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Neuroblastoma cell lines can be induced to undergo sustained growth arrest and differentiation using retinoic acid and 13-cis-retinoic acid.  We have shown that treating patients with 13-cis-retinoic acid after completion of chemotherapy and radiotherapy, and especially after completion of myeloablative chemoradiotherapy, improves event-free survival (1).

Unfortunately, many neuroblastoma patients treated with myeloablative therapy and then 13-cis-retinoic acid will still develop recurrent tumor.  Thus, we have focused on identifying drugs which are effective against those neuroblastoma cells that are resistant to existing therapies.

One of the current focuses of our research is our observation that the retinoid fenretinide (4-HPR) is cytotoxic for neuroblastoma cells resistant to many drugs, including 13-cis-retinoic acid (2).  We have also shown that 4-HPR generates large amounts of ceramide, which opens the possibility that we can use modulators of ceramide metabolism to enhance the anti-tumor effect of 4-HPR (2).   Particularly exciting is the ability of 4-HPR to kill neuroblastoma (and other kinds of tumor cells) by both apoptosis and necrosis (Figure 1) which is probably why 4-HPR can kill tumor cells resistant to other drugs. 

Clinical trials to test the ability of 4-HPR to treat neuroblastoma and other tumors are in progress and we have ongoing laboratory studies developing new drugs to use in combination with 4-HPR.

References

1.  Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, Swift P, Shamada H, Black CG, Brodeur GM, Gerbing R, Reynolds CP: Treatment of high risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. New Eng J Med 341:1165-1173, 1999.