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TRENDS in Pharmacological Sciences
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Vol.24 No.3 March 2003
Cell-cycle dysregulation and
anticancer therapy
Zoe A. Stewart, Matthew D. Westfall and Jennifer A. Pietenpol
Department of Biochemistry, Center in Molecular Toxicology and the Vanderbilt-Ingram Cancer Center, Vanderbilt University School
of Medicine, Nashville, 37232TN, USA
Cell-cycle dysregulation is a hallmark of tumor cells. The
ability of normal cells to undergo cell-cycle arrest after
damage to DNA is crucial for the maintenance of genomic
integrity. The biochemical pathways that stop the cell
cycle in response to cellular stressors are called checkpoints. Defective checkpoint function results in genetic
modifications that contribute to tumorigenesis. The regulation of checkpoint signaling also has important clinical
implications because the abrogation of checkpoint function can alter the sensitivity of tumor cells to chemotherapeutics. Here, we provide an overview of the mechanisms
that regulate the cell cycle, current anticancer therapies
that target checkpoint signaling pathways, and strategies
for the development of novel chemotherapeutic agents.
Eukaryotic cells have evolved signaling pathways to
coordinate cell-cycle transitions and ensure faithful
replication of the genome before cell division. Cell-cycle
progression is stimulated by protein kinase complexes,
each of which consists of a cyclin and a cyclin-dependent
kinase (CDK) [1]. CDKs are expressed constitutively
throughout the cell cycle, whereas cyclin levels are
restricted by transcriptional regulation of cyclin-encoding
genes and by ubiquitin-mediated degradation [2]. CDK
activation requires the binding of a cyclin partner in
addition to site-specific phosphorylation [1].
The complexes cyclin-D – CDK4, cyclin-D – CDK6,
cyclin-E – CDK2 and cyclin-A – CDK2 regulate the progression from G1 phase to S phase [1]. The retinoblastoma
protein (pRB) is a crucial substrate of activated cyclin–CDK
complexes in the G1 phase. pRB is sequentially phosphorylated by cyclin-D – CDK4,6 and cyclin-E – CDK2
during G1 phase progression, and either represses or
activates transcription, depending on its phosphorylation
state and associated proteins [3]. Hypophosphorylated
pRB binds to and inactivates members of the E2F family of
transcription factors [3]. Because E2F family members
mediate transcription of genes required for DNA synthesis,
binding of hypophosphorylated pRB to E2F arrests cells in
the G1 phase. During G1-phase progression, CDK-mediated
hyperphosphorylation of pRB results in the dissociation of
pRB and E2F and entry into the S phase (Fig. 1).
Progression from G2 to M phase is regulated by the
cyclin-B – CDK1 complex. Inactive cyclin-B –CDK1 complexes accumulate during the G2 phase of the cell cycle
Corresponding author: Jennifer A. Pietenpol ([email protected]).
because phosphorylation of CDK1 by Wee1 and Myt1
inhibit CDK1 activity [4]. Entry into mitosis requires that
cyclin-B–CDK1 complexes are activated by CDC25C phosphatase, which removes the inhibitory phosphorylation of
CDK1 [4]. Mitotic exit occurs after ubiquitination and proteolytic degradation of cyclin B by the anaphase-promoting
complex (APC), which inactivates CDK1 (Fig. 2) [2].
Cell-cycle checkpoints
Eukaryotic cells have developed control mechanisms that
restrain cell-cycle transitions in response to stress. These
p16
G1 phase
pRB
E2F
CDK4
Cyclin D
P
p21
P
pRB
E2F
CDK2
Cyclin E
P P P
pRB
P P P
E2F
S phase
E2F
pRB
S phase genes
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Fig. 1. During G1-phase progression, cyclin-D–CDK4 and cyclin-E–CDK2 complexes are activated. These sequentially phosphorylate the retinoblastoma protein
(pRB) transcription factor. Binding of hypophosphorylated pRB to E2F transcription factors inhibits entry into S phase. However, hyperphosphorylated pRB
releases E2F, which results in activation of genes required for S-phase entry. Members of the INK4A and Cip/Kip CDKI families (represented by p16 and p21, respectively) can inhibit cyclin–CDK complexes and mediate G1 –S cell-cycle arrest.
Abbreviations: CDK, cyclin-dependent kinase; CDKI, CDK inhibitor.
