title: Potent antitumor effect of SN-38-incorporating polymeric micelle, NK012, against malignant glioma.
abstract: Recent published reports on clinical trials of CPT-11 indicate the effectiveness of this compound, a prodrug of SN-38, against malignant glioma in combination with anti-vascular endothelial growth factor antibody. Here, we determined if NK012, and SN-38 incorporating micelle, can be an appropriate formulation for glioblastoma treatment compared with CPT-11. In vitro cytotoxicity was evaluated against several glioma lines with NK012, CPT-11, SN-38, ACNU, CDDP and etoposide. For the in vivo test, a human glioma line (U87MG) transfected with the luciferase gene was inoculated into nude mice brain for pharmacokinetic analysis by fluorescence microscopy and high-performance liquid chromatography after intravenous injection of NK012 and CPT-11. In vivo antitumor activity of NK012 and CPT-11 was evaluated by bioluminescence image and Kaplan-Meier analyses. The growth-inhibitory effects of NK012 were 34- to 444-fold more potent than those of CPT-11. Markedly enhanced and prolonged distribution of free SN-38 in the xenografts was observed after NK012 injection compared with CPT-11. NK012 showed significantly potent antitumor activity against an orthotopic glioblastoma multiforme xenograft and significantly longer survival rate than CPT-11 (p = 0.0014). This implies that NK012 can pass through the blood brain tumor barrier effectively. NK012, which combines enhanced distribution with prolonged sustained release, may be ideal for glioma treatment. Currently, a phase I study of NK012 is almost complete in Japan and the US. The present translational study warrants the clinical phase II study of NK012 in patients with malignant glioma.
authors.affiliation: Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Kuroda
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kuratsu
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yasunaga
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Koga
authors.forename: Yohei
authors.initials: Y
authors.lastname: Saito
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008823:Micelles; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008823:Micelles; D000077146:Irinotecan; D002166:Camptothecin