Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors.

Inhibitors of alpha(v)beta(3) and alpha(v)beta(5) integrin have entered clinical trials as antiangiogenic agents for cancer treatment but generally have been unsuccessful. Here we present in vivo evidence that low (nanomolar) concentrations of RGD-mimetic alpha(v)beta(3) and alpha(v)beta(5) inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering alpha(v)beta(3) integrin and vascular endothelial growth factor receptor-2 trafficking, thereby promoting endothelial cell migration to VEGF. The proangiogenic effects of low concentrations of RGD-mimetic integrin inhibitors could compromise their efficacy as anticancer agents and have major implications for the use of RGD-mimetic compounds in humans.

Assessment of the biological and pharmacological effects of the alpha nu beta3 and alpha nu beta5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors.

BACKGROUND: Cilengitide, an antiangiogenic agent that inhibits the binding of integrins alpha(nu)beta(3) and alpha(nu)beta(5) to the extracellular matrix, was studied at two dose levels in cancer patients to determine the optimal biological dose. PATIENTS AND METHODS: The doses of cilengitide were 600 or 1200 mg/m(2) as a 1-h infusion twice weekly every 28 days. A novel dose escalation scheme was utilized that relied upon the biological activity rate. RESULTS: Twenty patients received 50 courses of cilengitide with no dose-limiting toxic effects. The pharmacokinetic (PK) profile revealed a short elimination half-life of 4 h, supporting twice weekly dosing. Of the six soluble angiogenic molecules assessed, only E-selectin increased significantly from baseline. Analysis of tumor microvessel density and gene expression was not informative due to intrapatient tumor heterogeneity. Although several patients with evaluable tumor biopsy pairs did reveal posttreatment increases in tumor and endothelial cell apoptosis, these results did not reach statistical significance due to the aforementioned heterogeneity. CONCLUSIONS: Cilengitide is a well-tolerated antiangiogenic agent. The biomarkers chosen in this study underscore the difficulty in assessing the biological activity of antiangiogenic agents in the absence of validated biological assays.

Combined transductional and transcriptional targeting of melanoma cells by artificial virus-like particles.

BACKGROUND: Artificial virus-like particles (AVPs) represent a novel type of liposomal vector resembling retroviral envelopes. AVPs are serum-resistant and non-toxic and can be endowed with a peptide ligand as a targeting device. The vitronectin receptor, alphavbeta3-integrin, is commonly upregulated on malignant melanoma cells. In the present study we investigated whether AVPs carrying cyclic peptides with an RGD integrin binding motif (RGD-AVPs) are suitable for the specific and efficient transduction of human melanoma cells. METHODS: Plasmid DNA was complexed with low molecular weight non-linear polyethyleneimine and packaged into anionic liposomes. Transduction efficiencies were determined after transient transfection of different cell lines in serum-free medium using green fluorescent protein or luciferase reporter genes. RESULTS: We demonstrated that RGD-AVPs transduced human melanoma cells with high efficiencies of > 60%. Efficient transduction was clearly dependent on the presence of the cyclic RGD ligand and was selective for melanoma cells. The specificity of the vector system could be further enhanced by using the melanocyte-specific tyrosinase promoter to drive transgene expression. CONCLUSION: Our findings suggest that the AVP technology is a useful approach for generating highly efficient and specific non-viral vectors for melanoma targeting, in particular in a setting of combined transductional and transcriptional targeting.