett K, Walsh W, Elias I. A phase I dose escalation study of the matrix metalloproteinase inhibitor BAY 12-9566 administered orally in patients with advanced solid tumours. Ann Oncol. 2000 Dec;11(12):1579-84. PubMed PMID: 11205466.

35: Hidalgo M, Eckhardt SG. Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst. 2001 Feb 7;93(3):178-93. Review. PubMed PMID: 11158186.

36: Hamada T, Arima N, Shindo M, Sugama K, Sasaguri Y. Suppression of adjuvant arthritis of rats by a novel matrix metalloproteinase-inhibitor. Br J Pharmacol. 2000 Dec;131(8):1513-20. PubMed PMID: 11139426; PubMed Central PMCID: PMC1572509.

37: Brown PD. Ongoing trials with matrix metalloproteinase inhibitors. Expert Opin Investig Drugs. 2000 Sep;9(9):2167-77. PubMed PMID: 11060801.

38: Zucker S, Eckhardt SG, Rowinsky EK. Plasma MMPs as surrogates of BAY 12-9566. J Clin Oncol. 2000 Apr;18(8):1805-6. PubMed PMID: 10764446.

39: Bengtson EM, Rigas JR. New oral chemotherapeutic agents for lung cancer. Drugs. 1999;58 Suppl 3:57-69. Review. PubMed PMID: 10711843.

40: Rowinsky EK, Humphrey R, Hammond LA, Aylesworth C, Smetzer L, Hidalgo M, Morrow M, Smith L, Garner A, Sorensen JM, Von Hoff DD, Eckhardt SG. Phase I and pharmacologic study of the specific matrix metalloproteinase inhibitor BAY 12-9566 on a protracted oral daily dosing schedule in patients with solid malignancies. J Clin Oncol. 2000 Jan;18(1):178-86. PubMed PMID: 10623708.

41: Gatto C, Rieppi M, Borsotti P, Innocenti S, Ceruti R, Drudis T, Scanziani E, Casazza AM, Taraboletti G, Giavazzi R. BAY 12-9566, a novel inhibitor of matrix metalloproteinases with antiangiogenic activity. Clin Cancer Res. 1999 Nov;5(11):3603-7. PubMed PMID: 10589777.

42: BAY12-9566. BAY 12 9566, BAY12 9566. Drugs R D. 1999 Feb;1(2):142-3. PubMed PMID: 10566009.

43: Rothenberg ML, Nelson AR, Hande KR. New drugs on the horizon: matrix metalloproteinase inhibitors. Stem Cells. 1999;17(4):237-40. PubMed PMID: 10437989.

44: Billinghurst RC, O'Brien K, Poole AR, McIlwraith CW. Inhibition of articular cartilage degradation in culture by a novel nonpeptidic matrix metalloproteinase inhibitor. Ann N Y Acad Sci. 1999 Jun 30;878:594-7. PubMed PMID: 10415783.

45: Leff RL. Clinical trials of a stromelysin inhibitor. Osteoarthritis, matrix metalloproteinase inhibition, cartilage loss, surrogate markers, and clinical implications. Ann N Y Acad Sci. 1999 Jun 30;878:201-7. Review. PubMed PMID: 10415731.

46: Brown PD. Clinical studies with matrix metalloproteinase inhibitors. APMIS. 1999 Jan;107(1):174-80. Review. PubMed PMID: 10190295.

47: Nelson NJ. Inhibitors of angiogenesis enter phase III testing. J Natl Cancer Inst. 1998 Jul 1;90(13):960-3. PubMed PMID: 9665141.