SpringerLink
Log in

PI-88 and Related Heparan Sulfate Mimetics

  • Chapter
  • First Online:
Heparanase

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1221))

Abstract

The heparan sulfate mimetic PI-88 (muparfostat) is a complex mixture of sulfated oligosaccharides that was identified in the late 1990s as a potent inhibitor of heparanase. In preclinical animal models it was shown to block angiogenesis, metastasis and tumor growth, and subsequently became the first heparanase inhibitor to enter clinical trials for cancer. It progressed to Phase III trials but ultimately was not approved for use. Herein we summarize the preparation, physicochemical and biological properties of PI-88, and discuss preclinical/clinical and structure-activity relationship studies. In addition, we discuss the PI-88-inspired development of related HS mimetic heparanase inhibitors with improved properties, ultimately leading to the discovery of PG545 (pixatimod) which is currently in clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Ferro, V., Hammond, E., & Fairweather, J. K. (2004). The development of inhibitors of heparanase, a key enzyme involved in tumour metastasis, angiogenesis and inflammation. Mini Reviews in Medicinal Chemistry, 4, 693–702.

    Article  CAS  PubMed  Google Scholar 

  2. Hammond, E., Bytheway, I., & Ferro, V. (2006). Heparanase as a target for anticancer therapeutics: New developments and future prospects. In M. Delehedde & H. Lortat-Jacob (Eds.), New developments in therapeutic glycomics (pp. 251–282). Trivandrum: Research Signpost.

    Google Scholar 

  3. Miao, H. Q., Liu, H., Navarro, E., Kussie, P., & Zhu, Z. (2006). Development of heparanase inhibitors for anti-cancer therapy. Current Medicinal Chemistry, 13, 2101–2111.

    Article  CAS  PubMed  Google Scholar 

  4. McKenzie, E. A. (2007). Heparanase: A target for drug discovery in cancer and inflammation. British Journal of Pharmacology, 151, 1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jia, L., & Ma, S. (2016). Recent advances in the discovery of heparanase inhibitors as anti-cancer agents. European Journal of Medicinal Chemistry, 121, 209–220.

    Article  CAS  PubMed  Google Scholar 

  6. Rivara, S., Milazzo, F. M., & Giannini, G. (2016). Heparanase: A rainbow pharmacological target associated to multiple pathologies including rare diseases. Future Medicinal Chemistry, 8, 647–680.

    Article  CAS  PubMed  Google Scholar 

  7. Parish, C. R., Coombe, D. R., Jakobsen, K. B., Bennett, F. A., & Underwood, P. A. (1987). Evidence that sulphated polysaccharides inhibit tumour metastasis by blocking tumour-cell-derived heparanases. International Journal of Cancer, 40, 511–518.

    Article  CAS  PubMed  Google Scholar 

  8. Vlodavsky, I., Friedmann, Y., Elkin, M., Aingorn, H., Atzmon, R., Ishai-Michaeli, R., Bitan, M., Pappo, O., Peretz, T., Michal, I., Spector, L., & Pecker, I. (1999). Mammalian heparanase: Gene cloning, expression and function in tumor progression and metastasis. Nature Medicine, 5, 793–802.

    Article  CAS  PubMed  Google Scholar 

  9. Hulett, M. D., Freeman, C., Hamdorf, B. J., Baker, R. T., Harris, M. J., & Parish, C. R. (1999). Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis. Nature Medicine, 5, 803–809.

    Article  CAS  PubMed  Google Scholar 

  10. Chhabra, M., & Ferro, V. (2018). The development of assays for heparanase enzymatic activity: Towards a gold standard. Molecules, 23, 2971.

    Article  PubMed Central  CAS  Google Scholar 

  11. Freeman, C., & Parish, C. R. (1998). Human platelet heparanase: Purification, characterization and catalytic activity. The Biochemical Journal, 330, 1341–1350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Freeman, C., Browne, A. M., & Parish, C. R. (1999). Evidence that platelet and tumour heparanases are similar enzymes. The Biochemical Journal, 342, 361–368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Freeman, C., & Parish, C. R. (1997). A rapid quantitative assay for the detection of mammalian heparanase activity. The Biochemical Journal, 325, 229–237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Parish, C. R., Freeman, C., Brown, K. J., Francis, D. J., & Cowden, W. B. (1999). Identification of sulfated oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity. Cancer Research, 59, 3433–3441.

    CAS  PubMed  Google Scholar 

  15. Kudchadkar, R., Gonzalez, R., & Lewis, K. D. (2008). PI-88: A novel inhibitor of angiogenesis. Expert Opinion on Investigational Drugs, 17, 1769–1776.

