Breast Cancer Research and Treatment

, Volume 125, Issue 2, pp 363–375

The PHSCN dendrimer as a more potent inhibitor of human breast cancer cell invasion, extravasation, and lung colony formation

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

DOI: 10.1007/s10549-010-0826-y

Cite this article as:
Yao, H., Veine, D.M., Fay, K.S. et al. Breast Cancer Res Treat (2011) 125: 363. doi:10.1007/s10549-010-0826-y

Abstract

The α5β1 integrin fibronectin receptor is an attractive therapeutic target in breast cancer because it plays key roles in invasion and metastasis. While its inactive form is widely expressed, activated α5β1 occurs only on tumor cells and their associated vasculature. The PHSCN peptide has been shown to bind activated α5β1 preferentially, thereby blocking invasion in vitro, and inhibiting growth, metastasis and tumor recurrence in preclinical models. Moreover in a recent Phase I clinical trial, systemic PHSCN monotherapy was well tolerated, and metastatic disease failed to progress for 4–14 months in 38% of patients receiving it. A significantly more potent PHSCN derivative, the PHSCN–polylysine dendrimer (Ac-PHSCNGGK-MAP) has recently been developed. We report that it is 1280- to 6700-fold more potent than the PHSCN peptide at blocking α5β1 mediated SUM-149 PT and MDA-MB-231 human breast cancer cell invasion of naturally occurring basement membranes in vitro. Chou–Talalay analysis of these data suggested that invasion inhibition by the PHSCN dendrimer was highly synergistic. We also report that, consistent with its enhanced invasion-inhibitory potency, the PHSCN dendrimer is 700- to 1100-fold more effective than the PHSCN peptide at preventing SUM-149 PT and MDA-MB-231 extravasation in the lungs of athymic, nude mice. Our results also show that many extravasated SUM-149 PT and MDA-MB-231 cells go on to develop into metastatic colonies, and that pretreatment with the PHSCN dendrimer is more than 100-fold more effective at reducing lung colony formation. Since many patients newly diagnosed with breast cancer already have locally advanced or metastatic disease, the availability of a well-tolerated, nontoxic systemic therapy that can prevent metastatic progression by blocking invasion could be very beneficial.

Keywords

Breast cancerInvasionExtravasationLung metastasisIntegrin fibronectin receptorMMP-1

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

Standard deviation

SEM

Standard error of the mean

PECAM-1

Platelet endothelial cell adhesion molecule-1

OCT

Optimal cutting temperature

FITC

Fluorescein isothiocyanate

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

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