title: Genetically engineered Bifidobacterium longum for tumor-targeting enzyme-prodrug therapy of autochthonous mammary tumors in rats.
abstract: A fundamental obstacle in systemic therapy for cancer patients is the specific targeting of therapy directly to solid tumors. A strain of the domestic bacterium Bifidobacterium longum, which is non-pathogenic and anaerobic, showed selective localization to and proliferation within solid tumors after systemic application. Here, we propose a novel approach to cancer gene therapy in which anaerobic and non-pathogenic bacteria of the genus B. longum are used to achieve tumor-specific gene delivery and enzyme-prodrug therapy. We constructed a plasmid, pBLES100-S-eCD, which included eCD. Transfected B. longum produced CD in hypoxic tumors and achieved tumor site-specific conversion of 5-FC to 5-FU. Furthermore, we demonstrated antitumor efficacy in rat bearing autochthonous mammary tumors injected with the transfected B. longum directly or intravenously. This method was confirmed to be effective for enzyme-prodrug therapy not only by intratumoral injection but also by systemic administration. To estimate the toxicity of this bacterial vector, the systemic immunogenicity was evaluated by ASA reaction and the anaphylactic activity of IgG was evaluated by PCA reaction in guinea pigs. In the ASA reaction, no anaphylaxis symptoms were observed in any immunized guinea pigs injected with transfected B. longum. In the PCA reaction, B. longum/S-eCD specific-PCA-induced antibody was not detected. Thus, we proposed that anaerobic bacteria of the genus B. longum were an attractive and safe tumor-targeting vector and transfected B. longum was a potential anticancer agent that could effectively and specifically treat solid tumors.
authors.affiliation: Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sasaki
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimori
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hamaji
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Hama
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Ito
authors.forename: Jun
authors.initials: J
authors.lastname: Amano
authors.forename: Shun'ichiro
authors.initials: S
authors.lastname: Taniguchi
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D000964:Antimetabolites, Antineoplastic / Q000032:analysis / Q000378:metabolism / Q000627:therapeutic use; D001644:Bifidobacterium / Q000235:genetics* / Q000254:growth & development / Q000276:immunology; D043525:Cytosine Deaminase / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000032:analysis / Q000378:metabolism / Q000627:therapeutic use; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D006168:Guinea Pigs; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000201:enzymology / Q000628:therapy*; D010957:Plasmids / Q000235:genetics; D011355:Prodrugs / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000942:Antigens, Bacterial; D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D043525:Cytosine Deaminase; D005472:Fluorouracil