RETINOIC ACID RECEPTORS IN NEUROBLASTOMA DIFFERENTIATION

Project: Research project

Description

Neuroblastoma is the most common extracranial childhood solid tumor with
about 1/4 of cases presenting with extensive disease and a disease free
survival of only 10-15% regardless of therapy. Retinoic acid (RA) is
capable of inducing some neuroblastoma cells to differentiate in vitro
and the regression of some neuroblastomas in vivo, however many
neuroblastoma cells are resistant or become resistant to the effects of
RA. The recent characterization of nuclear RA receptors has given
considerable insight into the mechanisms whereby RA exerts effects on
cell proliferation and differentiation. Although there have been
numerous investigations into the induction of differentiation of
neuroblastoma cells by RA, there have been almost no studies regarding
the role of RA receptors. These receptors have been shown to play a
critical central role in the RA induced differentiation of acute
promyelocytic leukemia as well as in normal embryological development.
The studies in this proposal will determine which RA receptors are
present in neuroblastoma cells (RAR-alpha,Beta,gamma and RXR-alpha,Beta,
gamma) and why some neuroblastoma cells are sensitive to RA-induced
terminal differentiation while others are not. Emphasis will be placed
on extensively characterizing RA receptor structure, function, and number
in cultured neuroblastoma cell lines and determining the genetic basis
for any observed RA receptor abnormalities. RA receptors will be
retrovirally transduced into neuroblastoma cell lines that are resistant
to RA to determining which RA receptors are important in RA induced
differentiation of neuroblastoma cells. Finally, neuroblastoma cells
that are sensitive to RA or infected with various RA receptor vectors and
exhibit an in vitro response to RA, will be injected into nude mice and
observed for their response to RA to see if an in vitro response
translates into an in vivo response. These studies will provide insight
into the molecular mechanisms of neuroblastoma cell sensitivity and
resistance to RA and more clearly define the role of the activated RA
receptor in neuroblastoma cell differentiation with the hope of
identifying a more rational use of RA in the treatment of neuroblastoma.
StatusFinished
Effective start/end date7/1/944/30/00

Funding

  • National Institutes of Health: $108,280.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Retinoic Acid Receptors
Neuroblastoma
Tretinoin
Cell Differentiation
Cell Line
Nude Mice
Cultured Cells

ASJC

  • Medicine(all)
  • Neuroscience(all)