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Combination
of phenylbutyrate and 13-cis retinoic acid inhibits prostate tumor growth and
angiogenesis
Pili R, Kruszewski MP, Hager BW, Lantz J, Carducci
MA
The Johns Hopkins Oncology Center, Baltimore, Maryland 21231,
USA
Differentiation-inducing agents, such as retinoids and short-chain fatty acids,
have an inhibitory effect on tumor cell proliferation and tumor growth in
preclinical studies.
Clinical trials involving these compounds as single agents
have been suboptimal in terms of clinical benefit.
Our study evaluated the
combination of phenylbutyrate (PB) and 13-cis retinoic acid (CRA) as a
differentiation and antiangiogenesis strategy for prostate cancer.
On the basis
of previous evidence, common signal transduction pathways and possible
modulation of retinoid receptors and retinoid response elements by PB could be
responsible for such activities.
We assessed the effect of the combination of PB
and CRA on human and rodent prostate carcinoma cell lines.
The combination of PB
and CRA inhibited cell proliferation and increased apoptosis in vitro in an
additive fashion as compared with single agents (P < 0.014).
Prostate tumor
cells treated with both PB and CRA revealed an increased expression of a subtype
of retinoic acid receptor (retinoic acid receptor-beta), suggesting a molecular
mechanism for the biological additive effect.
The combination of PB and CRA also
inhibited prostate tumor growth in vivo (up to 82-92%) as compared with single
agents (P < 0.025).
Histological examination of tumor xenografts revealed
decreased in vivo tumor cell proliferation, an increased apoptosis rate, and a
reduced microvessel density in the animals treated with combined drugs,
suggesting an antiangiogenesis effect of this combination.
Thus, endothelial
cell treatment with both PB and CRA resulted in reduced in vitro cell
proliferation.
In vivo testing using the Matrigel angiogenesis assay showed an
additive inhibitory effect in the animals treated with a combination of PB + CRA
(P < 0.004 versus single agents).
In summary, this study showed an additive
inhibitory effect of combination of differentiation agents PB and CRA on
prostate tumor growth through a direct effect on both tumor and endothelial
cells.
PMID: 11245454 [PubMed - indexed for MEDLINE]
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