title: Incorporation of the anticancer agent KRN5500 into polymeric micelles diminishes the pulmonary toxicity.
abstract: KRN5500 is a highly active new semi-synthetic water-insoluble anticancer agent. The only mechanism of anticancer activity of KRN5500 described so far is an inhibitory effect on protein synthesis. At the time of writing, a phase I clinical trial is under way at the National Cancer Center Hospital, Tokyo, and at the National Cancer Institute in the USA. Although preclinical data did not indicate lung toxicity, some cases of severe pulmonary disorder were reported in the phase I clinical trials. This study has been conducted to examine whether incorporation of KRN5500 into polymeric micelles (KRN/m) could reduce the toxic effects caused by the current formulation of KRN5500. The in vitro and in vivo antitumor activities of KRN5500 and KRN/m were compared. Pulmonary toxicity of KRN5500 and KRN/m was studied using a bleomycin (BLM)-induced lung injury rat model. In BLM-rats, extensive pulmonary hemorrhage with diapedesis was observed with KRN5500 i.v. bolus injection at the dose of 3 mg/kg, which is equivalent to 21.0 mg/m2 (level 5) of the Japanese phase I trial. However, toxicity was not observed when rats were administered KRN / m at the equivalent dose to KRN5500 in potency. Electron microscopy of the lung treated with KRN5500 showed disruption of the alveolar type II membrane with release of lamellar debris. Furthermore, in vivo, KRN/m showed similar antitumor activity to KRN5500. These results indicate that KRN/m may be useful for reducing the pulmonary toxicity associated with the current formulation of KRN5500, while fully maintaining its antitumor activity.
authors.affiliation: Department of Medicine, National Cancer Center, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mizumura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Teruo
authors.initials: T
authors.lastname: Okano
authors.forename: Takanori
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Fuminori
authors.initials: F
authors.lastname: Moriyasu
authors.forename: Tadao
authors.initials: T
authors.lastname: Kakizoe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001761:Bleomycin / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D005260:Female; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011684:Purine Nucleosides / Q000008:administration & dosage* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D011684:Purine Nucleosides; D001761:Bleomycin; C092296:KRN 5500