Although the treatment outcome for children with advanced-stage neuroblastoma has improved, 5-year event-free survival in most studies is less than 30% (Castel et al. 2001). In a few studies (e.g.,Kaneko et al. 2002) survival reaching 34% for patients with MYCN amplification (more than ten copies) receiving intensified regimens of cytotoxic agents has been reported. While the survival rate is significantly increased over that of less intensive regimens, two-thirds of high-risk patients with MYCN amplification succumb to their disease. Furthermore, the survival of patients with advanced disease without MYCN amplification (less than ten copies) is not much greater (Kaneko et al. 2002); thus, there is still a need to develop more effective, less toxic therapies that will boost survival probability for these children (Brodeur 2002; Tsuchida et al. 2003).

This chapter focuses on the potential of preclinical animal model systems in development of new therapies. Each model has both limitations and uses; the art is to recognize the model attributes and not to extrapolate results beyond the true useful range for that model, i.e., each type of model has a functional use and it is likely that no one class of model will be useful for all applications. For example, syngeneic animal tumor models may have particular value in development of active immunity approaches, whereas heterotransplant models, such as human tumors in immune-deficient mice,have a more restricted application.

Cytotoxic therapies still play the major role in neuroblastoma treatment inducing high complete response rates even in a subset of patients with stage-4

MYCN amplified disease (Castel and Canete 2004; Donfrancesco et al. 2004). Bone marrow or peripheral blood stem cell transplants appear to have some value increasing relapse-free survival, at least in some studies (Goldsby and Matthay 2004; Imaizumi et al. 2001; Valteau-Couanet et al. 2000; Matthay et al. 1999). Differentiation agents and immunotherapies may also increase survival in patients having a complete or good partial response during induction therapy. It is against this background that we consider the use of preclinical models with particular emphasis on contemporary approaches to therapy with novel cytotoxic agents,"molecularly targeted" agents, anti-angiogenic agents, and immunotherapy approaches to treating neuroblastoma.

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