The antiangiogenic effects of tyroservatide on animal models of hepatocellular carcinoma.
OBJECTIVE
To investigate the tumor inhibition and antiangiogenic effects of Tyroservatide (YSV, a small polypeptide composed of 3 amino acids. The chemical structure of YSV is l-tyrosine-l-serine-l-valine, molecular structure is C(17)H(25)N(3)O(6), and molecular weight is 367.40 Da) on human hepatocarcinoma SMMC-7721 transplanted tumors in nude mice.


METHODS
The nude mice bearing xenografts of human hepatocarcinoma SMMC-7721 tumors were daily given intraperitoneal injection of YSV or saline as a control group after the tumor was implanted, total four groups with six mice in each. Calculating tumor volume and measuring tumor weight determined the extent of inhibition of xenografts. The microvessel density (MVD) of tumor tissue was measured by immunohistochemistry. Angiogenesis-related gene expression profile in tumor tissue was assayed by Oligo gene chip and checked by real-time PCR. The Serum concentration of selected factors was measured by ELISA.


RESULTS
YSV at 160, 320, or 640 microg/kg/day inhibited tumor growth in nude mice by 42.62, 60.66, and 27.59%, respectively, which were lower than that of control (P < 0.05). Immunohistochemical staining of the tumor tissue showed the decrease in MVD of tumor tissue after YSV injection. Comparing the 113 genes related with angiogenesis, we found that 18 genes showed the significant difference between the YSV groups and the control; vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) were the leading ones. The mRNA level as well as ELISA of VEGF and IL-8 in YSV group (320 microg/kg/day) were significantly decreased compared with the control (P < 0.05).


CONCLUSIONS
YSV could inhibit the growth of human hepatocarcinoma SMMC-7721 tumor in nude mice, which might attribute to the inhibition of expression of angiogenesis-related factors in mRNA and protein level.
Zhang
Ning
N
Liver Cancer Institute of Fudan University, 200032 Shanghai, People's Republic of China.
Wang
Lu
L
Liang
Ying
Y
Zhao
Yi-Ming
YM
Xue
Qiong
Q
Wu
Wei-Zhong
WZ
Sun
Hui-Chuan
HC
Fan
Jia
J
Tang
Zhao-You
ZY
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D008114:Liver Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D009842:Oligopeptides; D012333:RNA, Messenger; C510683:tripeptide tyroservatide