RC:
Phenylbutyrate and related aromatic fatty acids
are some of the least appreciated agents with
solid scientific evidence, established efficacy,
low toxicity as well as oral bioavailability
for cancer treatment. It is a potent differentiating
agent effective in inducing apoptosis,
and in the class of histone
deacetylase inhibitors (HDACs)
and
has anti-tumor activity in part based on
modification of chromatin structure, modulation
of protein kinase C, attenuating the expression
of Bcl-X(L), DNA-PK, caveolin-1, and VEGF (See
Ref)
and also via activation of PPAR
gamma receptor (See
Ref), although the exact
mechanisms involved are still obscure perhaps
by regulation of DNA transcription. Studies/Trials
have shown HDAC cancer inhibitory effects in
cell culture (eg malignant B cells as in CLL
or NHL, retinoblastoma, neuroblastoma, melanoma,
glioma, myeloma, cervical, lung, breast, ovarian,
colon and prostate cancers) animal models (acute
leukemias APL and AML, liver, breast, colon
cancers) and in human with both hematological
and solid tumors, and phenylbutyrate has been
demonstrated to have clinical efficacy in patient
with glioblastoma (one published
case of complete remission) and
in preventing leukemic transformation in myeloproliferative
conditions. The agent is available in this country
as an investigational agent for cancer or an
orphan drug for a rare inborn error of metabolism
in children. Given orally, it can achieve biologically
effective and meaningful blood levels at relatively
low doses and has limited side-effects (MA Carducci
at Hopkins did much work on this drug: See his
review
as
well as his report on the phase
I trial of oral phenylbutyrate
in refractory solid tumors. It has been demonstrated
to potentiate chemotherapeutic agents synergistic
with cytarabine,
etoposide, topotecan, BCNU,
FUDR and hydroxyurea
Phenylbutyrate is also synergistic with retinoic
acid (another differentiating agent) (See Ref)
and may be synergistic with PPARgamma agonists
(See Ref),
cox-2 inhibitors and interferons
(See
Ref) as well. It may also have
other anti-cancer effects such as antiangiogenesis
as well.
Phenylbutyrate is an ingredient of Burzynski's
"Antineoplaston" therapy but its efficacy
and low toxicity as well as oral availability
justifies much wider usage, but I find it particularly
applicable for hematologic
and childhood malignancies, retinoblastoma and
neuroblastoma, as well as glioblastoma and medullary
thyroid
cancers. It can be used in cocktail
fashion as treatment to enhance survival (even
while on certain chemotherapies such as BCNU,
5FU and others above) or as a preventative in
the adjuvant setting for patients who are in
remission after cytoreductive therapies. Our
patients can obtain pure phenylbutyrate from
reputable compounding pharmacies under our prescription
after carefully considering their therapeutic
options and signing the requisite consents for
a compassionate trial. The only downside to
this treatment is relative expense and the large
number of capsules to swallow each day [depending
on dose]. Other HDAC inhibitors that may potentially
be useful includes the anti-seizure medication
valproic acid (See Ref)
which may be particularly appropriate to use
in cocktail fashion in brain tumors.
|