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Comparison of angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockade for the prevention of premalignant changes
Update time:2012-02-29 15:55:00   【 Font: Large  Medium Small

Aim: We investigate and compare the possible antitumor activity of clinically used angiotensin converting enzyme(ACE) inhibitors; captopril, perindopril and angiotensin II type 1 receptor (AT1R) blocker, losartan against hepatocarcinogenesis initiated by diethylnitrosoamines (DENA) and promoted by carbon tetrachloride (CCl4).Main methods: Diethylnitrosamine (DENA) (200 mg/kg i.p.) initiated and carbon tetrachloride (CCl4) (2 ml/kg i.p.) promoted hepatocarcinogenesis in male Wistar rats after 8 weeks.

Results: Hepatocarcinogenesis was manifested biochemically by elevation of serum hepatic tumor markers tested;α-feto protein (AFP) and carcinoembryonic antigen (CEA). In addition, hepatic carcinogenesiswas further confirmed by a significant increase in hepatic tissue growth factors; vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF). Moreover a marked increase in matrix metalloproteinase-2 and hydroxyproline content were also observed. Hepatocarcinogenesis was further confirmed by a significant decrease in hepatic endostatin and metallothonein level.

Key findings: Long-termadministration of the selected drugs for 2 weeks before and throughout the experimental period produced a significant protection against hepatic carcinogenesis. The present results claimed that different doses of the selected drugs succeeded in normalization of serum tumor markers. Furthermore, the drugs reduced the elevated level in the hepatic growth factors, matrix metalloproteinase-2 and hydroxyproline induced by the hepatocarcinogen. Moreover, the ameliorationwas also accompanied by augmentation of hepatic content of metallothionein and endostatin. Histopathological examination of liver tissues of rats treated with DENA–CCl4 correlated with the biochemical observations.

Significance: These findings suggest a similar protective effect of ACE inhibitors; captopril; perindopril and AT1R blocker, losartan against premalignant stages of liver cancer in the DENA initiated and CCl4 promoted hepatocarcinogenesis model in rats. Therefore, RAS especially angiotensin II (Ang II) and AT1R interaction plays a pivotal role hepatocarcinogenesis development.

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Source:Life Sciences      by MA. Mansour, H AI-Ismaeel, AC . Al-Rikabi, et al.
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