184
Cancer Chemotherapy, Theoretical Foundations of
receiving chemotherapy alone. While can-
cer therapies that inhibit angiogenesis
remain in their infancy, clinical studies
like the Avastin trial emphasize future
potential.
10
Regulating Protein Turnover
Increasing evidence suggests that drugs
that influence protein degradation may
prove to be beneFcial in cancer treatment.
As we have discussed, protein degrada-
tion plays a crucial role in regulating
cell viability, not only in the control of
damaged proteins but also in controlling
key regulatory processes. The turnover of
many cell cycle regulatory proteins is re-
quired for normal cell cycle control, for
example, the Cdk inhibitor p27 whose
degradation is enhanced in certain tumor
cells. Similarly, signaling to the N±
κ
B
transcription factor is dependent upon
protein turnover of its speciFc inhibitor
I
κ
B, allowing N±-
κ
Bt
oa
c
t
i
v
a
t
eav
a
-
riety of genes including cytokines (like
tumor necrosis factor) and antiapoptotic
proteins.
The proteasome plays a central role in
regulating protein turnover. The 26S pro-
teasome is a large multiprotein complex
composed of a 20S catalytic complex to-
gether with two 19S regulatory subunits
that degrade proteins targeted by ubiqui-
tination through the addition of ubiquitin
to lysine residues. Ubiquitinated proteins
are broken down to short peptides by the
central subunit rings of the proteasome,
which contain multiple active sites recog-
nizing threonine as the catalytic residue
(±ig. 7).
It has become increasingly clear that
compounds that block proteasome func-
tion possess potential as anticancer agents.
The Frst compounds identiFed exhibited
inappropriate pharmacokinetic properties
but ultimately led to the generation of
compounds with improved properties, in-
cluding PS-341 (known as Velcade and
developed by Millenium). Velcade has
activity across a wide range of tumor
cells but appears to act preferentially on
tumor cells compared to normal cells.
Myeloma cells undergo apoptosis when
treated with Velcade, in contrast, for exam-
ple, to normal bone marrow stromal cells,
which exhibit a much reduced sensitivity
proFle.
Other promising properties of protea-
some inhibitors relate to the potential
utility in resistant disease. Velcade will
arrest the growth of myeloma cells that
are resistant to conventional chemother-
apies, and overexpression of Bcl2 does
not affect the sensitivity of myeloma to
Velcade. Velcade was the Frst protea-
some inhibitor to enter clinical trials in
hematological malignancy and solid tu-
mors. While the drug is rapidly cleared
from plasma (over 90% clearance within
15 min of administration), early indica-
tions of efFcacy were observed in Phase
I trials. EfFcacy was subsequently con-
Frmed in a Phase II trial on patients
with refractory multiple myeloma. Velcade
has successfully completed Phase III clin-
ical trials in multiple myeloma, and is
the Frst proteasome inhibitor to be ap-
proved (by the US ±DA), for multiple
myeloma.
11
Conclusions and Perspectives
We are beginning to see subtle hints that
exploiting mechanism-based approaches
will deliver improved cancer medicines
over many existing chemotherapeutics.
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