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

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 cancer Invasion Extravasation Lung metastasis Integrin 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

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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

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