title: PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models.
abstract: BACKGROUND
  PG545 is a heparan sulfate (HS) mimetic that inhibits tumour angiogenesis by sequestering angiogenic growth factors in the extracellular matrix (ECM), thus limiting subsequent binding to receptors. Importantly, PG545 also inhibits heparanase, the only endoglycosidase which cleaves HS chains in the ECM. The aim of the study was to assess PG545 in various solid tumour and metastasis models.
  
  
  METHODS
  The anti-angiogenic, anti-tumour and anti-metastatic properties of PG545 were assessed using in vivo angiogenesis, solid tumour and metastasis models. Pharmacokinetic (PK) data were also generated in tumour-bearing mice to gain an understanding of optimal dosing schedules and regimens.
  
  
  RESULTS
  PG545 was shown to inhibit angiogenesis in vivo and induce anti-tumour or anti-metastatic effects in murine models of breast, prostate, liver, lung, colon, head and neck cancers and melanoma. Enhanced anti-tumour activity was also noted when used in combination with sorafenib in a liver cancer model. PK data revealed that the half-life of PG545 was relatively long, with pharmacologically relevant concentrations of radiolabeled PG545 observed in liver tumours.
  
  
  CONCLUSIONS
  PG545 is a new anti-angiogenic clinical candidate for cancer therapy. The anti-metastatic property of PG545, likely due to the inhibition of heparanase, may prove to be a critical attribute as the compound enters phase I clinical trials.
authors.affiliation: Progen Pharmaceuticals Ltd, 16 Benson Street, Toowong, Brisbane, QLD 4066, Australia. keithd@progen-pharma.com
authors.forename: K
authors.initials: K
authors.lastname: Dredge
authors.forename: E
authors.initials: E
authors.lastname: Hammond
authors.forename: P
authors.initials: P
authors.lastname: Handley
authors.forename: T J
authors.initials: TJ
authors.lastname: Gonda
authors.forename: M T
authors.initials: MT
authors.lastname: Smith
authors.forename: C
authors.initials: C
authors.lastname: Vincent
authors.forename: R
authors.initials: R
authors.lastname: Brandt
authors.forename: V
authors.initials: V
authors.lastname: Ferro
authors.forename: I
authors.initials: I
authors.lastname: Bytheway
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005966:Glucuronidase / Q000494:pharmacology / Q000627:therapeutic use*; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D012503:Saponins / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D000099175:Heparanase
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D005966:Glucuronidase; D012503:Saponins; D000099175:Heparanase; C557899:PG 545