Anti-hepatoma effect of arsenic trioxide on experimental liver cancer induced by 2-acetamidofluorene in rats.
OBJECTIVE
To study the anti-hepatoma efficiency of arsenic trioxide (As(2)O(3)) in the treatment of experimental rat hepatocellular carcinoma (HCC) induced by 2-acetamidofluorene (2-FAA) and to elucidate the possible mechanisms.


METHODS
SD rats (2 mo old) had been fed with 2-FAA for 8 wk to induce HCC, and then they were treated with As(2)O(3) or matrine. On d 29, the rats were killed and the liver was weighed and liver tumors were counted. The histological changes of liver tissue were observed under microscope, and the cellular dynamic parameters were studied by flow cytometry. Immunohistochemistry (two-step method) was used to observe the expression of vascular endothelial growth factor (VEGF) and micro-vessel density (MVD) on consecutive sections. The pathological parameters were also analyzed, the levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBi), and direct bilirubin (DBi).


RESULTS
The number of liver tumors decreased significantly in groups treated with As(2)O(3), especially in medium-dose (1 mg/kg) group (t = 2.80, P<0.01). As(2)O(3) caused HCC cell death via apoptosis; necrosis was seen and apoptosis was common when the dose was 1 mg/kg. Proliferation index decreased sharply in medium-dose (1 mg/kg) group (7.87+/-4.11 vs 24.46+/-6.49, t = 2087, P<0.01), but not in 0.2 mg/kg group. However, S-phase fraction decreased dramatically in both groups, it reached the bottom level only when the dose was 1 mg/kg compared with control (0.40+/-0.13 vs 3.01+/-0.51, t = 2.97, P<0.01), and it was obviously accompanied with accumulation of cells in G(0)/G(1) (G(0)/G(1) restriction). The expressions of VEGF and MVD in medium-dose (1 mg/kg) group were significantly lower than normal saline group (0.63+/-0.74 vs 2.44+/-0.88, P<0.05; 15.75+/-3.99 vs 47.44+/-13.41, t = 2.80, P<0.01). Compared with normal saline group, medium- and low-dose groups As(2)O(3) and matrine lowered the levels of ALT in serum (61.46+/-9.46, 63.75+/-20.40, 61.18+/-13.00 vs 108.98+/-29.86, t = 2.14, P<0.05), but had no effect on the level of serum AST, TBi, and DBi.


CONCLUSIONS
As(2)O(3) had inhibitory effect on growth of experimental HCC in rats induced by 2-FAA, but had no obvious effect on normal hepatic cells. The mechanisms may involve decrease of cell division, accumulation of cells in G(0)/G(1) phase, apoptosis of tumor cells, and inhibitory effect on angiogenesis through blocking VEGF.
Tan
Bing
B
Department of Digestive Medicine, Affiliated Hospital of Nantong Medical College, Nantong 226001, Jiangsu Province, China.
Huang
Jie-Fei
JF
Wei
Qun
Q
Zhang
Hong
H
Ni
Run-Zhou
RZ
D015073:2-Acetylaminofluorene / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000627:therapeutic use*; D002273:Carcinogens / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010087:Oxides / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000970:Antineoplastic Agents; D001152:Arsenicals; D002273:Carcinogens; D010087:Oxides; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D015073:2-Acetylaminofluorene; D000077237:Arsenic Trioxide