Tumor regression and curability of preclinical neuroblastoma models by PEGylated SN38 (EZN-2208), a novel topoisomerase I inhibitor.
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Tumor regression and curability of preclinical neuroblastoma models by PEGylated SN38 (EZN-2208), a novel topoisomerase I inhibitor.

Clin Cancer Res. 2010 Aug 11;

Authors: Pastorino F, Loi M, Sapra P, Becherini P, Cilli M, Emionite L, Ribatti D, Greenberger LM, Horak ID, Ponzoni M

PURPOSE: Treatment of neuroblastoma (NB) is successful in less than half of patients with high-risk disease. The anti-tumor activity of a water soluble pegylated SN38 drug conjugate (EZN-2208), was compared with CPT-11 (a pro-drug for SN38) in preclinical models of human NB.EXPERIMENTAL DESIGN: The in vitro cytotoxicity of EZN-2208 was tested by counting trypan blue dye- and annexin-V-positive cells, while its therapeutic efficacy evaluated, in terms of survival, anti-tumor, and anti-angiogenic activities, in subcutaneous luciferase-transfected, pseudometastatic and orthotopic NB animal models.RESULTS: EZN-2208 was about 100-fold more potent than CPT-11 in vitro, by inducing apoptosis/necrosis and p53 expression and by reducing HIF-1/ HIF-2 expression. EZN-2208 gave superior antitumor effects compared to CPT-11 in NB xenografts. EZN-2208 treatment always resulted in lack of tumor detection at the end of trials whereas only small therapeutic effects were observed with CPT-11, as assessed by luciferase assay, tumor size, or even staining histological sections of tumors with antibodies recognizing NB cells and cell proliferation. In NB model resistant to Doxorubicin (D), Cisplatin, Vincristine (V), Fenretinide and Topotecan (T), EZN-2208 induced 100% curability. It also blocked tumor relapsed after TVD-combined treatment. Mechanistic experiments showed statistically significant enhanced TUNEL and Histone H2ax staining and decreased VEGF, CD31, MMP-2 and MMP-9 expression in tumors removed from EZN-2208-treated mice and radiating vessels invading the tumor implanted onto the chorioallantoic membranes. CONCLUSIONS: EZN-2208 should be considered a most promising novel anti-NB agent and ongoing phase I study in pediatric patients should identify the optimal dose for Phase II study.

PMID: 20702613 [PubMed - as supplied by publisher]

Read the complete post at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?tmpl=NoSidebarfile&db=PubMed&cmd=Retrieve&list_uids=20702613&dopt=Abstract

Posted 13 Aug 2010 5:29 AM by pubmed: neuroblastoma
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There is nothing quite as devastating as hearing that word - neuroblastoma. In seconds your world is turned upside down and your normal life is but a distant memory. You are thrust into a confusing world full of fear. Your child has cancer.

We know. We have been there. The Neuroblastoma Foundation is here for you.

Welcome to our website. It is a place for you to find answers and ask questions. One of the primary goals of the Neuroblastoma Foundation is to ensure that parents, patients and health care professionals find the information they need to make the best treatment decisions possible for children and adults affected by neuroblastoma. There is a vast amount of information throughout the internet, much of which is encapsulated in medical jargon that is so complex that even many medical professionals have difficulty in interpreting its meaning. We are here to help to decipher this information and to make sure you (and your oncologist) understand exactly what it means to you. From treatment decisions to side effects we have parents and experts that have experienced it all and are willing to distill it for you.