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

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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.

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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

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Acknowledgments

The authors wish to thank Dr. Philip Andrews for his suggestion of utilizing MAP peptides. All peptides were synthesized by the University of Michigan Protein Structure Facility (Dr. Henriette A. Remmer). The masses of the MAP peptides were verified by Angela Walker, Ph.D of the Michigan Proteome Consortium (Dr. Philip C. Andrews). This research was supported by a Department of the Army IDEA award, W81XWH-06-1-0371, to DLL.

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Authors and Affiliations

  1. Department of Radiation Oncology and Comprehensive Cancer Center, University of Michigan, Room 4424F Medical Science 1, 1301 Catherine Street, Ann Arbor, MI, 48109-5637, USA

    Hongren Yao, Donna M. Veine, Kevin S. Fay, Evan D. Staszewski, Zhao-Zhu Zeng & Donna L. Livant

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  1. Hongren Yao
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  2. Donna M. Veine
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Correspondence to Donna L. Livant.

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Yao, H., Veine, D.M., Fay, K.S. et al. The PHSCN dendrimer as a more potent inhibitor of human breast cancer cell invasion, extravasation, and lung colony formation. Breast Cancer Res Treat 125, 363–375 (2011). https://doi.org/10.1007/s10549-010-0826-y

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