کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2754994 1149803 2013 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Preclinical and Clinical Evaluation of Forodesine in Pediatric and Adult B-Cell Acute Lymphoblastic Leukemia
موضوعات مرتبط
علوم پزشکی و سلامت پزشکی و دندانپزشکی بیهوشی و پزشکی درد
پیش نمایش صفحه اول مقاله
Preclinical and Clinical Evaluation of Forodesine in Pediatric and Adult B-Cell Acute Lymphoblastic Leukemia
چکیده انگلیسی

BackgroundThe discovery that purine nucleoside phosphorylase (PNP) deficiency leads to T-cell lymphopenia was the basis for introducing PNP inhibitors for T-cell leukemias. Forodesine is an orally bioavailable PNP inhibitor with picomolar potency. Because T lymphoblasts and indolent chronic lymphocytic leukemia (CLL) B cells inherently elicit favorable pharmacokinetics to accumulate deoxyguanosine triphosphate (dGTP), forodesine demonstrated promising activity in preclinical and clinical settings for patients with T-cell acute lymphoblastic leukemia (T-ALL) and B-cell CLL (B-CLL). However, the use of forodesine in B-cell ALL (B-ALL) is unknown.Patients and MethodsLeukemic blasts obtained from pediatric patients with de novo B-ALL (n = 10) were incubated with forodesine and deoxyguanosine (dGuo), and the biological end points of apoptosis, intracellular dGTP accumulation, and inhibition of RNA and DNA synthesis were measured. Additionally, adult patients with B-ALL (n = 2) were intravenously infused with 80 mg/m2/d daily for 5 days. After therapy, clinical response, toxicity, laboratory biomarkers including PNP enzyme inhibition, and plasma forodesine, dGuo, and intracellular dGTP levels were analyzed.ResultsOur in vitro investigations demonstrated that forodesine treatment inhibited proliferation and induced modest apoptosis in de novo B-ALL lymphoblasts. There was time-dependent accumulation of dGTP and inhibition of RNA and DNA synthesis. During therapy, neither patient achieved a complete response (CR), but there was disease stabilization for several weeks in both patients. There was significant maintained inhibition of PNP enzyme in red blood cells, accumulation of forodesine and dGuo in plasma, and intracellular dGTP accumulation in both patients.ConclusionOur preclinical and clinical investigations suggest that forodesine has activity in B-ALL. However, it needs to be either infused with dGuo or combined with established chemotherapeutic agents based on mechanistic rationale.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Clinical Lymphoma Myeloma and Leukemia - Volume 13, Issue 4, August 2013, Pages 458–466
نویسندگان
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