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

Activated alpha5beta1 integrin is specifically present on tumor cells and the endothelial cells of tumor-associated blood vessels, playing a crucial role in invasion and metastasis. The PHSCN peptide (Ac-PHSCN-NH₂) selectively binds to activated alpha5beta1, effectively blocking invasion in vitro and inhibiting growth, metastasis, and tumor recurrence in preclinical prostate cancer models. In a Phase I clinical trial, systemic administration of Ac-PHSCN-NH₂ was well tolerated, and one-third of treated patients experienced a delay in metastatic disease progression for 4 to 14 months.

We have developed a more potent derivative known as the PHSCN-polylysine dendrimer (Ac-PHSCNGGK-MAP). In vitro invasion assays using serum-free basement membranes demonstrated that the PHSCN dendrimer was 130 to 1900 times more effective than the PHSCN peptide in blocking alpha5beta1-mediated invasion by DU 145 and PC-3 human prostate cancer cells, regardless of whether invasion was triggered by serum or by the Ac-PHSRN-NH₂ peptide under serum-free conditions. Additionally, the PHSCN dendrimer was approximately 800 times more effective than the PHSCN peptide in preventing the extravasation of DU 145 and PC-3 cells in the lungs of athymic mice. Chou-Talalay analysis indicated that the inhibition of both in vitro invasion and in vivo extravasation by the PHSCN dendrimer is highly synergistic.

We observed that many extravasated DU 145 and PC-3 cells developed into metastatic colonies, and a single pretreatment with the PHSCN dendrimer was 100 times more effective than the PHSCN peptide in reducing lung colony formation. Given that many newly diagnosed prostate cancer patients present with locally advanced or metastatic disease, the availability of a well-tolerated, non-toxic systemic therapy like the PHSCN dendrimer—capable of preventing metastatic progression through invasion inhibition—could be highly beneficial.