This review will summarize the rationale for pursuing investigations i
nto the use of retinoids for pediatric patients with cancer, describe
the phase I results of all-trans-retinoic acid (ATRA) in children, and
discuss the results of a series of preclinical and clinical pharmacok
inetic studies of ATRA. The prognosis for children with advanced stage
neuroblastoma, the most common extracranial solid tumor of childhood,
has remained poor despite significant increases in the intensity of m
ulti-modality therapy. Observations that neuroblastoma has the potenti
al in vivo to differentiate into the more mature neuronal phenotype of
a ganglioneuroma or to spontaneously regress, combined with the abili
ty of ATRA to induce differentiation of neuroblastoma cell lines in vi
tro, suggests that neuroblastoma may be a prime candidate for a retino
id-based approach to differentiation therapy. We previously performed
a standard pediatric phase I trial of ATRA and defined the maximum tol
erated dose (MTD) in children to be 60 mg/m(2)/day, significantly lowe
r than the MTD in adult patients. Pharmacokinetic results revealed tha
t the plasma half-life of ATRA was short (45 min) relative to 13-cis-R
A (12-24 h), and that plasma drug exposure decreased significantly by
day 28 of daily drug administration. Preclinical studies using an i.v.
formulation of ATRA in a Rhesus monkey pharmacokinetic model then dem
onstrated that ATRA is eliminated by a capacity-limited (saturable) pr
ocess. This elimination process was rapidly induced within the first w
eek of daily i.v. ATRA administration, and suggested that an intermitt
ent schedule of drug administration might allow for down-regulation of
the elimination process. These pre-clinical studies formed the basis
for investigating whether an intermittent schedule of ATRA administrat
ion would allow for repeated periods of relatively higher plasma drug
concentrations. Preliminary results of two clinical trials using inter
mittent schedules of administration suggest that this approach may res
ult in significantly higher plasma drug exposure over time. Plans to s
tudy the role of intermittent schedules of ATRA administration in pedi
atric phase II trials in patients with neuroblastoma are underway.