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Discovery,Development, and Clinical Applications of Bortezomib

Discovery,Development, and Clinical Applications of Bortezomib

ABSTRACT: Proteasome inhibition is a novel, targeted approach in cancer therapy. Both natural and synthetic proteasome inhibitors selectively penetrate cancer cells, disrupting the orderly destruction of key regulatory proteins involved in tumorigenesis and metastasis. Disrupting the orderly destruction of regulatory proteins causes an imbalance of these proteins within the cell, which interferes with the systematic activation of signaling pathways required to maintain tumor cell growth and survival; therefore, cellular replication is inhibited and apoptosis ensues. Bortezomib (PS-341, Velcade), the first proteasome inhibitor evaluated in human clinical trials, has been approved by the US Food and Drug Administration for use in patients with refractory or relapsed multiple myeloma. Preclinical study results show that bortezomib suppresses tumor cell growth, induces apoptosis, overcomes resistance to standard chemotherapy agents and radiation therapy, and inhibits angiogenesis. Phase I study results established the antitumor activity of bortezomib, administered alone or in combination with standard chemotherapy agents, in patients with advanced hematologic malignancies or solid tumors, usually without additive toxicities. The results of phase II studies further supported the antitumor activity of bortezomib in patients with refractory or relapsed multiple myeloma and non- Hodgkin’s lymphoma; less impressive results were observed in patients with stage IV renal cell cancer. Studies evaluating bortezomib in earlier stages of multiple myeloma, including first-line therapy, are under way. Evidence suggests that certain prognostic factors, such as older age and bone marrow containing more than 50% plasma cells, may be useful in predicting response and survival time in multiple myeloma patients receiving bortezomib. Further studies of bortezomib are needed to establish its full spectrum of activity, the ideal regimens for various tumor types, and clinically useful prognostic indicators that predict successful outcomes.

Agreater understanding of cancer
molecular biology has led
to the development of several
agents that target specific intracellular
signal transduction pathways involved
in cancer cell development and
progression.[1] One pathway, the
ubiquitin-proteasome pathway (UPP),
is primarily responsible for the systematic
degradation of cell cycle regulatory
proteins and has recently
received considerable attention.[2,3]
In cancer cells, the UPP is essential to
the mechanisms underlying tumorigenesis
and metastasis, including cell
cycle arrest, apoptosis, and angiogenesis.[
2] Disruption of the UPP, particularly
in rapidly dividing cancer cells,
can potentially arrest or retard cancer
progression by interfering with mechanisms
that confer malignant properties
to the cell.[4-6] Furthermore,
disruption of the UPP may interrupt
and potentially reverse mechanisms
of de novo and acquired resistance to
chemotherapy or radiation therapy.[6]

A variety of proteasome inhibitors,
both natural and synthetic, have been
shown to disrupt the UPP pathway.[4-
6] In 2003, the first proteasome inhibitor,
bortezomib (PS-341, Velcade), was
approved by the US Food and Drug
Administration (FDA) for the treatment
of recurrent and/or refractory
multiple myeloma. In 2004, the European
Commission also approved
the use of bortezomib for this indication
in European Union member
countries.[7]

This article reviews proteasome
function and inhibition, the results of
preclinical studies demonstrating tumoricidal
effects of proteasome inhibition
(PI), and the results of phase I
and II clinical trials evaluating bortezomib
in the treatment of various hematologic
malignancies and solid
tumors.

Proteasome Function
and Inhibitors

Cellular homeostasis and the ability
of cells to function in their environment
depend on the systematic
degradation of regulatory proteins and
their inhibitors.[4] The majority of
proteins in eukaryotic cells are degraded
by the UPP, which consists of
a ubiquitin-conjugating system and
proteasome.[6,8] For a protein to be
recognized by a proteasome, several
ubiquitin molecules must first attach
to the side of the target protein, a
process carried out by a cascade of
enzymes; this polyubiquinated
sidechain flags the protein for destruction
by a proteasome.[5] Proteasomes
are responsible for degrading more
than 80% of all cellular proteins-
including several important proteins
that regulate tumor cell survival, proliferation,
invasion and metastasis, angiogenesis,
and apoptosis-such as the
cyclin B1 cell-cycle regulatory protein;
the p53 tumor suppressor gene;
the p21 and p27 cyclin-dependent kinase
inhibitors; Iκβ, an inhibitor of
nuclear factor-kappa beta (NF-κβ);
the p44/42 mitogen-activated protein
kinase (MAPK); and the bax proapoptotic
protein.[4-6] Proteasome inhibition
results in accumulation of these
cellular proteins, resulting in antitumor
effects, such as cell-cycle arrest,
apoptosis, and downregulation of angiogenesis.[
6]

Because proteasomes are essential
components of eukaryotic cell protein
degradation, PI would seemingly
kill both normal and malignant cells.
However, all cells do not respond similarly
to PI. The results of several preclinical
studies suggest that malignant
cells are more susceptible to PI than
are normal cells.[9,10] The molecular
basis for this differential susceptibility
of cells to PI remains undetermined,
although several interesting theories
are being investigated.[5,6,9] For a
more in-depth discussion of UPP and
PI, refer to the article entitled "Pharmacology,
Pharmacokinetics, and
Practical Applications of Bortezomib"
in this supplement.

