Eradication of hepatoma and colon cancer in mice with Flt3L gene therapy in combination with 5-FU.
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.
Hou
Sheng
S
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.
Kou
Geng
G
Fan
Xiaoqiang
X
Wang
Hao
H
Qian
Weizhu
W
Zhang
Dapeng
D
Li
Bohua
B
Dai
Jianxin
J
Zhao
Jian
J
Ma
Jing
J
Li
Jing
J
Lin
Birong
B
Wu
Mengchao
M
Guo
Yajun
Y
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
D000964:Antimetabolites, Antineoplastic; D008565:Membrane Proteins; C084881:flt3 ligand protein; D005472:Fluorouracil