Neuroblastoma 36], dibutyryl cAMP [37], nerve growth

Neuroblastoma is
the most common extra cranial solid tumour found in children. It originates
from adrenal medulla and paraspinal or periaortic regions of the sympathetic
nervous system. 20,21. These tumors rarely undergo histological maturation
or differentiation in vivo and may turn to benign state or complete resolution 22.  Some
of the genes whose mutation may predispose an individual for neuroblastoma
include ALK 23 and PHOX2B 
 24. Treatment of neuroblastoma involves
chemotherapy, radiation therapy, or retinoid therapy alone or in combinations.
Retinoic acid (RA), a vitamin-A metabolite is known to induce the
differentiation of neuroblastoma 25. Although RA significantly increases survival in
neuroblastoma patients 26, resistance to RA therapy develops in more than 50%
of patients with neuroblastoma. The other two, chemotherapy
and radiation therapy have severe side effects especially in growing children.
Neuroblastoma cells are widely used as a model system to study the process of neuronal
differentiation, axonal growth and signaling pathways as these cells have the
feature of unlimited proliferation and ability to be differentiated into
neurogenic cells 27-32. Human neuroblastoma cell lines
LA-N-5 and IMR-32 are known to undergo proper differentiation in culture
conditions by different agents like RA 25,
33, forskolin 34, phorbol esters
35,
36, dibutyryl cAMP 37, nerve growth factor 38 and vasoactive
intestinal peptide 39. Neuroblastoma
cells in culture conditions contain low levels of cAMP and most of the differentiating
agents elevate their intracellular cAMP levels 37,
40-44. However there are also
reports  that differentiation of LA-N-5
or IMR-32 by nerve growth factor, dibutyryl cyclic AMP, or 12-O-tetradecanoylphorbol-13-acetateRA
does not occur through elevated levels of cAMP 39,
45, indicating that
cAMP elevation pathway may not be the only way to induce differentiation.  Most of these differentiation inducing agents
have been undertaken for limited trials for therapeutic purposes but have met
with little success 46-48 except RA (Isotretinoin).

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