title: Local delivery system of cytotoxic agents to tumors by focused sonoporation.
abstract: Recently, ultrasound-targeting microbubble destruction has been employed in molecular gene therapy, and a new potent nonviral gene transfer method known as 'sonoporation' has been developed. We investigated the efficiency of sonoporation toward growth inhibition of human gingival squamous carcinoma cell line, Ca9-22, in vitro and in vivo. The cytotoxicity of bleomycin (BLM) was investigated using flow-cytometric analysis and Hoechst's staining in vitro assay systems. We found that the delivery of BLM by sonoporation induced cytotoxic effect toward Ca9-22 cells in vitro. Our in vivo results showed that tumors nearly disappeared in Ca9-22 cell-implanted nude KSN/slc mice treated with a low dose of BLM followed by sonoporation during the 4-week experimental period. Histological analysis revealed that the cytotoxic effect was mainly apoptosis. We previously reported that the cytolethal distending toxin B (cdtB) from Actinobacillus actinomycetemcomitans, a periodontopathic bacterium, is responsible for cell cycle arrest and apoptosis in vitro. Thus, we used sonoporation to transfect a cdtB-expressing plasmid into Ca9-22 cells and examined cell viability in vitro and in vivo. We found that an administration of cdtB-expressing plasmid followed by sonoporation-induced marked growth inhibition of Ca9-22 cells and apoptotic cells were also observed in vitro and in vivo. These findings suggest that local administration of cytotoxic agents with sonoporation is a useful method for molecular cancer therapy.
authors.affiliation: Department of Health Promotion, Division of Infections and Molecular Biology, Kitakyushu, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Iwanaga
authors.forename: K
authors.initials: K
authors.lastname: Tominaga
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: M
authors.initials: M
authors.lastname: Habu
authors.forename: H
authors.initials: H
authors.lastname: Maeda
authors.forename: S
authors.initials: S
authors.lastname: Akifusa
authors.forename: T
authors.initials: T
authors.lastname: Tsujisawa
authors.forename: T
authors.initials: T
authors.lastname: Okinaga
authors.forename: J
authors.initials: J
authors.lastname: Fukuda
authors.forename: T
authors.initials: T
authors.lastname: Nishihara
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001427:Bacterial Toxins / Q000235:genetics*; D001761:Bleomycin / Q000008:administration & dosage*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003603:Cytotoxins / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D005887:Gingival Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D014465:Ultrasonics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D003603:Cytotoxins; C447141:cytolethal distending toxin, Actinobacillus actinomycetemcomitans; D001761:Bleomycin