PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models

Dredge, K, Hammond, E, Handley, P, Gonda, TJ, Smith, MT, Vincent, C, Brandt, R, Ferro, V and 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 5: 635-642. doi:10.1038/bjc.2011.11


Author Dredge, K
Hammond, E
Handley, P
Gonda, TJ
Smith, MT
Vincent, C
Brandt, R
Ferro, V
Bytheway, I
Title PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models
Journal name British Journal of Cancer   Check publisher's open access policy
ISSN 0007-0920
1532-1827
Publication date 2011-02
Sub-type Article (original research)
DOI 10.1038/bjc.2011.11
Open Access Status DOI
Volume 104
Issue 5
Start page 635
End page 642
Total pages 8
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2012
Language eng
Formatted 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.

Conclusion:

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.
© 2011 Cancer Research UK. All rights reserved.

Keyword Heparan sulfate
Angiogenesis
Heparanase
Anti-tumour
Anti-metastatic
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes online publication, 1 February, 2011.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Pharmacy Publications
UQ Diamantina Institute Publications
 
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Created: Sun, 13 Feb 2011, 08:11:55 EST by Professor Maree Smith on behalf of School of Pharmacy