    Article  CAS  PubMed  Google Scholar 

  16. Chen, P. J., Lee, P. H., Han, K. H., Fan, J., Cheung, T. T., Hu, R. H., Paik, S. W., Lee, W. C., Chau, G. Y., Jeng, L. B., Wang, H. J., Choi, J. Y., Chen, C. L., Cho, M., Ho, M. C., Wu, C. C., Lee, K. S., Mao, Y., Hu, F. C., & Lai, K. L. (2017). A phase III trial of muparfostat (PI-88) as adjuvant therapy in patients with hepatitis virus related hepatocellular carcinoma (HV-HCC) after resection. Annals of Oncology, 28, 213.

    Google Scholar 

  17. Ferro, V., Dredge, K., Liu, L., Hammond, E., Bytheway, I., Li, C., Johnstone, K., Karoli, T., Davis, K., Copeman, E., & Gautam, A. (2007). PI-88 and novel heparan sulfate mimetics inhibit angiogenesis. Seminars in Thrombosis and Hemostasis, 33, 557–568.

    Article  CAS  PubMed  Google Scholar 

  18. Dredge, K., Hammond, E., Davis, K., Li, C. P., Liu, L., Johnstone, K., Handley, P., Wimmer, N., Gonda, T. J., Gautam, A., Ferro, V., & Bytheway, I. (2010). The PG500 series: Novel heparan sulfate mimetics as potent angiogenesis and heparanase inhibitors for cancer therapy. Investigational New Drugs, 28, 276–283.

    Article  CAS  PubMed  Google Scholar 

  19. Ferro, V., Liu, L., Johnstone, K. D., Wimmer, N., Karoli, T., Handley, P., Rowley, J., Dredge, K., Li, C. P., Hammond, E., Davis, K., Sarimaa, L., Harenberg, J., & Bytheway, I. (2012). Discovery of PG545: A highly potent and simultaneous inhibitor of angiogenesis, tumor growth, and metastasis. Journal of Medicinal Chemistry, 55, 3804–3813.

    Article  CAS  PubMed  Google Scholar 

  20. Dredge, K., Brennan, T. V., Hammond, E., Lickliter, J. D., Lin, L., Bampton, D., Handley, P., Lankesheer, F., Morrish, G., Yang, Y., Brown, M. P., & Millward, M. (2018). A phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours. British Journal of Cancer, 118, 1035–1041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yu, G., Gunay, N. S., Linhardt, R. J., Toida, T., Fareed, J., Hoppensteadt, D. A., Shadid, H., Ferro, V., Li, C., Fewings, K., Palermo, M. C., & Podger, D. (2002). Preparation and anticoagulant activity of the phosphosulfomannan PI-88. European Journal of Medicinal Chemistry, 37, 783–791.

    Article  CAS  PubMed  Google Scholar 

  22. Ferro, V., Fewings, K., Palermo, M. C., & Li, C. (2001). Large-scale preparation of the oligosaccharide phosphate fraction of Pichia holstii NRRL Y-2448 phosphomannan for use in the manufacture of PI-88. Carbohydrate Research, 332, 183–189.

    Article  CAS  PubMed  Google Scholar 

  23. Parolis, L. A., Parolis, H., Kenne, L., Meldal, M., & Bock, K. (1998). The extracellular polysaccharide of Pichia (Hansenula) holstii NRRL Y-2448: The phosphorylated side chains. Carbohydrate Research, 309, 77–87.

    Article  CAS  PubMed  Google Scholar 

  24. Ferro, V., Li, C., Fewings, K., Palermo, M. C., Linhardt, R. J., & Toida, T. (2002). Determination of the composition of the oligosaccharide phosphate fraction of Pichia (Hansenula) holstii NRRL Y-2448 phosphomannan by capillary electrophoresis and HPLC. Carbohydrate Research, 337, 139–146.

    Article  CAS  PubMed  Google Scholar 

  25. Handley, P. N., Carroll, A., & Ferro, V. (2017). New structural insights into the oligosaccharide phosphate fraction of Pichia (Hansenula) holstii NRRL Y2448 phosphomannan. Carbohydrate Research, 446–447, 68–75.

    Article  PubMed  CAS  Google Scholar 

  26. Elli, S., Stancanelli, E., Handley, P. N., Carroll, A., Urso, E., Guerrini, M., & Ferro, V. (2018). Structural and conformational studies of the heparan sulfate mimetic PI-88. Glycobiology, 28, 731–740.

    Article  CAS  PubMed  Google Scholar 

  27. Ferro, V., Li, C., Wang, B., Fewings, K., King, A. R., Hammond, E., & Creese, B. R. (2002). Synthesis of [14C]- and [35S]-labelled PI-88 for pharmacokinetic and tissue distribution studies. Journal of Labelled Compounds and Radiopharmaceuticals, 45, 747–754.

