Clinical & Experimental Metastasis

, Volume 27, Issue 3, pp 173–184

Increased potency of the PHSCN dendrimer as an inhibitor of human prostate cancer cell invasion, extravasation, and lung colony formation

  • Hongren Yao
  • Donna M. Veine
  • Zhao-Zhu Zeng
  • Kevin S. Fay
  • Evan D. Staszewski
  • Donna L. Livant
Research Paper

DOI: 10.1007/s10585-010-9316-1

Cite this article as:
Yao, H., Veine, D.M., Zeng, Z. et al. Clin Exp Metastasis (2010) 27: 173. doi:10.1007/s10585-010-9316-1

Abstract

Activated α5β1 integrin occurs specifically on tumor cells and on endothelial cells of tumor-associated vasculature, and plays a key role in invasion and metastasis. The PHSCN peptide (Ac-PHSCN-NH2) preferentially binds activated α5β1, to block invasion in vitro, and inhibit growth, metastasis and tumor recurrence in preclinical models of prostate cancer. In Phase I clinical trial, systemic Ac-PHSCN-NH2 monotherapy was well tolerated, and metastatic disease progression was prevented for 4–14 months in one-third of treated patients. We have developed a significantly more potent derivative, the PHSCN-polylysine dendrimer (Ac-PHSCNGGK-MAP). Using in vitro invasion assays with naturally serum-free basement membranes, we observed that the PHSCN dendrimer was 130- to 1900-fold more potent than the PHSCN peptide at blocking α5β1-mediated invasion by DU 145 and PC-3 human prostate cancer cells, whether invasion was induced by serum, or by the Ac-PHSRN-NH2 peptide, under serum-free conditions. The PHSCN dendrimer was also approximately 800 times more effective than PHSCN peptide at preventing DU 145 and PC-3 extravasation in the lungs of athymic mice. Chou-Talalay analysis suggested that inhibition of both invasion in vitro and extravasation in vivo by the PHSCN dendrimer are highly synergistic. We found that many extravasated DU 145 and PC-3 cells go onto develop into metastatic colonies, and that a single pretreatment with the PHSCN dendrimer was 100-fold more affective than the PHSCN peptide at reducing lung colony formation. Since many patients newly diagnosed with prostate cancer already have locally advanced or metastatic disease, the availability of a well-tolerated, nontoxic systemic therapy, like the PHSCN dendrimer, which prevents metastatic progression by inhibiting invasion, could be very beneficial.

Keywords

Prostate cancerInvasionExtravasationLung metastasisIntegrin fibronectin receptor

Abbreviations

MAP

Multiantigenic peptide

SF

Serum-free

FBS

Fetal bovine serum

CI

Combination index

DRI

Dose reduction index

Ova

Ovalbumin

EDC

1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride

HBSS

Hanks buffered salt solution

MALDI

Matrix assisted laser desorption/ionization

MMP-1

Matrix metalloproteinase-1

ELISA

Enzyme-linked immunoabsorbant assay

DiI

1,1′-dilinoleyl-3,3,3′3′-tetramethylindocarbocyanine perchlorate

MAb

Monoclonal antibody

SD

First standard deviation

SEM

Standard error of mean

PECAM-1

Platelet endothelial cell adhesion molecule-1

O.C.T.

Optimal cutting temperature

FITC

Fluorescein isothiocyanate

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Hongren Yao
    • 1
  • Donna M. Veine
    • 1
  • Zhao-Zhu Zeng
    • 1
  • Kevin S. Fay
    • 1
  • Evan D. Staszewski
    • 1
  • Donna L. Livant
    • 1
  1. 1.Department of Radiation OncologyUniversity of MichiganAnn ArborUSA