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S5 | Editorial
doi:10.1038/nrd1748
S19 | doi:10.1038/nrd1737
INTRODUCTION
EDITORIAL OFFICE
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World Wide Web:
www.nature.com/nrd/focus/hotdrugs/2005
NATURE REVIEWS JOURNALS
Nature Reviews Cancer
Chief Editor: Ezzie Hutchinson
www.nature.com/reviews/cancer
Nature Reviews Drug Discovery
Chief Editor: Peter Kirkpatrick
www.nature.com/reviews/drugdisc
Nature Reviews Genetics
Chief Editor: Magdalena Skipper
www.nature.com/reviews/genetics
Nature Reviews Immunology
Chief Editor: Elaine Bell
www.nature.com/reviews/immunol
Nature Reviews Microbiology
Chief Editor: David OConnell
www.nature.com/reviews/micro
Nature Reviews Molecular
Cell Biology
Chief Editor: Arianne Heinrichs
www.nature.com/reviews/molcellbio
Nature Reviews Neuroscience
Chief Editor: Rachel Jones
www.nature.com/reviews/neuro
Azacitidine
Azacitidine
Drug properties
Azacitidine is a nucleoside analogue of cytidine that specifically inhibits DNA methylation by trapping DNA methyltransferases4
(FIG. 1). It was originally developed as a cytotoxic agent, and an application to the FDA
requesting its approval as such was turned
down more than 25 years ago. The discovery
in the early 1980s that it was a hypomethylating agent4, and the elucidation of the role of
DNA hypermethylation in cancer, have
prompted its re-evaluation and eventually
led to its recent approval. Azacitidine is
thought to exert its antineoplastic effects in
part by causing hypomethylation of DNA
and consequent reactivation of previously
silenced genes, including tumour-suppressor
genes4,5. It might also have activity through
incorporation into RNA, as well as direct
cytotoxicity.
Clinical data
S6
Indications
Basis of discovery
DNA methylation is a key epigenetic mechanism that results in the heritable silencing of
genes without a change in their coding
sequence3,4. Epigenetic processes are required
for the normal development of mammalian
cells, but are not used for the dynamic regulation of gene expression1. However, it is now
known that malignant cells can exploit the
process of DNA methylation to silence the
expression of genes that counteract the malignant phenotype, such as tumour-suppressor
genes3. Leukaemias and MDS are characterized by the hypermethylation and consequent silencing of multiple genes1,3, which
has led to interest in inhibiting DNA methylation as a therapeutic strategy for treating
these diseases.
NH2
N
HO
N
N
OH OH
Azacitidine
4-amino-1--Dribofuranosyl-striazin-2(1H)-one;
C8H12N4O5; Mr = 244;
CAS number: 320-67-2
DNA
replication
Strand
separation
Z
Z
DNMTs
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MAY 2005 | S 7
Bevacizumab
Bevacizumab
tumour angiogenesis was mediated by diffusible factors produced by tumour cells, and
this hypothesis stimulated efforts to identify
these factors1.
In the 1980s, such efforts led to the isolation of vascular endothelial growth factor
(VEGF), a potent stimulator of the growth
of endothelial cells, the main type of cell in
the inside lining of blood vessels1. It is now
known that VEGF, which activates receptor
tyrosine kinases on the surface of endothelial
cells (FIG. 1), is a key regulator of normal and
pathological blood vessel growth 1. In the
early 1990s, the demonstration that inhibition of VEGF-induced angiogenesis using a
monoclonal antibody against VEGF markedly
suppressed tumour growth in vivo3 led to the
development of bevacizumab.
Drug properties
Basis of discovery
VEGF
VEGFR1
Bevacizumab
VEGFR2
Proliferation
Migration
Survival
Angiogenesis
Permeability
Figure 1 | Simplified view of VEGF signalling and tumour angiogenesis. The receptors for vascular
endothelial growth factor (VEGF, also known as VEGF-A) VEGFR1 (also known as Flt1) and VEGFR2
(also known as Flk1 or KDR) are expressed on the surface of blood endothelial cells. VEGFR2 is
thought to be the major mediator of endothelial cell mitogenesis, survival and microvascular permeability,
whereas VEGFR1 does not seem to mediate an effective mitogenic signal in endothelial cells, but does
have other activities that can be important in tumour growth and metastasis, including the induction of
matrix metalloproteinases (MMPs). tPA, tissue plasminogen activator; uPA, urokinase-type plasminogen
activator. Adapted from REF. 1.
