Cancer Chemotherapy, Theoretical Foundations of
177
compound is active in mice where it
reduces the side effects, such as hair loss
and myelosuppression, of the widely used
cancer cytotoxic agent doxorubicin.
Although the anticipated clinical utility
of
p53
inhibitor
drugs
would
be
in
combination treatments to enhance the
efFcacy of a conventional cytotoxic, a
shortcoming of this approach could lie in
the potential mutagenic activity resulting
from p53 inhibition. Developing a p53
inhibitor with a sufFciently short half-life
may overcome such a concern.
6
Regulating the Cancer Cell Cycle: E2F and
Cdks
Abnormal cellular growth and division is
a hallmark of tumor cells. It is acquired
through a multistep process involving the
gradual transformation of a normal cell
to a tumor cell, and it involves mutation
of critical pathways that act to restrain
proliferation, together with the activation
of those that promote proliferation.
The retinoblastoma tumor suppressor
protein (pRb) provides a perfect example
of how a crucial point of growth control
can become abnormal in tumor cells,
and
thereby
contribute
to
tumor
cell
growth. An important function of pRb
is in regulating cell cycle progression
through G1 into S phase, particularly
passage through the restriction point,
where it influences the activity of the
E2± family of transcription factors (±ig. 3).
E2± coordinates the timely expression of a
large body of genes required for cell cycle
progression (including DNA synthesis,
cyclins, and regulatory proteins), and it
is the progressive phosphorylation of pRb
that relieves its physical interaction with
E2±, thereby enabling E2± to activate target
genes (±ig. 3).
Tumor cells employ diverse mecha-
nisms to overcome the tumor suppressor
activity of pRb. The Rb gene is mutated
in about 25% of human tumors, crippling
pRbsotha
ti
tisno
tab
letob
indtoE2±
.
Alternatively, aberrant levels of upstream
regulators of pRb, like cyclin D-dependent
kinase, occur which leads to the consti-
tutive phosphorylation of pRb and release
of E2±. Because of the high frequency of
abnormal pRb control, it is believed that
deregulation of the pRb/E2± pathway is es-
sential in achieving the transformed state.
In this respect, E2± is an obvious target
for therapeutic intervention, and several
approaches have been made toward its
validation as a cancer target. That E2±
plays a crucial role in the cell cycle is
supported by E2± knockout cells, in which
inactivation of E2±-1, -2 and -3 causes cell
cycle arrest. ±urthermore, administering
short oligonucleotides containing the E2±
DNA binding site to sequestor E2± activity
away from cellular target genes, the so-
called
decoy
approach, prevents cellular
proliferation, and short peptides that block
E2± function by inhibiting dimerization
(with its essential partner protein DP-1) or
its interaction with DNA cause apoptosis
in tumor cells. ±urthermore, a small
molecule
that
is
believed
to
act
by
modulating the E2± pathway has entered
Phase I clinical studies.
Other regulatory factors involved in
control of the pRb/E2± pathway, including
cyclin-dependent kinases (Cdk) have also
attracted considerable attention as a drug
target. Though most members of the Cdk
family control cell cycle transitions such as
cyclin D/Cdk4 and cyclin E/Cdk2 (±ig. 3),
other members have been assigned much
more speciFc roles, like cyclinT1/Cdk9,
which regulates targets including RNA
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