title: Eradication of hepatoma and colon cancer in mice with Flt3L gene therapy in combination with 5-FU.
abstract: We developed a recombinant defective adenovirus with an insert of gene encoding extracellular domain of mouse Flt3L (Ad-mFlt3L) under control of cytomegalovirus promoter to investigate the biological efficacy of Flt3L in combination with chemotherapeutical drug, 5-FU, in eliciting an effective anti-cancer immunity in mouse hepatoma and colon cancer model systems. The constructed Ad-mFlt3L efficiently infected hepatoma and colon cancer cells both in vitro and in vivo, leading to a high production of mFlt3L proteins in association with accumulation of DCs, NK cells and lymphocytes in local tumor tissues. Administration of Ad-mFlt3L can protect bone marrow injury caused by 5-Fu and stimulates proliferation and maturation of lymphocytes, APCs and NKs. Intratumoral injection of Ad-mFlt3L followed by an intraperitoneal administration of 5-Fu significantly inhibited tumor growth and cured established tumors. Adenovirus mediated Flt3L gene therapy synergies with chemotherapeutic drug, 5-Fu, in elicitation of long-lasting antitumor immunity. The tumor specific immunity can be adoptively transferred into naïve animals successfully by transfusion of CD3+CD8+ T cells from the treated mice. The data suggests that adenovirus mediated Flt3L gene therapy in combination with 5-Fu chemotherapy may open a new avenue for development of anti-cancer chemogenetherapy.
authors.affiliation: International Joint Cancer Institute and Institute of Hepatobiliary Surgery, The Second Military Medical University, New Library Building 10th-11th Floor, 800 Xiang Yin Road, Shanghai, 200433, People's Republic of China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Hou
authors.forename: Geng
authors.initials: G
authors.lastname: Kou
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Fan
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Weizhu
authors.initials: W
authors.lastname: Qian
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhang
authors.forename: Bohua
authors.initials: B
authors.lastname: Li
authors.forename: Jianxin
authors.initials: J
authors.lastname: Dai
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Birong
authors.initials: B
authors.lastname: Lin
authors.forename: Mengchao
authors.initials: M
authors.lastname: Wu
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D019264:Adoptive Transfer; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D003587:Cytomegalovirus / Q000235:genetics; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006410:Hematopoiesis / Q000187:drug effects; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D013154:Spleen / Q000276:immunology
chemical_list: D000964:Antimetabolites, Antineoplastic; D008565:Membrane Proteins; C084881:flt3 ligand protein; D005472:Fluorouracil