title: Hyperthermia-enhanced tumor accumulation and antitumor efficacy of a doxorubicin-conjugate with a novel macromolecular carrier system in mice with non-small cell lung cancer.
abstract: A novel drug delivery system (DDS) compound was formed by binding doxorubicin hydrochloride (DXR) to the macromolecular carrier carboxymethyldextran polyalcohol (CM-Dex-PA) via the peptidyl spacer (GGFG: Gly-Gly-Phe-Gly). Its use in a murine tumor model confirmed that the DDS (CM-Dex-PA-GGFG-DXR) was retained in the blood and distributed in tumor tissue. The combined use of hyperthermia (HT: 41-42 degrees C for 40 min) and DXR-conjugate (5, 10 or 20 mg/kg i.v.) on tumor accumulation and efficacy was investigated in a murine model of non-small cell lung cancer. Tumor size was measured and the tumor inhibition rate (IR) was calculated. The mean tumor concentration of conjugated DXR in the DXR-conjugate group was 9.40 microg/g compared with 19.04 microg/g in the DXR-conjugate + HT group (p=0.0008). The antitumor efficacy of the DXR-conjugate was significantly enhanced in the groups receiving the combination therapy (p=0.0039, p=0.0250). Significant differences were found between the groups given DXR and those given DXR-conjugate (p=0.0492, p=0.0104). The results demonstrate that the antitumor efficacy of DXR-conjugate is significantly superior to that of DXR alone and the combined use of DXR-conjugate and HT increases the drug's concentration in the tumor, with significant enhancement of antitumor efficacy.
authors.affiliation: Division of General Thoracic Surgery, Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan. t.oyama@ashikaga.jrc.or.jp
authors.forename: Takahiko
authors.initials: T
authors.lastname: Oyama
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kawamura
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Abiko
authors.forename: Yotaro
authors.initials: Y
authors.lastname: Izumi
authors.forename: Masazumi
authors.initials: M
authors.lastname: Watanabe
authors.forename: Eiji
authors.initials: E
authors.lastname: Kumazawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kuga
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Shiose
authors.forename: Koichi
authors.initials: K
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000628:therapy*; D003911:Dextrans / Q000008:administration & dosage / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006979:Hyperthermia, Induced; D008175:Lung Neoplasms / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D003911:Dextrans; D004337:Drug Carriers; D004317:Doxorubicin; C014392:carboxymethyl dextran