ment of
histones onto specific genes, thus masking their genetic material and turning
them off. The scientists turned to a drug called Trichostatin A, one of a family
of drugs called histone deacetylase inhibitors. These drugs prevent histones
from doing their job, thus favoring gene expression and possibly antagonizing
the activity of transcription repressors such as PML-RAR and PLZF-RAR . The
drug combination worked well in the mice resistant to retinoic acid alone (those
with the PLZF-RAR gene fusion), and was even more effective in mice already
sensitive to retinoic acid (those with the PML-RAR gene fusion). Indeed, the leukemia cells matured to become normal white blood cells. Moreover, the
drugs produced no adverse side effects.
"This study is critically important for two reasons," said Dr. Warrell,
the pioneer of retinoic acid for APL. "Narrowly, it explains why patients with
APL may develop resistance to retinoic acid, and provides a therapy which can
potentiate the response to retinoic acid as well as prevent or overcome the loss
of response to this drug. More broadly, it opens up an exciting new pathway for
the treatment of many types of cancers."
One such cancer might be non-Hodgkin's lymphoma, a disease that strikes
far more patients than APL: More than 50,000 people in the United States are
diagnosed with non-Hodgkin's lymphoma each year. Mutations in a gene called
BCL-6 make up the most frequent genetic alteration in non-Hodgkin's lymphoma.
Alterations in BCL-6 -- which belongs to the same family of genes as PLZF -- turn
on this transcription repressor, leading to lymphoma. "We plan to take our new
findings with APL and apply them to design transcription therapy for patients
with non-Hodgkin's lymphoma," said Dr. Pandolfi, who is currently planning such
a clinical trial. Researchers intend to evaluate Trichostatin A as well as a
similar drug called sodium phenylbutyrate.
'"/>
Contact: Kelli Stauning
stauningk@mskcc.org
212-639-3573
Memorial Sloan-Kettering Cancer Center
26-Jan-1998
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