[Antitumor effects of interferon-gamma-inducible protein 10 combined with gemcitabine].
OBJECTIVE
Interferon-gamma-inducible protein 10 (IP-10), a member of alpha-chemoattractant family, is an inhibitor of tumor angiogenesis. Chemotherapy combined with antiangiogenic therapy has synergistic effects. This study was designed to explore antitumor effect of IP-10 combined with gemcitabine in tumor-bearing mice.


METHODS
pBLAST-IP-10 was transferred into E.coli to prepare and purify plasmid IP-10. Hepatocarcinoma H22 model was established in BALB/c miceu Lewis lung cancer LL/2 model was established in C57BL/6 mice. The mice were divided into 4 groups, and treated with IP-10, gemcitabine, IP-10 plus gemcitabine, and normal saline (control), respectively. Protein level of IP-10 in serum was detected by ELISA. Survival rate of mice, tumor volume, and side effects of treatment were observed. Microvessel density (MVD) of tumor tissue was detected by immunohistochemistry. Apoptosis of tumor cells was detected by TUNEL method.


RESULTS
After treatment of IP-10, IP-10 protein reached the peak level of (16.8+/-3.6) ng/ml at the 14th day, and remained a high level of (14.0+/-2.1) ng/ml at the 35th day. Compared with the controls, tumor volume of mice in the combination therapy group had significant regression, or disappeared. Nine weeks after inoculation of tumor cells, survival rate of mice was significantly higher in combination group than in IP-10, gemcitabine, and control groups (90% vs. 55%, 0%, and 0%, P < 0.005). No obvious side effects were observed. MVD of tumor tissues was significantly lower in combination group than in IP-10, gemcitabine, and control groups (15.8+/-2.4 vs. 45.6+/-2.0, 50.2+/-3.5, and 51.3+/-3.0, P < 0.01). At the 35th day after inoculation of tumor cells, apoptosis index was significantly higher in combination group than in IP-10, gemcitabine, and control groups (85.5+/-10.2 vs. 21.4+/-5.5, 8.4+/-2.0, 4.2+/-0.7, P < 0.01).


CONCLUSIONS
Therapy of IP-10 combined with gemcitabine has significantly synergistic antitumor effect compared with IP-10 or gemcitabine alone.
Mei
Kai
K
MOE Key Laboratory of Biotherapy of Human Diseases, Biotherapy Research Center of Cancer, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China.
Tian
Ling
L
Wei
Yu-Quan
YQ
Li
Jiong
J
Wen
Yan-Jun
YJ
Kan
Bing
B
Deng
Hong-Xin
HX
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000473:pathology*; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D004926:Escherichia coli / Q000235:genetics; D005260:Female; D008114:Liver Neoplasms, Experimental / Q000097:blood / Q000098:blood supply / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000473:pathology; D009389:Neovascularization, Pathologic; D010957:Plasmids; D014162:Transfection; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D003841:Deoxycytidine; D000093542:Gemcitabine