Numerous natural and synthetic
compounds inhibit the activity of proteasomes.
Many of these compounds
bind to and interfere with the chymotrypsin-
like activity (one of three types
of proteolytic activity within the proteasome)
of the proteasome.[4,9]
However, many of these inhibitors
also lack specificity for the proteasome,
have poor metabolic stability,
or bind irreversibly to the proteasome.[
4,5] An ideal proteasome inhibitor
would exhibit metabolic
stability, enzyme specificity, reversible
binding to the proteasome, and
selective cytotoxicity toward malignant
cells.[2]

The natural proteasome inhibitors
include lactacystin, expoxyketones
(epoxomicin and eponemycin), and
TMC-95 cyclic peptides. The synthetic
compounds include the peptide vinyl
sulfones, peptide aldehydes
(MG132 and PSI), and the peptide
boronic acids.[4,5] The peptide aldehydes
were one of the first groups of
proteasome inhibitors discovered.
However, their fast dissociation rate
from the proteasome and their rapid
transportation out of the cell by the
multidrug resistance (MDR) transporter
limited their usefulness as a therapeutic
strategy.[9] Because of these
limitations, the peptide boronic acids,
were developed by replacing an aldehyde
group with boronic acid; peptide
boronic acids have a slower
dissociation rate and up to 1,000-fold
higher potency than those of the peptide
aldehydes.[4,5] The peptide boronic
acids are selective for
proteasomes and form covalent and
reversible complexes within the chymotrypsin-
like site of proteasomes,
thereby inhibiting proteasome activity.[
5,11]

Bortezomib

Bortezomib is a peptide boronic
acid and the first proteasome inhibitor
to be approved for use in humans.
The results of a preclinical study by
the National Cancer Institute (NCI) in
60 cancer cell lines determined that
bortezomib had substantial in vitro
cytotoxicity against multiple human
tumors.[11] The NCI also compared
the mechanism of cytotoxicity of bortezomib
with that of 60,000 compounds
and determined bortezomib's
mechanism to be unique.[11] Although
the exact mechanism of cytotoxicity
of bortezomib and other
proteasome inhibitors has yet to be
fully elucidated, inhibition of proteasomes
by these agents affects numerous
cellular pathways, all of which
result in increased apoptosis of affected
cells.[11]

Preclinical Data
The NCI study results showing the
cytotoxic activity of bortezomib led
to the evaluation of this agent in numerous
murine xenograft models, representing
a wide variety of malignancies
(eg, multiple myeloma and
colorectal, pancreatic, prostate, and
ovarian cancers).[10-14] In these models,
bortezomib decreased tumor volume,
confirming its in vivo
effectiveness as an antineoplastic
agent. Bortezomib also demonstrated
an increased tumoricidal effect in human
xenografts when combined with
various standard chemotherapy
agents, including cisplatin, docetaxel
(Taxotere), fluorouracil (5-FU), gemcitabine
(Gemzar), irinotecan (Camptosar),
and paclitaxel.[12-15]

Results of preclinical studies of
multiple myeloma cell lines have also
demonstrated the ability of bortezomib
to circumvent chemotherapy or radiation
resistance and inhibit angiogenesis.[
16-22] The primary mechanism
by which bortezomib overcomes drug
resistance may be the downregulation
of NF-κB.[16,18-21] NF-κB activity
in resistant myeloma cell lines is higher
than that in nonresistant cell
lines.[16] Bortezomib also downregulates
or disrupts other resistance pathways
or mechanisms, such as the
p44/42 MAPK pathway, topoisomerase
II-α, Bcl-2, or the transcription
of genes involved in DNA
damage repair.[18,19] Furthermore,
bortezomib is not a substrate for the
multidrug resistance protein, a protein
that is overexpressed in tumors
resistant to a variety of chemotherapy
agents.[19]

Bortezomib's effects on the tumor
microenvironment include disruption
of cellular adhesion of cancer cells to
bone marrow stromal cells; this adhesion
is recognized as a principal promoter
of tumor cell growth and
survival. Cell-cell adhesion initiates
the production of growth factors (eg,
interleukin-6) that stimulate tumor resistance
to chemotherapy.[17,18] Finally,
bortezomib has been shown to
inhibit tumor angiogenesis, probably
as a result of decreased vascular endothelial
cell growth factor secretion
and high levels of endothelial cell
apoptosis. In preclinical models, bortezomib
markedly decreased microvessel
density and inhibited the
activity of proangiogenic cytokines
(eg, vascular endothelial growth factor
[VEGF]).[16,22] The ability of
bortezomib to inhibit tumor cell proliferation,
selectively induce apoptosis
in proliferating cells, alter the tumor
microenvironment, inhibit
angiogenesis, and overcome resistance
to standard therapies encouraged investigators
to initiate clinical trials
with this agent.

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