    Article  CAS  Google Scholar 

  28. Karoli, T., Liu, L., Fairweather, J. K., Hammond, E., Li, C. P., Cochran, S., Bergefall, K., Trybala, E., Addison, R. S., & Ferro, V. (2005). Synthesis, biological activity, and preliminary pharmacokinetic evaluation of analogues of a phosphosulfomannan angiogenesis inhibitor (PI-88). Journal of Medicinal Chemistry, 48, 8229–8236.

    Article  CAS  PubMed  Google Scholar 

  29. Levidiotis, V., Freeman, C., Punler, M., Martinello, P., Creese, B., Ferro, V., van der Vlag, J., Berden, J. H., Parish, C. R., & Power, D. A. (2004). A synthetic heparanase inhibitor reduces proteinuria in passive Heymann nephritis. Journal of the American Society of Nephrology: JASN., 15, 2882–2892.

    Article  CAS  PubMed  Google Scholar 

  30. Hammond, E., Li, C. P., & Ferro, V. (2010). Development of a colorimetric assay for heparanase activity suitable for kinetic analysis and inhibitor screening. Analytical Biochemistry, 396, 112–116.

    Article  CAS  PubMed  Google Scholar 

  31. Gandhi, N. S., Freeman, C., Parish, C. R., & Mancera, R. L. (2012). Computational analyses of the catalytic and heparin-binding sites and their interactions with glycosaminoglycans in glycoside hydrolase family 79 endo-β-D-glucuronidase (heparanase). Glycobiology, 22, 35–55.

    Article  CAS  PubMed  Google Scholar 

  32. Wu, L., Viola, C. M., Brzozowski, A. M., & Davies, G. J. (2015). Structural characterization of human heparanase reveals insights into substrate recognition. Nature Structural & Molecular Biology, 22, 1016–1022.

    Article  CAS  Google Scholar 

  33. Cochran, S., Li, C., Fairweather, J. K., Kett, W. C., Coombe, D. R., & Ferro, V. (2003). Probing the interactions of phosphosulfomannans with angiogenic growth factors by surface plasmon resonance. Journal of Medicinal Chemistry, 46, 4601–4608.

    Article  CAS  PubMed  Google Scholar 

  34. Quiros, R. M., Rao, G., Plate, J., Harris, J. E., Brunn, G. J., Platt, J. L., Gattuso, P., Prinz, R. A., & Xu, X. (2006). Elevated serum heparanase-1 levels in patients with pancreatic carcinoma are associated with poor survival. Cancer, 106, 532–540.

    Article  CAS  PubMed  Google Scholar 

  35. Xu, X., Rao, G., Quiros, R. M., Kim, A. W., Miao, H. Q., Brunn, G. J., Platt, J. L., Gattuso, P., & Prinz, R. A. (2007). In vivo and in vitro degradation of heparan sulfate (HS) proteoglycans by HPR1 in pancreatic adenocarcinomas. Loss of cell surface HS suppresses fibroblast growth factor 2-mediated cell signaling and proliferation. The Journal of Biological Chemistry, 282, 2363–2373.

    Article  CAS  PubMed  Google Scholar 

  36. Xu, X., Ding, J., Rao, G., Shen, J., Prinz, R. A., Rana, N., & Dmowski, W. P. (2007). Estradiol induces heparanase-1 expression and heparan sulphate proteoglycan degradation in human endometrium. Human Reproduction, 22, 927–937.

    Article  CAS  PubMed  Google Scholar 

  37. Rao, G., Liu, D., **ng, M., Tauler, J., Prinz, R. A., & Xu, X. (2010). Induction of heparanase-1 expression by mutant B-Raf kinase: Role of GA binding protein in heparanase-1 promoter activation. Neoplasia, 12, 946–956.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hazel, S. J. (2003). A novel early chorioallantoic membrane assay demonstrates quantitative and qualitative changes caused by antiangiogenic substances. The Journal of Laboratory and Clinical Medicine, 141, 217–228.

    Article  CAS  PubMed  Google Scholar 

  39. Joyce, J. A., Freeman, C., Meyer-Morse, N., Parish, C. R., & Hanahan, D. (2005). A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer. Oncogene, 24, 4037–4051.

    Article  CAS  PubMed  Google Scholar 

  40. Liang, X. J., Yuan, L., Hu, J., Yu, H. H., Li, T., Lin, S. F., & Tang, S. B. (2012). Phosphomannopentaose sulfate (PI-88) suppresses angiogenesis by downregulating heparanase and vascular endothelial growth factor in an oxygen-induced retinal neovascularization animal model. Molecular Vision, 18, 1649–1657.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Francis, D. J., Parish, C. R., McGarry, M., Santiago, F. S., Lowe, H. C., Brown, K. J., Bingley, J. A., Hayward, I. P., Cowden, W. B., Campbell, J. H., Campbell, G. R., Chesterman, C. N., & Khachigian, L. M. (2003). Blockade of vascular smooth muscle cell proliferation and intimal thickening after balloon injury by the sulfated oligosaccharide PI-88: Phosphomannopentaose sulfate directly binds FGF-2, blocks cellular signaling, and inhibits proliferation. Circulation Research, 92, e70–e77.

