Clinical Cancer esearch cer Therapy : Preclinical or Regression and Curability of Preclinical Neuroblastoma els by PEGylated SN 38 ( EZN-2208 ) , a Novel R oisomerase I Inhibitor

wnloaded pose: Treatment of neuroblastoma is successful in less than half of patients with high-risk disease. titumor activity of a water soluble pegylated SN38 drug conjugate, EZN-2208, was compared with 1 (a prodrug for SN38) in preclinical models of human neuroblastoma. erimental Design: The in vitro cytotoxicity of EZN-2208 was tested by counting trypan blue dye– nnexin V–positive cells, whereas its therapeutic efficacy was evaluated, in terms of survival, and mor and antiangiogenic activities, in s.c. luciferase-transfected, pseudometastatic, and orthotopic blastoma animal models. ults: EZN-2208 was about 100-fold more potent than CPT-11 in vitro, by inducing apoptosis/ sis and p53 expression and by reducing hypoxia-inducible factor (HIF)-1α/HIF-2α expression. 208 gave superior antitumor effects compared with CPT-11 in neuroblastoma xenografts. EZNtreatment always resulted in lack of tumor detection at the end of trials whereas only small theraeffects were observed with CPT-11, as assessed by luciferase assay or tumor size, or even by staining ogic sections of tumors with antibodies recognizing neuroblastoma cells and cell proliferation. In a blastoma model resistant to doxorubicin, cisplatin, vincristine, fenretinide, and topotecan, EZNinduced 100% curability. It also blocked tumor relapse after topotecan-vincristine-doxorubicin ined treatment. Mechanistic experiments showed statistically significantly enhanced terminal deoxeotidyl transferase–mediated dUTP nick end labeling and Histone H2ax staining as well as ded vascular endothelial growth factor, CD31, matrix metalloproteinase (MMP)-2, and MMP-9 sion in tumors removed from EZN-2208–treated mice and radiating vessels invading the tumor nted onto the chorioallantoic membranes. clusions: EZN-2208 should be considered a most promising novel antineuroblastoma agent. Con An ongoing phase I study in pediatric patients should identify the optimal dose for a phase II study. Clin Cancer Res; 16(19); 4809–21. ©2010 AACR.