Menu Close

Unraveling the mechanisms by which these therapies affect the heart and vasculature is crucial for improving drug design and finding alternative therapies to protect patients predisposed to cardiovascular disease

Unraveling the mechanisms by which these therapies affect the heart and vasculature is crucial for improving drug design and finding alternative therapies to protect patients predisposed to cardiovascular disease. Temsirolimus is a potent and highly specific inhibitor of mTOR. It inhibits cell proliferation, cell growth, survival pathways and tumor angiogenesis [91]. The safety and effectiveness of temsirolimus were shown in a clinical trial of 626 patients divided into three groups: one received temsirolimus alone; the second, interferon alpha; and the third group received a combination of both drugs. The best median overall survival was observed in the group receiving temsirolimus alone [92]. The most common drug related adverse events associated with temsirolimus was anemia, however various adverse metabolic effects have also been reported, including elevations in serum glucose, triglycerides, and cholesterol [93]. In addition, interstitial pneumonitis has also been reported, and can be a life threatening toxicity associated with temsirolimus [94]. This novel inhibitor of mammalian target of rapamycin has been demonstrated to prolong overall survival and delay of disease in patients Rabbit Polyclonal to PGCA2 (Cleaved-Ala393) with advanced renal cell carcinoma [95]. The most frequent cardiovascular side effect reported with temsirolimus is hypertension [95]. Hypertension has also been reported with another inhibitor of mTOR, Everolimus (RAD-001). Similar to temsirolimus, Everolimus inhibits mTOR by binding to FKBP-12 and forming a complex that in turn binds and inhibits mTOR kinase, however this drug is administered orally unlike Temsirolimus, which is infused. In a phase III study of renal cancer, 410 patients that had failed a kinase inhibitor treatment were randomized into two groups: one that received placebo, and one that received Everolimus. The results of this trial showed an improved progression free survival when compared to placebo. This agent has been approved for usage in patients that have failed VEGF inhibitor treatment. Similar to the side effects observed with temsirolimus treatment, patients receiving Everolimus have reported to have skin rash, fatigue, hyperglycemia, and hyperlipidemia [96]. Furthermore, Everolimus has a potent immunosuppressive activity that was developed for the usage in acute and chronic rejection of solid organs. It inhibits smooth muscle proliferation and neointimal thickening and is used to reduce the risks of vasculopathy in heart transplantation [97]. As detailed previously mTOR may promote blood vessel formation, and blocking its signaling affects vessel growth, which may contribute to the hypertensive effects observed in patients. Dysregulation of mTOR signaling can lead to loss of expression of the von Hippel-Lindau tumor suppressor VXc-?486 gene. This results VXc-?486 in increased expression of hypoxia-inducible factor 1 (HIF-1) and its target gene products, such as VEGF. VEGF and other factors induced by HIF-1 are thought to be the key drivers of tumor angiogenesis [98]. Therefore, inhibition of mTOR may also affect VEGF expression, and have some of the same side effects described above for the anti-VEGF directed therapies [99]. Hormone Signaling Pathways Some breast cancers are exquisitely sensitive to withdrawal of estrogen or inhibition of estrogen signaling through the estrogen receptor (ER). This had lead to very successful molecular targeting of ER and the aromatase enzyme responsible for the first steps of estrogen synthesis for treatment of these cancers. However, there are also multiple cell types in the cardiovascular system that contain ER and are hormone sensitive. The relationship between increased incidence of coronary artery disease and post-menopausal status as VXc-?486 well as the failure of the hormone replacement clinical trials emphasizes the importance of estrogen signaling in the cardiovascular system [100]. Tamoxifen has mixed estrogenic and anti-estrogenic activities, and has both been associated with increased risk of thromboembolism including stroke [101]. This risk has been suggested to be lower with some other anti-estrogen therapies, despite a very similar mechanism of action, thus each drug may need to be evaluated individually for this effect [102]. Amongst patients with embolic phenomena on tamoxifen, there was an increased incidence of factor V Leiden mutations, and the presence of such mutations was associated with a 5-fold increase in risk of these events [103]. The thromboembolic risk of aromatase inhibitors has been shown to be less than or equivalent to that seen with tamoxifen [104-106]. Tamoxifen and toremifene have been shown to have favorable effects on lipid profiles, decreasing total and LDL cholesterol (both), and increasing HDL (toremifiene) [107, 108]. These effects may be predicted to be due to estrogenic effects of tamoxifen or toremifene, leading to the idea that aromatase inhibitors may have adverse effects on lipid profiles. Anastrozole and letrozole have been suggested to lead to mild increases in serum cholesterol; whereas, examestane appears to have.