Quantitative Analysis of Biomarkers Defines an Optimal Biological Dose for Recombinant Human Endostatin in Primary Human Tumors

摘要: Purpose: In a recent study, we presented preliminary evidence for biological activity in Phase I dose-finding study (15–600 mg/m2) of recombinant human endostatin patients with refractory solid tumors. Here, conducted additional biomarker analyses to correlate changes tumor biology dose. Experimental Design: Excisional biopsies were obtained at baseline and after 56 days therapy. Laser scanning cytometry (LSC) was used quantify levels whole tissue sections. Apoptosis cells (TCs) tumor-associated endothelial (ECs) quantified by fluorescent three-color anti-CD31/terminal deoxynucleotidyl transferase-mediated nick end labeling staining. Microvessel densities measured LSC-guided vessel contouring. Levels EC BCL-2 hypoxia-inducible factor 1α determined immunofluorescence LSC quantification. The results, including blood flow positron emission tomography, analyzed using quadratic polynomial model. Results: Significant increases death decreases microvessel density observed, maximal effects dose 249 mg/m2 (95% confidence interval, 159–338) 257 183–331), respectively. contrast, TC uniformly low did not dose. Maximal nuclear minimal Bcl-2 observed ∼250 mg/m2, although the reach statistical significance. Conclusions: data suggest that had optimal doses our cohort patients. Endostatin’s failure induce high may explain its lack significant clinical this trial.