PI-88 and Novel Heparan Sulfate Mimetics Inhibit Angiogenesis

Vito Ferro; Keith Dredge; Ligong Liu; Edward Hammond; Ian Bytheway; Caiping Li; Ken Johnstone; Tomislav Karoli; Kat Davis; Elizabeth Copeman; Anand Gautam

doi:10.1055/s-2007-982088

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2007; 33(5): 557-568
DOI: 10.1055/s-2007-982088

PI-88 and Novel Heparan Sulfate Mimetics Inhibit Angiogenesis

Vito Ferro¹ , Keith Dredge¹ , Ligong Liu¹ , Edward Hammond¹ , Ian Bytheway¹ , Caiping Li¹ , Ken Johnstone¹ , Tomislav Karoli¹ , Kat Davis¹ , Elizabeth Copeman¹ , Anand Gautam¹

¹Drug Design Group, Progen, Pharmaceuticals Ltd., Toowong Queensland, Australia

Abstract

ABSTRACT

The heparan sulfate (HS) mimetic PI-88 is a promising inhibitor of tumor growth and metastasis expected to commence phase III clinical evaluation in 2007 as an adjuvant therapy for postresection hepatocellular carcinoma. Its anticancer properties are attributed to inhibition of angiogenesis via antagonism of the interactions of angiogenic growth factors and their receptors with HS. It is also a potent inhibitor of heparanase, an enzyme that plays a key role in both metastasis and angiogenesis. A series of PI-88 analogs have been prepared with enhanced chemical and biological properties. The new compounds consist of single, defined oligosaccharides with specific modifications designed to improve their pharmacokinetic properties. These analogs all inhibit heparanase and bind to the angiogenic fibroblast growth factor 1 (FGF-1), FGF-2, and vascular endothelial growth factor with similar affinity to PI-88. However, compared with PI-88, some of the newly designed compounds are more potent inhibitors of growth factor-induced endothelial cell proliferation and of endothelial tube formation on Matrigel. Representative compounds were also tested for antiangiogenic activity in vivo and were found to reduce significantly blood vessel formation. Moreover, the pharmacokinetic profile of several analogs was also improved, as evidenced primarily by lower clearance in comparison with PI-88. The current data support the development of HS mimetics as potent antiangiogenic anticancer agents.

KEYWORDS

PI-88 - heparan sulfate mimetics - heparanase inhibitors - angiogenesis inhibitors - sulfated oligosaccharides