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Genotoxic stress
P
ATM
ATR
p53
Chk1,2
14–3–3σ
CDK
P
Cytoplasmic
sequestration
P P P
pRB
P
CDC25C
CDC25C
Cytoplasmic
sequestration
CDC25C
pRB
P P P
P
E2F
CDK1
E2F
14–3–3
CDK1
p21
Cyclin
X
Cyclin-B1–CDK1
synthesis blocked
CDK1
Cyclin B
Active
Mitosis
MYT1, Wee1
Cyclin B
Inactive
G2 arrest
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Fig. 2. Activation of the G2-phase checkpoint after genotoxic stress. In response to genotoxic stress, the ATM, ATR signaling pathway is activated, which leads to the phosphorylation and activation of Chk1 and Chk2 and the subsequent phosphorylation of CDC25C. Phosphorylated CDC25C is sequestered in the cytoplasm by 14–3 –3 proteins,
which prevents activation of cyclin-B–CDK1 by CDC25C and results in G2 arrest. Activated ATM –ATR also activates p53-dependent signaling. This contributes to the
maintenance of G2 arrest by upregulating 14– 3– 3s, which sequesters CDK1 in the cytoplasm. In addition, p53 induces the transactivation of p21, a CDKI that binds to
cyclin–CDK complexes, reduces phosphorylation of pRB and, thus, prevents E2F from promoting the synthesis of cyclin B and CDK1. p21 also blocks mitotic entry by
binding and inhibiting cyclin-B–CDK1 complexes directly. Abbreviations: ATM, ataxia telangiectasia mutated; ATR, ATM and Rad3-related; CDK1, cyclin-dependent kinase
1; CDKI, CDK inhibitor; Chk1, checkpoint kinase 1; MYT1, membrane-associated tyrosine- and threonine-specific cdc2 inhibitory kinase; pRB, retinoblastoma protein.
regulatory pathways are termed cell-cycle checkpoints [5].
Cells can arrest transiently at cell-cycle checkpoints to
allow for the repair of cellular damage. Alternatively, if
damage is irreparable, checkpoint signaling might activate pathways that lead to programmed cell death. Loss of
checkpoint integrity can allow the propagation of DNA
lesions and result in permanent, genomic alterations [5].
Checkpoint pathways that regulate cell-cycle progression
are disrupted frequently in tumor cells, which underscores
the importance of intact checkpoint signaling for maintaining the genome.
G1 –S checkpoint
Inhibition of G1-phase cyclin –CDK complexes plays a key
role in the function of the G1–S checkpoint. CDKs are
negatively regulated by a group of functionally related
proteins called CDK inhibitors (CDKIs) of which there are
two families, the INK4 inhibitors and the Cip/Kip
inhibitors [1]. The INK4 family has four members:
p16INK4A (p16), p15INK4B (p15), p18INK4C (p18) and
p19INK4D (p19); and the Cip/Kip family has three
members: p21Waf1/Cip1 (p21), p27Kip1 (p27) and
p57Kip2 (p57). The INK4 family inhibits CDK4 and
CDK6 activity during G1 phase specifically, whereas the
Cip/Kip family can inhibit CDK activity during all phases
of the cell cycle [1]. Both families of CDKI have important
roles in the G1 –S checkpoint (Fig. 1). After normal cells
are exposed to genotoxic agents, transcription of p21 is
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activated by the p53 tumor suppressor protein. The p21
protein binds to and inactivates cyclin-E – CDK2 complexes, which results in pRB hypophosphorylation and
cell-cycle arrest at the G1– S transition [6]. p16 mediates
the p53-independent G1 arrest in response to DNA
damage in several cell types through abrogation of
cyclin-D – CDK4 and cyclin-D – CDK6-mediated phosphorylation of pRB [7].
G2 checkpoint
Genotoxic stress also triggers checkpoint pathways that
initiate cell-cycle arrest in the G2 phase. After DNA damage,
ATM (ataxia telangiectasia mutated)- and ATR (ATM and
Rad3-related)-dependent signaling induces G2 cell-cycle
arrest by inhibiting CDK1 (Fig. 2). ATM activates human
checkpoint kinase 2 (Chk2) in cells that are exposed to
ionizing radiation, whereas ATR signaling mediates activation of Chk1 in cells treated with ultraviolet radiation [8].
Chk1 and Chk2 phosphorylate CDC25C, which generates a
consensus binding site for 14 – 3 – 3 proteins. Binding of
14 – 3 – 3 proteins to CDC25C results in nuclear export and
cytoplasmic sequestration of the phosphatase, with subsequent G2 arrest caused by inhibition of CDK1 [8]. Recent
studies indicate that p53 is required to sustain the G2-phase
arrest induced by DNA damage in tumor cells [9,10]. p53
maintains the G2 checkpoint by upregulating transcription
of 14 – 3 –3s and p21, which inhibit G2 progression by
sequestrating CDK1 in the cytoplasm and by inactivating
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(a)
Unattached kinetochores,
disruption of microtubules
APC
Metaphase
BUB1,
BUB3
Anaphase
MAD2,
BUBR1
Apoptosis
(b)
Unattached kinetochores,
disruption of microtubules
APC
Metaphase
X
BUB1,
BUB3
X
Anaphase
Aberrant
MAD2, mitotic exit
BUBR1
Aneuploid cell
TRENDS in Pharmacological Sciences
Fig. 3. Improper chromosome alignment on the mitotic spindle, disruption of microtubule dynamics and unattached kinetochores can activate the spindle checkpoint.
