Neuroblastoma tumorigenesis is related in part to defects in cellular differentiation. A number of agents, including 13-cis-RA, are capable of inducing NB differentiation in vitro, and a phase-III trial has definitively shown the clinical benefit of high-dose pulse 13-cis-RA following consolidation therapy; however, there are still tumors that do not respond to 13-cis-RA, even at the time of minimal residual disease, and additional therapies in the post-myeloabla-tive period are clearly needed. Pre-clinical studies have shown that cytotoxic retinoid fenretinide (4-HPR) can achieve multi-log cell kills against NB cell lines resistant to 13-cis-RA, especially when combined with modulators of ceramide metabolism. A challenge with 4-HPR is that the current oral (capsule) formulation is poorly bioavailable and is not suitable for administration to young children. New formulations are currently in development. Randomized clinical trials are needed to determine if incorporating new approaches to treating minimal residual disease in high-risk NB patients, such as use of 4-HPR┬▒ceramide modulators, can improve eventfree survival.

Acknowledgements. The authors thank D.R. Reed for outstanding editorial assistance. This work was supported in part by the Neil Bogart Memorial Laboratories of the T.J. Martell Foundation for Leukemia, Cancer, and AIDS Research and by National Cancer Institute Grant CA81403.

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