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Cited by 79Neuroblastoma Research and TreatmentsCancer therapeutics and mechanismsGlioma Diagnosis and Treatment

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Tumor Regression and Curability of Preclinical Neuroblastoma Models by PEGylated SN38 (EZN-2208), a Novel Topoisomerase I Inhibitor

Pastorino, Fabio, Loi, Monica, Sapra, Puja, Becherini, Pamela, Cilli, Michele, Emionite, Laura, Ribatti, Domenico, Greenberger, Lee M., Horak, Ivan D., Ponzoni, Mirco·2010·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-10-1354
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Abstract

Purpose Treatment of neuroblastoma is successful in less than half of patients with high-risk disease. The antitumor activity of a water soluble pegylated SN38 drug conjugate, EZN-2208, was compared with CPT-11 (a prodrug for SN38) in preclinical models of human neuroblastoma. Experimental design The in vitro cytotoxicity of EZN-2208 was tested by counting trypan blue dye- and Annexin V-positive cells, whereas its therapeutic efficacy was evaluated, in terms of survival, and antitumor and antiangiogenic activities, in s.c. luciferase-transfected, pseudometastatic, and orthotopic neuroblastoma 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 hypoxia-inducible factor (HIF)-1α/HIF-2α expression. EZN-2208 gave superior antitumor effects compared with CPT-11 in neuroblastoma 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 or tumor size, or even by staining histologic sections of tumors with antibodies recognizing neuroblastoma cells and cell proliferation. In a neuroblastoma model resistant to doxorubicin, cisplatin, vincristine, fenretinide, and topotecan, EZN-2208 induced 100% curability. It also blocked tumor relapse after topotecan-vincristine-doxorubicin combined treatment. Mechanistic experiments showed statistically significantly e…

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  • PEG-SN38 (or EZN-2208) has been shown to downregulate both HIF-1α and HIF-2α in a neuroblastoma model.

    “PEG-SN38 (or EZN-2208) has been shown to downregulate both HIF-1α and HIF-2α in a neuroblastoma model (Pastorino et al., 2010), and a phase I study of PEG-SN38 in patients with neuroblastoma and other solid tumors showed low toxicity and supported further study of this drug in neuroblastoma (Norris et al., 2014).”

    From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Pastorino et al., 2010

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Metadata

Authors
Pastorino, F., Loi, M., Sapra, P., Becherini, P., Cilli, M., Emionite, L., Ribatti, D., Greenberger, L. M., Horak, I. D., & Ponzoni, M.
Affiliations
  • University of Bari Aldo Moro (IT)
  • Pfizer (United States) (US)
  • Ospedale Policlinico San Martino (IT)
  • Authors' Affiliations: 1Experimental Therapies Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, and 2Animal Research Facility, National Cancer Institute, Genoa, Italy; 3Enzon Pharmaceuticals, Piscataway, New Jersey; and 4Department of Human Anatomy, University of Bari, Bari, Italy
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2010-09-29
Volume
16
Issue
19
Pages
4809-4821
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-10-1354
OpenAlex
W2137425495
Cited by
79
References
54
Citations by year
2026: 2 · 2025: 1 · 2024: 3 · 2023: 8 · 2022: 4 · 2021: 4 · 2020: 5 · 2019: 2 · 2018: 7 · 2017: 3 · 2016: 6 · 2015: 7 · 2014: 5 · 2013: 7 · 2012: 4
FWCI
4.19
Type
journal article
Language
en
Open access
closed
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
Funders
  • Fondazione Italiana per la Lotta al Neuroblastoma
  • Associazione Italiana per la Ricerca sul Cancro
Topics
  • Health Sciences › Medicine › Oncology › Neuroblastoma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
  • Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
Keywords
neuroblastoma, topoisomerase I inhibitor, irinotecan, tumor regression, curability, anticancer activity, antiangiogenic activity, apoptosis, p53, HIF-1α, HIF-2α, tumor recurrence, vascular endothelial growth factor, MMP-2, MMP-9, CD31
MeSH terms
Irinotecan, Animals, Antineoplastic Agents, Camptothecin, Disease Models, Animal, DNA Topoisomerases, Type I, Drug Screening Assays, Antitumor, Female, Humans, Mice, Nude, Neoplasms, Experimental, Neovascularization, Pathologic, Neuroblastoma, Polyethylene Glycols, Survival Rate, Apoptosis, Cell Line, Tumor, Cell Proliferation, Mice, Topoisomerase I Inhibitors

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