Synergistic anti-tumor effect of recombinant chicken fibroblast growth factor receptor-1-mediated anti-angiogenesis and low-dose gemcitabine in a mouse colon adenocarcinoma model.
OBJECTIVE
To evaluate whether the combination of recombinant chicken fibroblast growth factor receptor-1 (FGFR-1) protein vaccine (cFR-1) combined with low-dose gemcitabine would improve anti-tumor efficacy in a mouse CT26 colon adenocarcinoma (CT26) model.


METHODS
The CT26 model was established in BABL/c mice. Seven days after tumor cell injection, mice were randomly divided into four groups: combination therapy, cFR-1 alone, gemcitabine alone, and normal saline groups. Tumor growth, survival rate of tumor-bearing mice, and systemic toxicity were observed. The presence of anti-tumor auto-antibodies was detected by Western blot analysis and enzyme-linked immunospot assay, microvessel density (MVD) of the tumors and tumor cell proliferation were detected by Immunohistochemistry staining, and tumor cell apoptosis was detected by TdT-mediated biotinylated-dUTP nick end label staining.


RESULTS
The combination therapy results in apparent decreases in tumor volume, microvessel density and tumor cell proliferation, and an increase in apoptosis without obvious side-effects as compared with either therapy alone or normal control groups. Also, both auto-antibodies and the antibody-producing B cells against mouse FGFR-1 were detected in mice immunized with cFR-1 vaccine alone or with combination therapy, but not in non-immunized mice. In addition, the deposition of auto-antibodies on endothelial cells from mice immunized with cFR-1 was observed by immunofluorescent stain-ing, but not on endothelial cells from control groups. Synergistic indexes of tumor volume, MVD, cell apoptosis and proliferation in the combination therapy group were 1.71 vs 1.15 vs 1.11 and 1.04, respectively, 31 d after tumor cell injection.


CONCLUSIONS
The combination of cFR-1-mediated anti-angiogenesis and low-dose gemcitabine synergistically enhances the anti-tumor activity without overt toxicity in mice.
Zheng
Shao-Jiang
SJ
Department of Pathology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
Zheng
Shao-Ping
SP
Huang
Feng-Ying
FY
Jiao
Chang-Liang
CL
Wu
Ren-Liang
RL
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D019496:Cancer Vaccines / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016220:Fibroblast Growth Factor 1 / Q000009:adverse effects / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011897:Random Allocation; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D015996:Survival Rate; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D019496:Cancer Vaccines; D011994:Recombinant Proteins; D003841:Deoxycytidine; D016220:Fibroblast Growth Factor 1; D000093542:Gemcitabine