    Article  CAS  PubMed  Google Scholar 

  42. Demir, M., Iqbal, O., Hoppensteadt, D. A., Piccolo, P., Ahmad, S., Schultz, C. L., Linhardt, R. J., & Fareed, J. (2001). Anticoagulant and antiprotease profiles of a novel natural heparinomimetic mannopentaose phosphate sulfate (PI-88). Clinical and Applied Thrombosis/Hemostasis, 7, 131–140.

    Article  CAS  Google Scholar 

  43. Djordjevic, M. A., Bezos, A., Susanti, Marmuse, L., Driguez, H., Samain, E., Vauzeilles, B., Beau, J. M., Kordbacheh, F., Rolfe, B. G., Schworer, R., Daines, A. M., Gresshoff, P. M., & Parish, C. R. (2014). Lipo-chitin oligosaccharides, plant symbiosis signalling molecules that modulate mammalian angiogenesis in vitro. PLoS One, 9, e112635.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Hossain, M. M., Hosono-Fukao, T., Tang, R., Sugaya, N., van Kuppevelt, T. H., Jenniskens, G. J., Kimata, K., Rosen, S. D., & Uchimura, K. (2010). Direct detection of HSulf-1 and HSulf-2 activities on extracellular heparan sulfate and their inhibition by PI-88. Glycobiology, 20, 175–186.

    Article  CAS  PubMed  Google Scholar 

  45. Khurana, A., Beleford, D., He, X., Chien, J., & Shridhar, V. (2013). Role of heparan sulfatases in ovarian and breast cancer. American Journal of Cancer Research, 3, 34–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Pavlakis N (2006) Pre-clinical development of the heparanase inhibitor PI-88 in combination with chemotherapy. PhD Thesis, The University of Sydney, Sydney, Australia.

    Google Scholar 

  47. Iversen, P. O., Sorensen, D. R., & Benestad, H. B. (2002). Inhibitors of angiogenesis selectively reduce the malignant cell load in rodent models of human myeloid leukemias. Leukemia, 16, 376–381.

    Article  CAS  PubMed  Google Scholar 

  48. Liao, B. Y., Wang, Z., Hu, J., Liu, W. F., Shen, Z. Z., Zhang, X., Yu, L., Fan, J., & Zhou, J. (2016). PI-88 inhibits postoperative recurrence of hepatocellular carcinoma via disrupting the surge of heparanase after liver resection. Tumour Biology, 37, 2987–2998.

    Article  CAS  PubMed  Google Scholar 

  49. Creese, B., Ferro, V., King, A.R., Mardon, K., Dickinson, R.G., Punler, M.J., Dodds, H. (2001). Pharmacokinetics of [35S]PI-88 in male rats. Proceedings of the Australian Society for Clinical and Experimental Pharmacology and Toxicology, 9, 57.

    Google Scholar 

  50. Creese, B., Ribbons, K., Harvey, W. D., McBurney, A., Douglas, S., & Fareed, J. (2001). Use of activated partial thromboplastin time (APTT) as a surrogate measure of plasma drug concentration in toxicity studies of PI-88, a novel anticancer and anticoagulant drug. Toxicology, 164, 232.

    Google Scholar 

  51. Naggi, A., Casu, B., Perez, M., Torri, G., Cassinelli, G., Penco, S., Pisano, C., Giannini, G., Ishai-Michaeli, R., & Vlodavsky, I. (2005). Modulation of the heparanase-inhibiting activity of heparin through selective desulfation, graded N-acetylation, and glycol splitting. The Journal of Biological Chemistry, 280, 12103–12113.

    Article  CAS  PubMed  Google Scholar 

  52. Wall, D., Douglas, S., Ferro, V., Cowden, W., & Parish, C. (2001). Characterisation of the anticoagulant properties of a range of structurally diverse sulfated oligosaccharides. Thrombosis Research, 103, 325–335.

    Article  CAS  PubMed  Google Scholar 

  53. Boucas, R. I., Jarrouge-Boucas, T. R., Lima, M. A., Trindade, E. S., Moraes, F. A., Cavalheiro, R. P., Tersariol, I. L., Hoppenstead, D., Fareed, J., & Nader, H. B. (2012). Glycosaminoglycan backbone is not required for the modulation of hemostasis: Effect of different heparin derivatives and non-glycosaminoglycan analogs. Matrix Biology, 31, 308–316.

