Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Therapies aimed at destruction of the tumor vasculature are now recognized as a promising approach against cancer, and it has been reported that the combination treatment with an angiogenic inhibitor and conventional chemotherapeutic drug exerted synergistic anti-cancerous effects. We previously reported that the clinically used angiotensin-converting enzyme inhibitor (ACE-I) exerted potent-anti-angiogenic activities. The aim of our current study was to examine the combined effect of ACE-I and 5-fluorouracil (5-FU), which is widely used for hepatogastrointestinal tumors, on hepatocellular carcinoma (HCC) growth and hepatocarcinogenesis. When used individually at low doses, neither 5-FU nor ACE-I exerted significant inhibitory effects on the HCC growth. However, the combination treatment of 5-FU and ACE-I showed a potent inhibitory effect on HCC growth along with suppression of neovascularization in the tumor. The expression level of the vascular endothelial growth factor, a potent angiogenic factor, was also suppressed, almost in conjunction with tumor growth inhibition. Furthermore, 5-FU and ACE-I treatment resulted in a marked increase of apoptosis in the tumor. In the hepatocarcinogenesis model, the combination treatment with 5-FU and ACE-I also showed a marked inhibitory effect on the development of preneoplastic lesions. The in vitro study demonstrated that this combination treatment inhibited endothelial cell tubular formation. Collectively, the combination treatment of 5-FU and ACE-I exerted a marked synergistic inhibitory effect on HCC growth via suppression of angiogenesis. This regimen also showed a chemopreventive effect against hepatocarcinogenesis. Since both 5-FU and ACE-I are widely used in clinical practice, this combination therapy may be an effective new therapeutic strategy against HCC in the future.
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PMID:Synergistic inhibition of hepatocellular carcinoma growth and hepatocarcinogenesis by combination of 5-fluorouracil and angiotensin-converting enzyme inhibitor via anti-angiogenic activities. 1720 85

The vascular endothelial growth factor (VEGF) signaling pathway (VSP) fulfills a cardinal role in endothelial cells and its inhibition has profound cardiovascular impact. This is true not only for the normal vasculature but also for the tumor vasculature when VSP inhibitors are used as anti-angiogenic therapies. Generalized endothelial dysfunction predisposes to vasoconstriction, atherosclerosis, platelet activation, and thrombosis (arterial more than venous). All of these have been reported with VSP inhibitors and collectively give rise to vascular toxicities, the most concerning of which are arterial thromboembolic events (ATE). VSP inhibitors include antibodies, acting extracelluarly on VEGF, such as bevacizumab and tyrosine kinases inhibitors, acting intracellularly on the kinase domain of VEGF receptors, such as sunintib and sorafenib. The addition of bevacizumab and VSP tyrosine kinase inhibitor therapy to the cancer treatment regimen is associated with a 1.5-2.5-fold and 2.3-4.6-fold increase risk of ATEs, respectively. Risk factors for ATEs while on VSP inhibitor therapy include age older than 65 years, previous thromboembolic events, history of atherosclerotic disease, and duration of VSP inhibitor therapy. In clinical practice, hypertension remains the most commonly noted vascular manifestation of VSP inhibition. Optimal blood pressure goals and preferred therapeutic strategies toward reaching these goals are not defined at present. This review summarizes current data on this topic and proposes a more intensive management approach to patients undergoing VSP inhibitor therapy including Systolic Blood PRessure Intervention Trial (SPRINT) blood pressure goals, pleiotropic vasoprotective agents such as angiotensin converting enzyme inhibitors, amlodipine, and carvedilol, high-dose statin therapy, and aspirin.
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PMID:Vascular toxicities with VEGF inhibitor therapies-focus on hypertension and arterial thrombotic events. 2970