Anti Angiogenic Agents

Preclinical data have been published supporting the importance of angiogenesis and invasion in progression and prognosis of neuroblastoma (see Chap. 16). An initial report on 50 human tumor samples pro vided data that increased tumor vascularity correlated with a poorer prognosis (Meitar et al. 1996), though this was contradicted by a later Spanish report (Canete et al. 2000). High-risk neuroblastomas over-express the avß integrin, an endothelial transmembrane receptor for neovascular proliferation, which can be blocked with a monoclonal antibody, vitaxin, or an RGD peptide, resulting in increased ce-ramide production and endothelial cell death (Erdre-ich-Epstein et al. 2000). Phase-I trials of both the monoclonal antibody and the peptide, cilengitide, have shown promise in adult cancers (Eskens et al. 2003; Tucker 2003). Matrix metalloproteinases, MMP-2, and MMP-9,have a key role in invasion and metastasis, and are over-expressed in the stroma of high-risk neuroblastoma (Sugiura et al. 1998; Ara et al. 1998; Bjornland et al. 2001). In vivo xenograft studies in neuroblastoma have shown that inhibitors of MMPs can decrease angiogenesis and prolong survival (Chantrain et al. 2004). A number of inhibitors are currently in clinical testing, with a few positive results in adult cancers (Ramnath and Creaven 2004). Thalidomide is another agent with antiangiogenic actions in neuroblastoma (Kerbel et al. 2000; Kaicker et al. 2003) currently in clinical cancer trials (Fine et al. 2000,2003). To date, no large-scale trial of anti-an-giogenic or anti-invasion agents has been accomplished in neuroblastoma, although as some of these agents become available and have completed phase-I testing in adults, they will be appropriate for further trials in children.

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