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

• Published in: Clinical & experimental metastasis Vol. 27; no. 3; pp. 173 - 184
• Main Authors: Yao, Hongren, Veine, Donna M, Zeng, Zhao-Zhu, Fay, Kevin S, Staszewski, Evan D, Livant, Donna L
• Format: Journal Article
• Language: English
• Published: Dordrecht Dordrecht : Springer Netherlands 01.03.2010; Springer Netherlands; Springer Nature B.V
• Subjects: Angiogenesis Inhibitors - metabolism; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Dendrimers - metabolism; Dendrimers - pharmacology; Dendrimers - therapeutic use; Disease Progression; Hematology; Humans; Inhibitory Concentration 50; Integrin alpha5beta1 - antagonists & inhibitors; Integrin alpha5beta1 - metabolism; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Male; Mice; Mice, Nude; Neoplasm Invasiveness - pathology; Neoplasm Invasiveness - prevention & control; Oligopeptides - metabolism; Oligopeptides - pharmacology; Oligopeptides - therapeutic use; Oncology; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Research Paper; Surgical Oncology; Tumor Cells, Cultured; Integrin fibronectin receptor; Lung metastasis; Prostate cancer; Extravasation; Invasion
• ISSN: 0262-0898; 1573-7276
• DOI: 10.1007/s10585-010-9316-1

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.