Angiogenic inhibitors: a new therapeutic strategy in oncology

Abstract

Angiogenesis is a multistep, complex and tightly regulated process that is necessary for tumor growth and metastasis. Based on data of preclinical models, several antiangiogenic compounds has been shown to modify activated tumor endothelium, which suggests that these compounds can improve cytotoxic drug delivery. Such agents have entered clinical trials as single agents or in combination with cytotoxic drugs, and have shown promising antitumor activity. The pharmacodynamic and pharmacokinetic characteristics of antiangiogenic drugs are reviewed here. Most of the early clinical testing of these agents was conducted in patients with advanced disease resistant to standard therapies. Phase III trials compared the efficacy of standard chemotherapy alone with standard chemotherapy in combination with an experimental angiogenesis inhibitor. Although some of these studies were negative or controversial, recent studies validated in large clinical trials with an anti-vascular endothelial growth factor antibody demonstrated significant clinical benefit and renewed enthusiasm for this therapeutic strategy. This review describes the clinical studies of antiangiogenic agents and highlights the challenges related to choosing appropriate strategies for the selection of patients, study design and choice of appropriate endpoints for the studies' development.

Impact of serum vascular endothelial growth factor on prognosis in patients with unresectable hepatocellular carcinoma after transarterial chemoembolization

“…Poor liver function was commonly identified as an adverse prognostic factor in previous studies [34][35][36][37][38][39] . However, as shown in this study, tumor progression including vascular invasion, extrahepatic metastasis and advanced BCLC stage rather than liver failure was the main adverse prognostic factor after TACE.…”

Low-dose metronomic cyclophosphamide treatment mediates ischemia-dependent K-ras mutation in colorectal carcinoma xenografts

“…This linkage paved the way to clinical trials with antiangiogenic agents, which in some cases have dramatically changed the standards of care (Miller et al, 2005a, b;Motzer and Bukowski, 2006;Varker et al, 2007). In particular, bevacuzimab/avastin, a humanized monoclonal-neutralizing antibody directed against vascular endothelial growth factor has since 2004 become incorporated into the first-line therapies in metastatic colorectal carcinoma (CRC) (Hurwitz et al, 2004) and other malignancies (Gasparini et al, 2005). In addition to such targeted antiangiogenic agents designed to obliterate a well-defined molecular mechanism (for example, vascular endothelial growth factor/vascular endothelial growth factor receptor pathway), blood vessel inhibitory properties have also been uncovered in drugs with ostensibly unrelated activities, including cytotoxic anticancer chemotherapeutics (Browder et al, 2000;Klement et al, 2000).…”

The contribution of targeted therapy to the neoadjuvant chemoradiation of rectal cancer

“…High VEGF expression was associated to progressive disease and poorer survival in several malignancies, including colon and rectal cancers [31][32][33]. The efficacy of inhibition of VEGF pathway is demonstrated by improvement of clinical outcome in patients affected by several advanced cancers [34]. In particular bevacizumab, a humanized monoclonal antibody inhibiting VEGF-A, in combination with standard chemotherapy regimens was beneficial both in term of response rate and survival as first-and second-line treatment of patients affected by mCRC.…”