S8
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It was initially believed that the VEGF receptors (VEGFRs) are present only on endothelial
cells, but recent studies have demonstrated that
VEGFRs are present on tumour cells9,10. So,
another potential mechanism of action of antiVEGF therapy is a direct effect on tumour cells,
where it might inhibit processes involved in
tumour progression and metastasis.
In addition to the above novel mechanisms
for anti-VEGF therapy, it is still believed that
anti-VEGF therapy can inhibit tumour angiogenesis. A detailed analysis has shown that the
addition of bevacizumab to chemotherapy
leads to a remarkable improvement in progression-free survival relative to the incremental
improvement in response rate as seen with
chemotherapy alone (A. Grothey, personal
communication). This observation suggests
that anti-VEGF therapy might indeed be antiangiogenic, although this is indirect evidence.
How do you see anti-VEGF therapy evolving in
the next few years?
Although most studies with bevacizumab have
been carried out in patients with advanced-stage
disease, future studies will include its use in
combination with other therapies in the neoadjuvant and adjuvant settings. Interesting
results have already been obtained with the use
of bevacizumab in addition to chemoradiation
therapy for locally advanced rectal and pancreatic cancers11,12, and ongoing trials in CRC
should provide some insight into the appropriate use of this agent in the adjuvant setting.
However, one must consider the long-term
effects of bevacizumab. In a meta-analysis of
randomized Phase III trials, a 2.3-fold increase
in arterial thrombotic events, including stroke,
myocardial infarction, angina and transient
ischaemic attacks, was noted. This is particularly
important in patients who will be receiving
bevacizumab in the adjuvant setting, and longterm follow up of cardiovascular events is crucial in such studies, especially as many patients
would remain disease-free without therapy or
with chemotherapy alone as adjuvant therapy.
Although anti-angiogenic therapy was originally intended for use as single-agent therapy,
and was then combined with chemotherapy,
there is also great potential for use in combination with other biological agents. One very
interesting observation during the past year has
been the results from the BOND2 study (a follow-up of the BOND1 study of cetuximab with
or without irinotecan in irinotecan-refractory
patients). In this study, patients with metastatic
CRC who had progressed on irinotecan-based
therapy were randomized to receive cetuximab
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MAY 2005 | S 9
Cetuximab
Cetuximab
Clinical data
Colorectal cancer is one of the most commonly diagnosed cancers, and has been estimated to be the fourth largest cause of cancer
deaths worldwide1. Recently, there have been
important advances in the therapy of this disease, such as the introduction of the cytotoxic
drugs irinotecan (Camptosar; Pfizer) and
oxaliplatin (Eloxatin; Sanofi-Aventis), and the
antibody bevacizumab (Avastin; Genentech/
Roche), which targets tumour angiogenesis.
Nevertheless, a major need remains for novel
agents for treating colorectal cancer, especially
for those patients who fail to respond to
current treatments or who develop resistance
to them.
Drug properties
S10
Cetuximab, used in combination with irinotecan, is approved by the FDA for the treatment
of EGFR-expressing, metastatic colorectal
carcinoma in patients who are refractory to
irinotecan-based chemotherapy6.
Cetuximab administered as a single agent
is approved by the FDA for the treatment of
EGFR-expressing, metastatic colorectal carcinoma in patients who are intolerant to
irinotecan-based chemotherapy6.
Ligand binding
Basis of discovery
Indications
Cetuximab
EGFR
Autophosphorylation
TK
TK
TK
TK
Gefitinib, erlotinib
Activation of signal-transduction
cascades (for example, MAPK)
Cell
proliferation
Apoptosis
Invasion and
metastasis
Angiogenesis
Figure 1 | EGFR and the mode of action of cetuximab. The epidermal growth factor receptor (EGFR)
is one of four members of the erbB family of receptor tyrosine kinases, which consist of an extracellular
domain that can bind ligands, a transmembrane domain and an intracellular tyrosine kinase domain8.
