Distinct properties of fenretinide and CD437 lead to synergistic responseswith chemotherapeutic reagents

The RAR beta/gamma -selective retinoids fenretinide and CD437 induce caspas e-dependent apoptosis but generate free radicals independently of caspases. Apoptosis, but not free radical generation, induced by these retinoids is inhibited by RAR beta/gamma -specific antagonists. Both fenretinide and CD4 37 induce apoptosis synergistically with cisplatin, carboplatin, or etoposi de. However, antioxidants inhibit this synergy to the level obtained with c hemotherapeutic drugs alone, and this implies that free radical generation is important in the synergistic response. Since apoptosis induced by fenret inide or CD437 is mediated by apoptotic pathways involving RARs and/or mito chondria and differs from mechanisms of chemotherapy-induced apoptosis this may explain the strong synergistic response seen between these synthetic r etinoids and chemotherapeutic drugs. These results suggest that fenretinide or CD437 may be useful adjuncts to neuroblastoma therapy. Med. Pediatr. On col. 35:663-668, 2000. (C) 2000 Wiley-Liss, Inc.