FTY720: a promising agent for treatment of metastatic hepatocellular carcinoma.
OBJECTIVE
Recurrence after resection and metastasis are common in hepatocellular carcinoma and are associated with poor prognosis. Therefore, effective treatment is urgently needed for improvement of patients' survival. Previously, we reported that FTY720 has an antimetastatic effect on hepatocellular carcinoma cell line through down-regulation of Rac signaling pathway. This study aims to investigate the in vivo antimetastatic potential of FTY720 in an orthotopic nude mice model using metastatic human hepatocellular carcinoma cell lines MHCC-97L (lower metastatic potential) and MHCC-97H (higher metastatic potential).


METHODS
The nude mice bearing liver tumors were randomized into a treatment group and a control group, each with 12 mice. FTY720 was administered at a dosage of 5 or 10 mg/kg via i.p. injection after 7 days of tumor inoculation. Thirty-five days later, the mice were sacrificed for record of intrahepatic and pulmonary metastases.


RESULTS
After 35 days of FTY720 treatment at the dosages of 5 and 10 mg/kg, all 12 mice in the treatment group were alive and well. FTY720 at the dosages of 5 and 10 mg/kg significantly suppressed the tumor volume and intrahepatic and pulmonary metastases in the metastatic nude mice model. FTY720 suppressed intrahepatic and pulmonary metastases by inhibition of Rac expression, which at least in part down-regulated the vascular endothelial growth factor expression and CD34 staining in a dose-dependent manner.


CONCLUSIONS
FTY720 is a promising novel therapeutic drug for treatment of hepatocellular carcinoma metastasis.
Lee
Terence K
TK
Centre for the Study of Liver Disease, Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China.
Man
Kwan
K
Ho
Joanna W
JW
Wang
Xiang Hong
XH
Poon
Ronnie T P
RT
Xu
Yang
Y
Ng
Kevin T
KT
Chu
Alan C
AC
Sun
Chris K
CK
Ng
Irene O
IO
Sun
Hui Chuan
HC
Tang
Zao You
ZY
Xu
Ray
R
Fan
Sheung Tat
ST
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D004195:Disease Models, Animal; D015536:Down-Regulation; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011409:Propylene Glycols / Q000627:therapeutic use*; D013110:Sphingosine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing; D020744:rac GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism
D018952:Antigens, CD34; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D020744:rac GTP-Binding Proteins; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine