Retinoid therapy of high-risk neuroblastoma.
Retinoids are derivatives of vitamin A that include all trans-retinoic acid (ATRA), 13-cis-retinoic acid, (13-cis-RA), and fenretinide (4-HPR). High levels of either ATRA or 13-cis-RA can cause arrest of cell growth and morphological differentiation of human neuroblastoma cell lines, and phase I trials showed that higher and more sustained drug levels were obtained with 13-cis-RA relative to ATRA. A phase III randomized trial showed that high-dose, pulse therapy with 13-cis-RA given after completion of intensive chemoradiotherapy (with or without autologous bone marrow transplantation) significantly improved event-free survival in high-risk neuroblastoma. The cytotoxic retinoid 4-HPR achieved multi-log cell kills in neuroblastoma cell lines resistant to ATRA and 13-cis-RA, and a pediatric phase I trial has shown it to be well tolerated. Cytotoxicity of 4-HPR is mediated at least in part by increasing tumor cell ceramide levels and combining 4-HPR with ceramide modulators increased anti-tumor activity in pre-clinical models. Thus, further clinical trials of 4-HPR in neuroblastoma, and of 4-HPR in combination with ceramide modulators, are warranted.
Reynolds
C Patrick
CP
Division of Hematology-Oncology, Children's Hospital of Los Angeles and The University of Southern California Keck School of Medicine, Los Angeles, CA 90054, USA. preynolds@chla.usc.edu
Matthay
Katherine K
KK
Villablanca
Judith G
JG
Maurer
Barry J
BJ
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy*; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000378:metabolism; D014212:Tretinoin / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D018168:Receptors, Retinoic Acid; D014212:Tretinoin