Vitamin A or retinol primarily from the diet plays a critical role in normal neural crest development. The metabolism and storage of retinol is mediated by a number of binding proteins and enzymes. Intracellu-lar retinol is metabolized to all-trans retinoic acid (ATRA). All-trans retinoic acid is a major mediator of the effects of vitamin A via activation of a number of RAR and RXR nuclear receptors that heterodimerize and regulate gene transcription (see below). Exposure of human neuroblastoma cell lines to supra-physiologic doses (micromolar) of ATRA caused a reduction of cell growth and induction of neurite extension and differentiation that was ultrastructurally, biochemically, and electro-physiologically similar to normal neural cells (Fig. 15.2; Sidell 1982; Abemayor and Sidell 1989).

The ATRA treatment of NB cells was accompanied by a decrease in the expression (Thiele et al. 1985) and transcription (Thiele and Israel 1988) of the MYCN gene. The decrease in MYCN expression preceded the ATRA-induced G1 arrest and evidence of morphologic differentiation (Thiele et al. 1985), and the MYCN over-expression blocked differentiation (Peverali et al. 1996). All-trans retinoic acid induced decreases in MYCN levels and increases in the cy-clin-dependent kinase inhibitor p27 which may mediate the G1 arrest of NB cell cycle (Matsuo and Thiele 1998; M. Nakamura et al. 2003). Pulse therapy with retinoic acid showed a sustained arrest of tu

mor cell proliferation in NB cell lines, suggesting that high-dose pulse retinoid therapy (as opposed to the more traditional low-dose continuous retinoid therapy) might be effective in vivo (Reynolds et al. 1991).

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