    Article  CAS  PubMed  Google Scholar 

  54. Khachigian, L. M., & Parish, C. R. (2004). Phosphomannopentaose sulfate (PI-88): Heparan sulfate mimetic with clinical potential in multiple vascular pathologies. Cardiovascular Drug Reviews, 22, 1–6.

    Article  CAS  PubMed  Google Scholar 

  55. Ferro, V. (2013). Heparan sulfate inhibitors and their therapeutic implications in inflammatory illnesses. Expert Opinion on Therapeutic Targets, 17, 965–975.

    Article  CAS  PubMed  Google Scholar 

  56. Parish CR, Cowden WB (2000) Preparation and use of sulfated oligosaccharides. USA Patent US 6,143,730.

    Google Scholar 

  57. Morris, A., Wang, B., Waern, I., Venkatasamy, R., Page, C., Schmidt, E. P., Wernersson, S., Li, J. P., & Spina, D. (2015). The role of heparanase in pulmonary cell recruitment in response to an allergic but not non-allergic stimulus. PLoS One, 10, e0127032.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Ziolkowski, A. F., Popp, S. K., Freeman, C., Parish, C. R., & Simeonovic, C. J. (2012). Heparan sulfate and heparanase play key roles in mouse beta cell survival and autoimmune diabetes. The Journal of Clinical Investigation, 122, 132–141.

    Article  CAS  PubMed  Google Scholar 

  59. Ma, P., Luo, Y., Zhu, X., Ma, H., Hu, J., & Tang, S. (2009). Phosphomannopentaose sulfate (PI-88) inhibits retinal leukostasis in diabetic rat. Biochemical and Biophysical Research Communications, 380, 402–406.

    Article  CAS  PubMed  Google Scholar 

  60. Simeonovic, C. J., Popp, S. K., Starrs, L. M., Brown, D. J., Ziolkowski, A. F., Ludwig, B., Bornstein, S. R., Wilson, J. D., Pugliese, A., Kay, T. W. H., Thomas, H. E., Loudovaris, T., Choong, F. J., Freeman, C., & Parish, C. R. (2018). Loss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans. PLoS One, 13, e0191360.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Khanna, M., Ranasinghe, C., Browne, A. M., Li, J. P., Vlodavsky, I., & Parish, C. R. (2019). Is host heparanase required for the rapid spread of heparan sulfate binding viruses? Virology, 529, 1–6.

    Article  CAS  PubMed  Google Scholar 

  62. Thakkar, N., Yadavalli, T., Jaishankar, D., & Shukla, D. (2017). Emerging roles of heparanase in viral pathogenesis. Pathogens., 6, 43.

    Google Scholar 

  63. Nyberg, K., Ekblad, M., Bergstrom, T., Freeman, C., Parish, C. R., Ferro, V., & Trybala, E. (2004). The low molecular weight heparan sulfate-mimetic, PI-88, inhibits cell-to-cell spread of herpes simplex virus. Antiviral Research, 63, 15–24.

    Article  CAS  PubMed  Google Scholar 

  64. Khanna, M., Ranasinghe, C., Jackson, R., & Parish, C. R. (2017). Heparan sulfate as a receptor for poxvirus infections and as a target for antiviral agents. The Journal of General Virology, 98, 2556–2568.

    Article  CAS  PubMed  Google Scholar 

  65. Lee, E., Pavy, M., Young, N., Freeman, C., & Lobigs, M. (2006). Antiviral effect of the heparan sulfate mimetic, PI-88, against dengue and encephalitic flaviviruses. Antiviral Research, 69, 31–38.

    Article  CAS  PubMed  Google Scholar 

  66. Scott, E. N., & Thomas, A. L. (2008). PI-88. Drugs Fut., 33, 21.

    Article  CAS  Google Scholar 

  67. Basche, M., Gustafson, D. L., Holden, S. N., O’Bryant, C. L., Gore, L., Witta, S., Schultz, M. K., Morrow, M., Levin, A., Creese, B. R., Kangas, M., Roberts, K., Nguyen, T., Davis, K., Addison, R. S., Moore, J. C., & Eckhardt, S. G. (2006). A phase I biological and pharmacologic study of the heparanase inhibitor PI-88 in patients with advanced solid tumors. Clinical Cancer Research, 12, 5471–5480.

    Article  CAS  PubMed  Google Scholar 

  68. Chow, L. Q. M., Gustafson, D. L., O’Bryant, C. L., Gore, L., Basche, M., Holden, S. N., Morrow, M. C., Grolnic, S., Creese, B. R., Roberts, K. L., Davis, K., Addison, R., & Eckhardt, S. G. (2008). A phase I pharmacological and biological study of PI-88 and docetaxel in patients with advanced malignancies. Cancer Chemotherapy and Pharmacology, 63, 65–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hudachek, S. F., Eckhardt, S. G., Hicks, B., & Gustafson, D. L. (2010). Population pharmacokinetic model of PI-88, a heparanase inhibitor. Cancer Chemotherapy and Pharmacology, 65, 743–753.