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References

REFERENCES

1 Carmeliet P, Jain R K. Angiogenesis in cancer and other diseases. Nature. 2000; 407 249-257
2 Bergers G, Benjamin L E. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003; 3 401-410
3 Herbst R S. Therapeutic options to target angiogenesis in human malignancies. Expert Opin Emerg Drugs. 2006; 11 635-650
4 Sasisekharan R, Shriver Z, Venkataraman G, Narayanasami U. Roles of heparan-sulphate glycosaminoglycans in cancer. Nat Rev Cancer. 2002; 2 521-528
5 Wegrowski Y, Maquart F X. Involvement of stromal proteoglycans in tumour progression. Crit Rev Oncol Hematol. 2004; 49 259-268
6 Lever R, Page C P. Novel drug development opportunities for heparin. Nat Rev Drug Discov. 2002; 1 140-148
7 Presta M, Leali D, Stabile H et al.. Heparin derivatives as angiogenesis inhibitors. Curr Pharm Des. 2003; 9 553-566
8 Parish C R, Freeman C, Brown K J, Francis D J, Cowden W B. Identification of sulfated oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity. Cancer Res. 1999; 59 3433-3441
9 Cochran S, Li C, Fairweather J K et al.. Probing the interactions of phosphosulfomannans with angiogenic growth factors by surface plasmon resonance. J Med Chem. 2003; 46 4601-4608
10 Khachigian L M, Parish C R. Phosphomannopentaose sulfate (PI-88): heparan sulfate mimetic with clinical potential in multiple vascular pathologies. Cardiovasc Drug Rev. 2004; 22 1-6
11 Hazel S J. A novel early chorioallantoic membrane assay demonstrates quantitative and qualitative changes caused by antiangiogenic substances. J Lab Clin Med. 2003; 141 217-228
12 Joyce J A, Freeman C, Meyer-Morse N, Parish C R, Hanahan D. A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer. Oncogene. 2005; 24 4037-4051 , [Corrigenda in Oncogene 2005;24:4163]
13 Ilan N, Elkin M, Vlodavsky I. Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis. Int J Biochem Cell Biol. 2006; 38 2018-2039
14 Hammond E, Bytheway I, Ferro V. Heparanase as a target for anticancer therapeutics: new developments and future prospects. In: Delehedde M, Lortat-Jacob H New Developments in Therapeutic Glycomics. Kerala, India: Research Signpost 2006: 251-282
15 Demir M, Iqbal O, Hoppensteadt D A et al.. Anticoagulant and antiprotease profiles of a novel natural heparinomimetic mannopentaose phosphate sulfate (PI-88). Clin Appl Thromb Hemost. 2001; 7 131-140
16 Yu G, Gunay N S, Linhardt R J et al.. Preparation and anticoagulant activity of the phosphosulfomannan PI-88. Eur J Med Chem. 2002; 37 783-791
17 Ferro V, Fewings K, Palermo M C, Li C. Large-scale preparation of the oligosaccharide phosphate fraction of Pichia holstii NRRL Y-2448 phosphomannan for use in the manufacture of PI-88. Carbohydr Res. 2001; 332 183-189
18 Ferro V, Li C, Fewings K et al.. Determination of the composition of the oligosaccharide phosphate fraction of Pichia (Hansenula) holstii NRRL Y-2448 phosphomannan by capillary electrophoresis and HPLC. Carbohydr Res. 2002; 337 139-146
19 Iversen P O, Sorensen D R, Benestad H B. Inhibitors of angiogenesis selectively reduce the malignant cell load in rodent models of human myeloid leukemias. Leukemia. 2002; 16 376-381
20 Rosenthal M A, Rischin D, McArthur G et al.. Treatment with the novel anti-angiogenic agent PI-88 is associated with immune-mediated thrombocytopenia. Ann Oncol. 2002; 13 770-776
21 Basche M, Gustafson D L, Holden S N et al.. A phase I biological and pharmacologic study of the heparanase inhibitor PI-88 in patients with advanced solid tumors. Clin Cancer Res. 2006; 12 5471-5480
22 Gautam A M, Ferro V, Wilson E A, Freeman C, Parish C. PI-88, a heparanase inhibitor showing promising evidence of patient benefit in phase II clinical trials. Paper presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications November 14-18, 2005 Philadelphia, PA
23 Chen P, Chang S, Lai C, Gautam A, Wilson E. Use of PI-88, a novel heparanase inhibitor, as adjuvant therapy in post-resection hepatocellular carcinoma: a large randomised phase II clinical trial. Paper presented at: Shanghai-Hong Kong International Liver Congress March 25-28, 2006 Shanghai, China
24 Poon R T, Fan S T, Lo C M et al.. Long-term prognosis after resection of hepatocellular carcinoma associated with hepatitis B-related cirrhosis. J Clin Oncol. 2000; 18 1094-1101
25 Karoli T, Liu L, Fairweather J K et al.. Synthesis, biological activity, and preliminary pharmacokinetic evaluation of analogues of a phosphosulfomannan angiogenesis inhibitor (PI-88). J Med Chem. 2005; 48 8229-8236
26 Nyberg K, Ekblad M, Bergström T et al.. The low molecular weight heparan sulfate-mimetic, PI-88, inhibits cell-to-cell spread of herpes simplex virus. Antiviral Res. 2004; 63 15-24
27 Wood J M, Bold G, Buchdunger E et al.. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 2000; 60 2178-2189
28 McCarty M F, Baker C H, Bucana C D, Fidler I J. Quantitative and qualitative in vivo angiogenesis assay. Int J Oncol. 2002; 21 5-10

Vito FerroPh.D.

Drug Design Group, Progen, Pharmaceuticals Ltd.

P.O. Box 2403, Toowong Qld 4066, Australia

Email: vito.ferro@progen-pharma.com.au