Retinoid therapy of high-risk neuroblastoma

Cancer Lett. 2003 Jul 18;197(1-2):185-92. doi: 10.1016/s0304-3835(03)00108-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Clinical Trials as Topic
  • Humans
  • Neuroblastoma / drug therapy*
  • Receptors, Retinoic Acid / drug effects
  • Receptors, Retinoic Acid / metabolism
  • Tretinoin / therapeutic use*


  • Antineoplastic Agents
  • Receptors, Retinoic Acid
  • Tretinoin