    Article  CAS  PubMed  Google Scholar 

  70. Rosenthal, M. A., Rischin, D., McArthur, G., Ribbons, K., Chong, B., Fareed, J., Toner, G., Green, M. D., & Basser, R. L. (2002). Treatment with the novel anti-angiogenic agent PI-88 is associated with immune-mediated thrombocytopenia. Annals of Oncology, 13, 770–776.

    Article  CAS  PubMed  Google Scholar 

  71. Lewis, K. D., Robinson, W. A., Millward, M. J., Powell, A., Price, T. J., Thomson, D. B., Walpole, E. T., Haydon, A. M., Creese, B. R., Roberts, K. L., Zalcberg, J. R., & Gonzalez, R. (2008). A phase II study of the heparanase inhibitor PI-88 in patients with advanced melanoma. Investigational New Drugs, 26, 89–94.

    Article  CAS  PubMed  Google Scholar 

  72. Khasraw, M., Pavlakis, N., McCowatt, S., Underhill, C., Begbie, S., de Souza, P., Boyce, A., Parnis, F., Lim, V., Harvie, R., & Marx, G. (2010). Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer. Annals of Oncology, 21, 1302–1307.

    Article  CAS  PubMed  Google Scholar 

  73. Liu, C. J., Lee, P. H., Lin, D. Y., Wu, C. C., Jeng, L. B., Lin, P. W., Mok, K. T., Lee, W. C., Yeh, H. Z., Ho, M. C., Yang, S. S., Lee, C. C., Yu, M. C., Hu, R. H., Peng, C. Y., Lai, K. L., Chang, S. S., & Chen, P. J. (2009). Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: A randomized phase II trial for safety and optimal dosage. Journal of Hepatology, 50, 958–968.

    Article  CAS  PubMed  Google Scholar 

  74. Liu, C.-J., Chang, J., Lee, P.-H., Lin, D.-Y., Wu, C.-C., Jeng, L.-B., Lin, Y.-J., Mok, K.-T., Lee, W.-C., Yeh, H.-Z., Ho, M.-C., Yang, S.-S., Yang, M.-D., Yu, M.-C., Hu, R.-H., Peng, C.-Y., Lai, K.-L., Chang, S. S.-C., & Chen, P.-J. (2014). Adjuvant heparanase inhibitor PI-88 therapy for hepatocellular carcinoma recurrence. World Journal of Gastroenterology, 20, 11384–11393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Cochran, S., Li, C. P., & Ferro, V. (2009). A surface plasmon resonance-based solution affinity assay for heparan sulfate-binding proteins. Glycoconjugate Journal, 26, 577–587.

    Article  CAS  PubMed  Google Scholar 

  76. Fairweather, J. K., Hammond, E., Johnstone, K. D., & Ferro, V. (2008). Synthesis and heparanase inhibitory activity of sulfated mannooligosaccharides related to the antiangiogenic agent PI-88. Bioorganic & Medicinal Chemistry, 16, 699–709.

    Article  CAS  Google Scholar 

  77. Zhou, J., Lv, S., Zhang, D., **a, F., & Hu, W. (2017). Deactivating influence of 3-O-glycosyl substituent on anomeric reactivity of thiomannoside observed in oligomannoside synthesis. The Journal of Organic Chemistry, 82, 2599–2621.

    Article  CAS  PubMed  Google Scholar 

  78. Gu, G., Wei, G., & Du, Y. (2004). Synthesis of a 6V-sulfated mannopentasaccharide analogue related to PI-88. Carbohydrate Research, 339, 1155–1162.

    Article  CAS  PubMed  Google Scholar 

  79. Valerio, S., Pastore, A., Adinolfi, M., & Iadonisi, A. (2008). Sequential one-pot glycosidations catalytically promoted: Unprecedented strategy in oligosaccharide synthesis for the straightforward assemblage of the antitumor PI-88 pentasaccharide. The Journal of Organic Chemistry, 73, 4496–4503.

    Article  CAS  PubMed  Google Scholar 

  80. Namme, R., Mitsugi, T., Takahashi, H., & Ikegami, S. (2005). Synthesis of PI-88 analogue using novel O-glycosidation of exo-methylenesugars. Tetrahedron Letters, 46, 3033–3036.

    Article  CAS  Google Scholar 

  81. Liu, L. G., Johnstone, K. D., Fairweather, J. K., Dredge, K., & Ferro, V. (2009). An improved synthetic route to the potent angiogenesis inhibitor benzyl manα(1→ 3)-manα(1→ 3)-manα(1→ 3)-manα(1→ 2)-man hexadecasulfate. Australian Journal of Chemistry, 62, 546–552.