A simplified illustration of the EGFR signal transduction pathway is shown. Binding of a ligand to EGFR
causes receptor dimerization (either with another EGFR monomer or with another member of the erbB
family), leading to tyrosine kinase activation8. The resultant receptor autophosphorylation initiates
signal-transduction cascades involved in cell proliferation and survival8. Cetuximab blocks binding of
ligands to EGFR, thereby inhibiting receptor phosphorylation and downstream events. Agents that
inhibit the tyrosine kinase activity of EGFR have also been developed and, of these, two have been
approved by the FDA so far: gefitinib (Iressa; AstraZeneca) and erlotinib (Tarceva; Genentech/Roche),
for the treatment of advanced non-small-cell lung cancer. MAPK, mitogen-activated protein kinase;
TGF-, transforming growth factor-; TK, tyrosine kinase domain.
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MAY 2005 | S 1 1
Clofarabine
Clofarabine
Indications
Basis of discovery
S12
NH2
N
NH2
NH2
N
O
HO
N
O
Cl
HO
HO N
O
HO
F N
O
Cl
OH
OH
Cladribine
OH
Fludarabine
OH
Clofarabine
2-chloro-9-(2-deoxy-2-fluoro-D-arabinofuranosyl)-9Hpurin-6-amine;
C10H11ClFN5O3; Mr = 303.68;
CAS number: 123318-82-1
Figure 1 | Clinically used purine nucleoside analogues. a | Chemical structures of cladribine and
fludarabine. b | Clofarabine, a hybrid of cladribine and fludarabine, is also substituted with a halogen at
position 2 of the purine ring, which makes it resistant to deamination by adenosine deaminase2.
Substitution of a fluorine moiety at the 2 carbon in the arabino configuration in clofarabine increases its
stability in acid compared with cladribine and its resistance to cleavage of the glycosidic bond by bacterial
purine nucleoside phosphorylases2,3, which for fludarabine leads to the formation of 2-F adenine, a toxic
compound with no antitumour selectivity.
| MAY 2005
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MAY 2005 | S 1 3
Erlotinib hydrochloride
Erlotinib
Lung cancer has been estimated to be the leading cause of cancer mortality worldwide1. The
most common form non-small-cell lung
cancer (NSCLC), which accounts for ~75% of
cases is too advanced to be operable in
>50% of patients, and standard first-line
chemotherapy based on platinum agents only
improves survival modestly2. Second-line
treatment options in patients with advanced
NSCLC are limited; docetaxel is the only established choice to be approved by the FDA.
The limited efficacy and lack of specificity
of cytotoxic chemotherapy in solid tumours
such as NSCLC has provided an impetus to
develop therapies that aim to specifically target
cancer cells by modulating the aberrant molecular pathways underlying tumour growth and
progression, in the hope of achieving greater
efficacy with fewer side effects. In particular,
HN
O
O
Autophosphorylation
TK
TK
TK
TK
N
HCl
Erlotinib hydrochloride
Erlotinib
N-(3-ethynylphenyl)-6,7-bis
(2-methoxyethoxy)-4-quinazolinamine;
C22H23N3O4HCl;
Mr = 429.90;
CAS registry number: 183319-69-9
Activation of signal-transduction
cascades (for example, MAPK)
Cell
proliferation
Apoptosis
Invasion and
metastasis
Angiogenesis
Figure 1 | EGFR signalling and erlotinib. a | Simplified illustration of signal transduction through the
epidermal growth factor receptor3,4 (EGFR). Ligand binding leads to receptor dimerization. This results in
receptor autophosphorylation, which is inhibited by erlotinib. b | Structure of erlotinib hydrochloride.
MAPK, mitogen-activated protein kinase; P, phosphate group; TGF, transforming growth factor; TK,
tyrosine kinase domain.
S14
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MAY 2005 | S 1 5
Pemetrexed disodium
Pemetrexed
dTMP
significantly increased median overall survival time of 12.1 months, compared with 9.3
months for those receiving cisplatin alone5,6.
