الفهرس 
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Abstract
Summary and Conclusion
Cancer is a generic term for a large group of diseases that can affect any part of the body. The growth of solid tumors is dependent on their capacity to induce angiogenesis. Anti-angiogenic therapeutic drugs act by inhibiting synthesis of angiogenic proteins by cancer cells and inhibiting the receptors of endothelia for angiogenic proteins. These inhibitors include small molecules that targeting angiogenic growth factors, such as VEGF and bFGF, or angiogenic growth factor receptors, such as VEGFR and PDGFR.
Renin-angiotensin system modulates cellular proliferation and angiogenesis. The aim of the current study was to test the antitumor activity of the ARB, olmesartan, in combination with sorafenib in tumor cell lines grown in-vitro and in-vivo. In particular, the anti-angiogenic effect of olmesartan was further elucidated in EAC solid tumors grown in mice.
Further, the study aimed to examine the contribution of Ang (1-7) in the anti-angiogenic effect of olmesartan through determining the impact of concurrent administration of an Ang (1–7) agonist or an Ang (1–7) antagonist on the anti-angiogenic effect of olmesartan. Moreover, the safety of olmesartan in combinations with sorafenib was assessed in mice.
The present results has shown that the monotherapy with sorafenib (30 mg/kg), olmesartan (3, 10 or 30 mg/kg) or their combination reduced the tumor weight compared to EAC-control.
In addition, concurrent administration of the Ang (1-7) agonist with olmesartan (30 mg/kg) enhanced the anti-tumor activity however; the Ang (1-7) antagonist diminished the antitumor effect of olmesartan. Furthermore, olmesartan produced a synergistic effect when used in combination with sorafenib in EAC solid tumor grown in mice. On the other hand, olmesartan did not produced any effect when used in-vitro.
Sorafenib and/or olmesartan reduced the serum levels of IGF-I, VEGF and their intra-tumoral receptor expression. However, concurrent administration of the Ang (1-7) agonist produced a further reduction in serum levels of IGF-I, VEGF and their intra-tumoral receptor expression when it was used with olmesartan. On the other hand, the administration of Ang (1-7) antagonist diminished the effect of olmesartan (30 mg/kg).
Monotherapy with olmesartan (3, 10 or 30 mg/kg) produced a dose-dependent reduction in MVD. Similarly, monotherapy with sorafenib produced a significant decrease in MVD. Combination therapy of olmesartan and sorafenib produced a marked reduction in MVD. In addition, administration of the Ang (1-7) agonist with olmesartan (30 mg/kg) reduced MVD while, the Ang (1-7) antagonist increased MVD.
The combined therapy increased the percentage survival of animals whereas; the body weight did not change compared to normal control group. In addition, the combination of olmesartan with sorafenib produced non-significant changes in complete blood count and liver functions. On the other hand, the combined therapy produced a significant increase in lymphocytes and BUN.
In conclusion, the present results showed that olmesartan (30 mg/kg) potentiated the anti-tumor effect of sorafenib. This anti-tumor effect of olmesartan wasn’t depending on the direct cytotoxic effect but depending on the anti-angiogenic effect. The anti-angiogenic effect of olmesartan was, at least in part, mediated through the inhibition of IGF-I/VEGF and their receptors. Furthermore, the anti-angiogenic effect of olmesartan was, at least in part, mediated through the Ang (1-7) receptor. Therefore, the present study proved the beneficial role of olmesartan as an adjuvant medication to sorafenib in the treatment of tumors. This treatment should be used under special circumstances; sorafenib was reported to increase blood pressure in cancer patients, and there is an emergent need for an antihypertensive remedy.
In addition, concomitant administration of olmesartan with sorafenib did not significantly augment its toxicity. The present study suggested that this combination offers no obvious toxicity thus might be evolve as a promising candidate with sorafenib. Further, long-term toxicity studies are still needed to rule out any adverse effects for this combination.