    Article  CAS  Google Scholar 

  82. Johnstone, K. D., Karoli, T., Liu, L., Dredge, K., Copeman, E., Li, C. P., Davis, K., Hammond, E., Bytheway, I., Kostewicz, E., Chiu, F. C., Shackleford, D. M., Charman, S. A., Charman, W. N., Harenberg, J., Gonda, T. J., & Ferro, V. (2010). Synthesis and biological evaluation of polysulfated oligosaccharide glycosides as inhibitors of angiogenesis and tumor growth. Journal of Medicinal Chemistry, 53, 1686–1699.

    Article  CAS  PubMed  Google Scholar 

  83. Dredge, K., Hammond, E., Handley, P., Gonda, T. J., Smith, M. T., Vincent, C., Brandt, R., Ferro, V., & Bytheway, I. (2011). PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models. British Journal of Cancer, 104, 635–642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hammond, E., Brandt, R., & Dredge, K. (2012). PG545, a heparan sulfate mimetic, reduces heparanase expression in vivo, blocks spontaneous metastases and enhances overall survival in the 4T1 breast carcinoma model. PLoS One, 7, e52175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hammond, E., Handley, P., Dredge, K., & Bytheway, I. (2013). Mechanisms of heparanase inhibition by the heparan sulfate mimetic PG545 and three structural analogues. FEBS Open Bio, 3, 346–351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ostapoff, K. T., Awasthi, N., Cenik, B. K., Hinz, S., Dredge, K., Schwarz, R. E., & Brekken, R. A. (2013). PG545, an angiogenesis and heparanase inhibitor, reduces primary tumor growth and metastasis in experimental pancreatic cancer. Molecular Cancer Therapeutics, 12, 1190–1201.

    Article  CAS  PubMed  Google Scholar 

  87. Boyango, I., Barash, U., Naroditsky, I., Li, J. P., Hammond, E., Ilan, N., & Vlodavsky, I. (2014). Heparanase cooperates with Ras to drive breast and skin tumorigenesis. Cancer Research, 74, 4504–4514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mondal, S., Roy, D., Camacho-Pereira, J., Khurana, A., Chini, E., Yang, L., Baddour, J., Stilles, K., Padmabandu, S., Leung, S., Kalloger, S., Gilks, B., Lowe, V., Dierks, T., Hammond, E., Dredge, K., Nagrath, D., & Shridhar, V. (2015). HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer. Oncotarget, 6, 33705–33719.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Shteingauz, A., Boyango, I., Naroditsky, I., Hammond, E., Gruber, M., Doweck, I., Ilan, N., & Vlodavsky, I. (2015). Heparanase enhances tumor growth and chemoresistance by promoting autophagy. Cancer Research, 75, 3946–3957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Jung, D. B., Yun, M., Kim, E. O., Kim, J., Kim, B., Jung, J. H., Wang, E., Mukhopadhyay, D., Hammond, E., Dredge, K., Shridhar, V., & Kim, S. H. (2015). The heparan sulfate mimetic PG545 interferes with Wnt/beta-catenin signaling and significantly suppresses pancreatic tumorigenesis alone and in combination with gemcitabine. Oncotarget, 6, 4992–5004.

    PubMed  Google Scholar 

  91. Winterhoff, B., Freyer, L., Hammond, E., Giri, S., Mondal, S., Roy, D., Teoman, A., Mullany, S. A., Hoffmann, R., von Bismarck, A., Chien, J., Block, M. S., Millward, M., Bampton, D., Dredge, K., & Shridhar, V. (2015). PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples. European Journal of Cancer, 51, 879–892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Brennan, T. V., Lin, L., Brandstadter, J. D., Rendell, V. R., Dredge, K., Huang, X., & Yang, Y. (2016). Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation. The Journal of Clinical Investigation, 126, 207–219.

    Article  PubMed  Google Scholar 

  93. Kundu, S., **ong, A., Spyrou, A., Wicher, G., Marinescu, V. D., Edqvist, P. D., Zhang, L., Essand, M., Dimberg, A., Smits, A., Ilan, N., Vlodavsky, I., Li, J. P., & Forsberg-Nilsson, K. (2016). Heparanase promotes glioma progression and is inversely correlated with patient survival. Molecular Cancer Research, 14, 1243–1253.

