Cancer Chemotherapy, Theoretical Foundations of
179
and Cdk2 at lower potency. In a similar
fashion to flavopiridol, roscovitine acts
as a competitive inhibitor and induces
apoptosis in tumor cells. Roscovitine (also
known as CYC 202) has completed a
Phase I clinical trial and appears to be
well tolerated.
Advances are continuing to be made in
improving the selectivity of Cdk inhibitors.
For
example,
a
number
of
oxindole-
substituted Cdk inhibitors have greater
than tenfold selectivity for Cdk2 against
a panel of other Cdks. In this respect,
it is hoped that the clinical development
of selectively acting Cdk inhibitors will
identify molecules with greater ef±cacy
than some of the broad-spectrum agents
currently in clinical development.
7
Targeting Chromatin Control in Cancer
Recent advances have highlighted a new
and exciting area for therapeutic interven-
tion, namely, the interplay between the
cell cycle and chromatin control. Chro-
matin is the DNA-proteinaceous material
in which chromosomal DNA resides in
the nucleus. The majority of chromatin
proteins is composed of histones that as-
semble into nucleosomes, and thereby as-
sist in DNA packaging and transcriptional
control. The histone tail is subject to a vari-
ety of enzymatic modi±cations, including
phosphorylation, acetylation, and methy-
lation, and many of the critical enzymes
responsible for these modi±cations have
recently come to light. Histone deacety-
lases (HDACs) are responsible for remov-
ing acetyl groups from lysine residues in
histones and many proteins involved in
the cell cycle (Fig. 4).
From the perspective of cancer ther-
apy, HDACs have gained recognition as
an important target, which, in part, re-
flects the identi±cation of proteins other
than histones that are subject to acety-
lation control. The activity of cell cycle
regulators including E2F, p53, and pRb
is influenced by acetylation, and pRb
controls E2F activity through the recruit-
ment of chromatin-modifying enzymes,
such as HDACs (Fig. 4). Several onco-
genic proteins have altered recruitment
of HDACs, which leads to aberrant gene
transcription. This is exempli±ed by the
fusion protein PML-RAR
α
, which occurs
through a chromosomal translocation in
acute promyelocytic leukemia (APL). The
PML-RAR
α
fusion protein recruits HDAC
and represses transcription, causing a
block to differentiation and promoting
the oncogenic phenotype in APL. Per-
haps, not surprisingly, compounds that
inhibit HDAC activity cause potent cell
cycle effects and frequently induce apopto-
sis; encouraging results of HDAC inhibitor
clinical trials have begun to validate HDAC
enzymes as drug targets.
SAHA
(suberoylanilide
hydroxamic
acid) is a small molecule HDAC inhibitor
that has reached Phase II clinical trials for
the treatment of solid and hematological
malignancy, and a range of other HDAC
inhibitors are gaining clinical acceptance,
for example, PXD101 is a highly potent
HDAC inhibitor that blocks proliferation
of tumor cells and has entered clinical
trials. In addition, a variety of studies
have
demonstrated
the
potential
for
synergy using combinations of HDAC
inhibitors
with
several
mechanistically
distinct
antitumor
agents,
such
as
SAHA, which together with radiotherapy,
produces an additive effect in human
prostate cancer spheroids. While HDAC
inhibitors
have
yet
to
be
completely
validated, nevertheless, they do represent
previous page 853 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 855 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off