کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2125073 1547219 2010 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours
چکیده انگلیسی

BackgroundNGR-hTNF consists of human tumour necrosis factor-alpha (hTNF-α) fused to the tumour-homing peptide NGR, a ligand of an aminopeptidase N/CD13 isoform, which is overexpressed on endothelial cells of newly formed tumour blood vessels. NGR-TNF showed a biphasic dose–response curve in preclinical models. This study exploring the low-dose range aimed to define safety and optimal biological dose of NGR-hTNF.Patients and methodsPharmacokinetics, plasma biomarkers and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were evaluated at baseline and after each cycle in 16 patients enrolled at four doubling-dose levels (0.2–0.4–0.8–1.6 μg/m2). NGR-hTNF was given intravenously as 1-h infusion every 3 weeks (q3w). Tumour response was assessed q6w.ResultsEighty-three cycles (median, 2; range, 1–29) were administered. Most frequent treatment-related toxicity was grade 1–2 chills (69%), occurring during the first infusions. Only one patient treated at 1.6 μg/m2 had a grade 3 drug-related toxicity (chills and dyspnoea). Both Cmax and AUC increased proportionally with dose. No shedding of soluble TNF-α receptors was observed up to 0.8 μg/m2. Seventy-five percent of DCE-MRI assessed patients showed a decrease over time of Ktrans, which was more pronounced at 0.8 μg/m2. Seven patients (44%) had stable disease for a median time of 5.9 months, including a colon cancer patient who experienced an 18-month progression-free time.ConclusionBased on tolerability, soluble TNF-receptors kinetics, anti-vascular effect and disease control, NGR-hTNF 0.8 μg/m2 will be further developed either as single-agent or with standard chemotherapy.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Cancer - Volume 46, Issue 1, January 2010, Pages 198–206
نویسندگان
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