Journal
CLINICAL CANCER RESEARCH
Volume 10, Issue 1, Pages 33-42Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-0736-3
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Funding
- NCI NIH HHS [CA91846, U54 CA090810, CA16672] Funding Source: Medline
- NIEHS NIH HHS [T32-ES-07290] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [P30CA016672, U54CA090810, P50CA091846] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [T32ES007290] Funding Source: NIH RePORTER
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Purpose: In a recent study, we presented preliminary evidence for biological activity in a Phase I dose-finding study (15-600 mg/m(2)) of recombinant human endostatin in patients with refractory solid tumors. Here, we conducted additional biomarker analyses to correlate changes in tumor biology with dose. Experimental Design: Excisional tumor biopsies were obtained at baseline and after 56 days of endostatin therapy. Laser scanning cytometry (LSC) was used to quantify biomarker levels in whole tissue sections. Apoptosis in tumor cells (TCs) and tumor-associated endothelial cells (ECs) was quantified by fluorescent three-color anti-CD31/terminal deoxynucleotidyl transferase-mediated nick end labeling staining. Microvessel densities were measured by LSC-guided vessel contouring. Levels of tumor-associated EC BCL-2 and hypoxia-inducible factor 1alpha were determined by immunofluorescence and LSC quantification. The results, including tumor blood flow measured by positron emission tomography, were analyzed using a quadratic polynomial model. Results: Significant increases in EC death and decreases in tumor microvessel density were observed, with maximal effects of endostatin at a dose of 249 mg/m(2) (95% confidence interval, 159-338) and 257 mg/m(2) (95% confidence interval, 183-331), respectively. In contrast, levels of TC death were uniformly low and did not correlate with endostatin dose. Maximal nuclear hypoxia-inducible factor 1alpha and minimal EC Bcl-2 levels were observed at similar to250 mg/m(2), although the changes did not reach statistical significance. Conclusions: The data suggest that endostatin had optimal biological activity at doses similar to250 mg/m(2) in our cohort of patients. Endostatin's failure to induce high levels of TC death may explain its lack of significant clinical activity in this Phase I trial.
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