Prevention of hepatic tumor growth and metastasis in rats with rapamycin.
- Author:
Wei WANG
1
;
Ge-Liang XU
;
Wei-Dong JIA
;
Zhi-Hua WANG
;
Jian-Sheng LI
;
Jin-Liang MA
;
Yong-Sheng GE
Author Information
- Publication Type:Journal Article
- MeSH: Animals; Carcinoma, Hepatocellular; blood supply; metabolism; pathology; Cyclosporine; pharmacology; therapeutic use; Disease Models, Animal; Hypoxia-Inducible Factor 1, alpha Subunit; genetics; metabolism; Immunohistochemistry; Immunosuppressive Agents; pharmacology; therapeutic use; Liver Neoplasms, Experimental; blood supply; metabolism; pathology; Male; Microvessels; pathology; Neoplasm Metastasis; Neovascularization, Pathologic; RNA, Messenger; metabolism; Random Allocation; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Sirolimus; pharmacology; therapeutic use; Vascular Endothelial Growth Factors; genetics; metabolism
- From: Chinese Journal of Hepatology 2009;17(3):193-197
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVESTo test the effect of rapamycin (RAPA) on hepatic tumor growth and metastasis in Sprague-Dawley (SD) rat model and explore the possible mechanism.
METHODSSD rat hepatocellular carcinoma (HCC) model with metastatic potential was induced by diethylnitrosamine (DEN) and N-nitrosomorpholine (NMOR). 120 SD rats were randomized into four groups 16 weeks after DEN and NMOR treatment, and received 4-week intraperitoneal injection of RAPA (1.5 or 4.5 mg x kg(-1) x d(-1)), CsA (25 mg x kg(-1) x d(-1)) or equal volume of 0.9% saline, respectively. Tumor growth and metastasis were checked after the 4-week treatment. Serum vascular endothelial growth factor (VEGF) was determined by enzyme-linked immunosorbent assay (ELISA). Antiangiogenetic effects were assessed by CD34 immunostaining. The levels of hypoxia-inducible factor 1 alpha (HIF-1 alpha) and VEGF proteins and mRNAs were detected by immunohistochemistry, western blot and reverse transcriptase-polymerase chain reaction (RT-PCR).
RESULTSThe mean liver weight (5.58% +/- 0.42% and 5.69% +/- 0.74%), the metastatic liver nodules (5.12 +/- 0.68 and 5.67 +/-1.12), the metastasis lung nodules (0.43 +/- 0.11 and 0.45 +/- 0.83), and the lung metastasis rate (17.2% and 14.8%) were lower in rats treated with RAPA 1.5 mg x kg(-1) x d(-1) or 4.5 mg x kg(-1) x d(-1) than those in rats treated with saline, which were 10.42% +/- 1.86%, 12.36 +/- 3.45, 1.81 +/- 0.3 and 50.0% respectively (P < 0.01 or P < 0.05). The intratumoral microvessel density (MVD), serum VEGF, and the levels of HIF-1 alpha and VEGF were lower in RAPA-treated rats than those in control rats. However, CsA-treated rats showed an opposite trend compared with the RAPA-treated rats.
CONCLUSIONRAPA can repress the expression of angiogenesis-promoting factors HIF-1 alpha and VEGF, and significantly inhibits the growth and metastasis of HCC.
