Combination of low-dose gemcitabine and recombinant quail vascular endothelial growth factor receptor-2 as a vaccine induces synergistic antitumor activities.
Vascular endothelial growth factor receptor-2 (VEGFR-2) has been shown to play a major role in inducing the full spectrum of VEGF biological response which is essential for tumor angiogenesis. We have demonstrated that immunotherapy of tumors with a vaccine based on quail homologous VEGFR-2 (qVEGFR) was effective in providing both protective and therapeutic antitumor immunity in several tumor models in mice. The purpose of this study was to determine whether the combination therapy of low-dose gemcitabine with qVEGFR as a vaccine could inhibit tumor growth to a greater extent. To test this concept, H22 hepatoma and Lewis lung carcinoma models were established in BALB/c mice and C57BL/6 mice, respectively. Mice were treated with either qVEGFR as a protein vaccine, gemcitabine, or both agents together. qVEGFR or low-dose chemotherapy treatment individually resulted in tumor inhibition to a certain extent.Remarkably, the combination therapy resulted in synergistic antitumor activity. Histological examination revealed that there was endothelial deposition of immunoglobulins within tumor tissues from mice treated with vaccine or combination therapy, especially intratumor angiogenesis was suppressed more significantly for the combination group. Also, ELISPOT analysis showed that mice treated with either qVEGFR alone or in combination with low-dose chemotherapy produced similar amount of anti-VEGFR antibody-producing B cells, which suggested that low-dose gemcitabine did not suppress the host's immune response, but potentiated the antitumor activity of the qVEGFR vaccine. Furthermore, TUNEL staining demonstrated a significant increase in the number of TUNEL-positive cells in the combination group compared with those of other groups. The observations may provide a new bio-chemotherapeutic approach for cancer.
Hou
Jian-Mei
JM
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, People's Republic of China.
Liu
Ji-Yan
JY
Yang
Li
L
Zhao
Xia
X
Tian
Ling
L
Ding
Zhen-Yu
ZY
Wen
Yan-Jun
YJ
Niu
Ting
T
Xiao
Fei
F
Lou
Yan-Yan
YY
Tan
Guang-Hong
GH
Deng
Hong-Xin
HX
Li
Jiong
J
Yang
Jin-Liang
JL
Mao
Yong-Qiu
YQ
Kan
Bing
B
Wu
Yang
Y
Li
Qiu
Q
Wei
Yu-Quan
YQ
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D020287:In Situ Nick-End Labeling; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011784:Quail; D011897:Random Allocation; D014614:Vaccines, Synthetic / Q000627:therapeutic use; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000627:therapeutic use*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D019496:Cancer Vaccines; D014614:Vaccines, Synthetic; D003841:Deoxycytidine; D040301:Vascular Endothelial Growth Factor Receptor-2; D000093542:Gemcitabine