Quantitative analysis of biomarkers defines an optimal biological dose for recombinant human endostatin in primary human tumors.
نویسندگان
چکیده
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 approximately 250 mg/m(2), although the changes did not reach statistical significance. CONCLUSIONS The data suggest that endostatin had optimal biological activity at doses approximately 250 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.
منابع مشابه
Endostatin inhibits human tongue carcinoma cell invasion and intravasation and blocks the activation of matrix metalloprotease-2, -9, and -13.
Endostatin, a 20-kDa collagen XVIII fragment, inhibits angiogenesis and tumor growth in vivo, but the mechanisms are still unclear. Matrix metalloproteases (MMPs), a family of extracellular and membrane-associated endopeptidases, collectively digest almost all extracellular matrix and basement membrane components, and thus play an important role in tumor progression. We studied the effects of r...
متن کاملAnti-Tumor Effect of a Novel Soluble Recombinant Human Endostatin: Administered as a Single Agent or in Combination with Chemotherapy Agents in Mouse Tumor Models
BACKGROUND Angiogenesis has become an attractive target in cancer treatment. Endostatin is one of the potent anti-angiogenesis agents. Its recombinant form expressed in the yeast system is currently under clinical trials. Endostatin suppresses tumor formation through the inhibition of blood vessel growth. It is anticipated that combined therapy using endostatin and cytotoxic compounds may exert...
متن کاملTissue examination to monitor antiangiogenic therapy: a phase I clinical trial with endostatin.
PURPOSE The purpose of this study was to determine the effect of the angiogenesis inhibitor endostatin on blood vessels in tumors and wound sites. EXPERIMENTAL DESIGN In a Phase I dose escalation study, cancer patients were treated with daily infusions of human recombinant endostatin. Tumor biopsies were obtained prior to and 8 weeks after initiation of treatment. Blood vessel formation in no...
متن کاملA Simplified Process for Purification and Refolding of Recombinant Human Interferon-α2b
Background: Interferon α-2b is a vital biotherapeutic produced through the recombinant DNA technology in E. coli. The recombinant IFN-α2b normally appears as intercellular IBs, which requires intensive refolding and purification steps. Method: Purification of IFN-α2b from solubilized IB was performed using two-phase extraction. To optimize refolding conditions, the effects of pH and different a...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Clinical cancer research : an official journal of the American Association for Cancer Research
دوره 10 1 Pt 1 شماره
صفحات -
تاریخ انتشار 2004