NSCLC is the most common form of lung
cancer, which is the leading cause of cancer
mortality worldwide. First-line therapy of
NSCLC is based on platinum agents, and docetaxel is the standard second-line treatment
option. Pemetrexed disodium was compared
with docetaxel in a randomized trial involving
571 patients with locally advanced metastatic
NSCLC after prior chemotherapy; patients
treated with pemetrexed disodium also received
folic acid and vitamin B12 supplements. Pemetrexed disodium did not show superiority over
docetaxel on the primary endpoint of survival,
and there were no statistically significant differences between pemetrexed disodium and docetaxel with respect to the secondary endpoints
such as objective response rate5. However,
pemetrexed disodium had a more favourable
safety profile than docetaxel; for example, it
caused significantly less neutropenia and febrile
neutropenia5,7.
Indications
Pemetrexed disodium in combination with cisplatin is approved by the FDA for the treatment
of patients with MPM whose disease is unresectable or who are otherwise not candidates
for curative surgery5. Pemetrexed disodium as a
single agent is also approved by the FDA for the
treatment of patients with locally advanced or
metastatic NSCLC after prior chemotherapy5.
b
DNA
dUMP
DHF
DHFR
H2N
TS
DNA, RNA
H
N
CO2
O
N
H
Na
7H2O
CO2
Na
HN
5,10-CH2-THF
THF
Purine
nucleotides
10-CHO-THF
GARFT
AlCARFT
acid, N-[4-[2-(2-amino-4,7-dihydro4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]
benzoyl]-,disodium salt, heptahydrate;
C20H19N5Na2O67H2O;
Mr = 597.49; CAS number: 150399-23-8
GAR
Drug properties
S16
Figure 1 | Folate metabolism and pemetrexed. a | Simplified illustration of some key enzymatic
reactions of folate metabolism, showing enzymes affected by pemetrexed, or its polyglutamates. These
multiple drug effects impair nucleotide synthesis and thereby inhibit cell proliferation. b | Structure of
pemetrexed disodium. AICARFT, aminoimidazole carboxamide ribonucleotide formyltransferase; DHFR,
dihydrofolate reductase; GARFT, glycinamide ribonucleotide formyltransferase; THF, tetrahydrofolate, TS,
thymidylate synthase.
| MAY 2005
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3.
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MAY 2005 | S 1 7
Online links
FURTHER INFORMATION
National Cancer Institute: http://www.nci.nih.gov/
Surveillance, Epidemiology, and End Results:
http://seer.cancer.gov/
Wood Mackenzie: http://www.woodmac.com
Access to this interactive links box is free online.
a 2003
b 2008
882
1,129
3,934
2,338
3,509
8,012
4,226
2,292
6,144
2,583
4,960
29,970
59,271
15,757
2,286
9,367
11,628
1,753
3,394
Colorectal/stomach
Supportive therapies
Others
Lymphoma
Breast cancer
Prostate cancer
5,048
Lung cancer
Ovarian cancer
Leukaemia
Figure 1 | The global oncology market divided by indication. Sales are in US $ million.
205.0
189.0
200
169.4
148.3
150
100
60.9
50
30.8
23.3
Colorectal
Breast
Lung
Leukaemia
Lymphoma
Prostate
Ovarian
Figure 2 | Estimated annual number of new cases of selected cancers in the United States in 2002.
Source: Surveillance, Epidemiology, and End Results (SEER), USA.
Companies
2003 sales
(US $ million)
2003 market
share (%)
Rank by 2008
forecast sales
2008
market share
4,478
14.9
10,444
17.6
Amgen
3,139
10.5
9,564
16.1
Sanofi-Aventis proforma
3,041
10.1
6,283
10.6
Novartis
2,907
9.7
6,867
11.6
AstraZeneca
2,743
9.2
5,028
8.5
Bristol-Myers Squibb
2,110
7.0
3,084
5.2
1,666
5.6
1,944
3.3
GlaxoSmithKline
1,635
5.5
10
1,921
3.2
Takeda
1,277
4.3
14
732
1.2
10
Eli Lilly
1,040
3.5
2,871
4.8
Pfizer
1,938
3.3
Top 10
24,036
80.2
49,944
84.3
Others
5,934
19.8
9,327
15.7
Total
29,970
100.0
59,271
100.0
MAY 2005 | S 1 9