    Article  CAS  PubMed  Google Scholar 

  94. Weissmann, M., Arvatz, G., Horowitz, N., Feld, S., Naroditsky, I., Zhang, Y., Ng, M., Hammond, E., Nevo, E., Vlodavsky, I., & Ilan, N. (2016). Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis. Proceedings of the National Academy of Sciences of the United States of America, 113, 704–709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Singh, P., Blatt, A., Feld, S., Zohar, Y., Saadi, E., Barki-Harrington, L., Hammond, E., Ilan, N., Vlodavsky, I., Chowers, Y., & Half, E. (2017). The heparanase inhibitor PG545 attenuates colon cancer initiation and growth, associating with increased p21 expression. Neoplasia, 19, 175–184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Spyrou, A., Kundu, S., Haseeb, L., Yu, D., Olofsson, T., Dredge, K., Hammond, E., Barash, U., Vlodavsky, I., & Forsberg-Nilsson, K. (2017). Inhibition of heparanase in pediatric brain tumor cells attenuates their proliferation, invasive capacity, and in vivo tumor growth. Molecular Cancer Therapeutics, 16, 1705–1716.

    Article  CAS  PubMed  Google Scholar 

  97. Weissmann, M., Bhattacharya, U., Feld, S., Hammond, E., Ilan, N., & Vlodavsky, I. (2018). The heparanase inhibitor PG545 is a potent anti-lymphoma drug: Mode of action. Matrix Biology, 77, 58–72.

    Google Scholar 

  98. Hammond, E., Haynes, N. M., Cullinane, C., Brennan, T. V., Bampton, D., Handley, P., Karoli, T., Lanksheer, F., Lin, L., Yang, Y., & Dredge, K. (2018). Immunomodulatory activities of pixatimod: Emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors. Journal for Immunotherapy of Cancer, 6, 54.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Ekblad, M., Adamiak, B., Bergstrom, T., Johnstone, K. D., Karoli, T., Liu, L., Ferro, V., & Trybala, E. (2010). A highly lipophilic sulfated tetrasaccharide glycoside related to muparfostat (PI-88) exhibits virucidal activity against herpes simplex virus. Antiviral Research, 86, 196–203.

    Article  CAS  PubMed  Google Scholar 

  100. Said, J., Trybala, E., Andersson, E., Johnstone, K., Liu, L., Wimmer, N., Ferro, V., & Bergstrom, T. (2010). Lipophile-conjugated sulfated oligosaccharides as novel microbicides against HIV-1. Antiviral Research, 86, 286–295.

    Article  CAS  PubMed  Google Scholar 

  101. Lundin, A., Bergstrom, T., Andrighetti-Frohner, C. R., Bendrioua, L., Ferro, V., & Trybala, E. (2012). Potent anti-respiratory syncytial virus activity of a cholestanol-sulfated tetrasaccharide conjugate. Antiviral Research, 93, 101–109.

    Article  CAS  PubMed  Google Scholar 

  102. Supramaniam, A., Liu, X., Ferro, V., & Herrero, L. J. (2018). Prophylactic antiheparanase activity by PG545 is antiviral in vitro and protects against Ross River virus disease in mice. Antimicrobial Agents and Chemotherapy, 62, e01959-17.

    Google Scholar 

  103. Said, J. S., Trybala, E., Görander, S., Ekblad, M., Liljeqvist, J.-Å., Jennische, E., Lange, S., & Bergström, T. (2016). The cholestanol-conjugated sulfated oligosaccharide PG545 disrupts the lipid envelope of herpes simplex virus particles. Antimicrobial Agents and Chemotherapy, 60, 1049–1057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Abassi, Z., Hamoud, S., Hassan, A., Khamaysi, I., Nativ, O., Heyman, S. N., Muhammad, R. S., Ilan, N., Singh, P., Hammond, E., Zaza, G., Lupo, A., Onisto, M., Bellin, G., Masola, V., Vlodavsky, I., & Gambaro, G. (2017). Involvement of heparanase in the pathogenesis of acute kidney injury: Nephroprotective effect of PG545. Oncotarget, 8, 34191–34204.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Muhammad, R. S., Abu-Saleh, N., Kinaneh, S., Agbaria, M., Sabo, E., Grajeda-Iglesias, C., Volkova, N., & Hamoud, S. (2018). Heparanase inhibition attenuates atherosclerosis progression and liver steatosis in E0 mice. Atherosclerosis, 276, 155–162.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia

    Mohit Chhabra & Vito Ferro

  2. Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia

    Mohit Chhabra & Vito Ferro

Authors
  1. Mohit Chhabra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vito Ferro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vito Ferro .

Editor information

Editors and Affiliations

  1. Technion Integrated Cancer Center (TICC) Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Haifa, Israel

    Israel Vlodavsky

  2. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    Ralph D. Sanderson

  3. Technion Integrated Cancer Center (TICC) Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Haifa, Israel

    Neta Ilan

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Chhabra, M., Ferro, V. (2020). PI-88 and Related Heparan Sulfate Mimetics. In: Vlodavsky, I., Sanderson, R., Ilan, N. (eds) Heparanase. Advances in Experimental Medicine and Biology, vol 1221. Springer, Cham. https://doi.org/10.1007/978-3-030-34521-1_19

Download citation

Publish with us

Policies and ethics

Search

Navigation