Spindle-checkpoint signaling is mediated by BUB1, BUB3, BUBR1 and MAD2, which localize to kinetochores. (a) Intact spindle-checkpoint signaling induces either
metaphase arrest through inhibition of the anaphase-promoting complex (APC) or apoptosis. (b) Defective spindle-checkpoint function that results from either loss of
BUB1- and BUB3-dependent signaling or abrogation of MAD2, BUBR1-mediated inhibition of the APC can lead to aberrant exit from mitosis and, in the absence of a
functional G1 –S checkpoint, generate aneuploid cells.
cyclin-B – CDK1 complexes, respectively (Fig. 2) [10– 13].
Furthermore, p21 can disrupt the interaction between
proliferating cell nuclear antigen (PCNA) and CDC25C to
induce G2 cell-cycle arrest [14].
Mitotic spindle checkpoint
The mitotic spindle checkpoint monitors the microtubule
structure and chromosome attachments of the mitotic
spindle and delays chromosome segregation during anaphase until defects in the mitotic spindle apparatus are
corrected (Fig. 3). The kinetochore-associated MAD2,
BUBR1, BUB1 and BUB3 proteins are crucial constituents
of the spindle-checkpoint pathway. MAD2 and BUBR1
regulate mitotic progression by direct interaction and
inhibition of the APC machinery, which prevents anaphase
entry in the presence of mitotic spindle dysfunction [15].
BUB1 and BUB3 also mediate mitotic arrest after
disruption of microtubules, because cells that lack either
BUB1 or BUB3 do not undergo mitotic arrest when treated
with spindle-disrupting agents [15].
Dysregulation of the cell cycle in human cancers
Loss of cell-cycle checkpoints is a hallmark of human
cancers. Alterations in components of the cell-cycle
machinery and checkpoint signaling pathways occur in
most human tumors. Ultimately, these genetic modifications result in the dysregulation of oncogenes and tumor
suppressor genes, which has important implications for
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the optimization of current therapeutic regimens and the
selection of novel cell-cycle targets.
Alterations in the constitutive cell-cycle machinery
Cell-cycle regulation by the tumor suppressor protein pRB
plays an integral role in preventing human tumors because
oncogenic alterations in cyclins, CDKs and other upstream
regulators of pRB occur in a variety of human tumors,
including breast and lung cancers, retinoblastoma and
osteosarcoma [3]. In tumors with a normal pRB-encoding
gene, modifications in components of the signaling pathways
that regulate pRB are frequently noted, such as increased
levels of cyclin D and cyclin E, amplification of the genes that
encode CDK4 and CDK6 and deletion of p16 [3]. For
example, ,50% of invasive breast cancers have elevated
cyclin D expression, compared with surrounding normal
breast epithelium [16], and transgenic mice that overexpress
human cyclin D1 or cyclin E in mammary cells develop
mammary adenocarcinomas [17,18]. Similarly, amplification of the genes that encode CDK4 and CDK6 occurs in
sarcomas, gliomas, melanomas and breast cancers [19].
Alterations in checkpoint signaling proteins
Genetic alterations of genes encoding cell-cycle checkpoint
signaling molecules are common in human tumors. Mutation
of p53 is the most frequently observed genetic lesion in
human tumors [6]. The importance of p53-dependent
signaling in tumor suppression is underscored by the
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finding that germline mutations of p53 result in LiFraumeni syndrome, a highly penetrant familial syndrome that is associated with significantly increased
incidence of brain tumors, breast cancers and sarcomas
[20]. In human tumors in which p53 is normal, p53
function might be disrupted by alterations in cellular
proteins that modulate the expression, localization and
activity of the protein. For example, during normal
cellular growth, Mdm2 binds p53 and targets it for
ubiquitin-mediated degradation [21]. In some tumors
with wild-type p53, the gene that encodes Mdm2 is
amplified, which results in overexpression of Mdm2 and
subsequent inactivation of p53 [22].
Modifications in CDKI function are also common in
human tumors. p27 is often expressed aberrantly in
human breast cancers and low concentrations of p27 are
associated with more aggressive breast tumors [23,24].
p27 haplo-insufficiency also renders murine mammary
epithelium more susceptible to oncogene-dependent transformation [25]. Likewise, decreased expression of p57 is
reported in human bladder cancers [26] and either deletion
of p15 and p16 or inactivation through methylation is
linked to the pathogenesis of human melanomas, lymphomas, mesotheliomas and pancreatic cancers [19].
Mutations in other components of pathways associated
with responses to DNA damage could lead to enhanced
tumorigenesis. For example, ATM mutations occur in ataxia
telangiectasia, a familial disease that is associated with an
elevated incidence of leukemias, lymphomas and breast
cancer [27]. Mutations of Chk2 and Chk1 also arise in human
cancers. Chk2 mutations are reported in human lung cancer
[28], whereas Chk1 mutations are observed in human colon
and endometrial cancers [29]. In addition, heterozygous
mutations in CHK2 occur in a subset of individuals with
Li-Fraumeni syndrome that lack p53 mutations [30].
Disruption of spindle checkpoints is also linked to the
pathogenesis of several human tumors. In human colon
carcinoma cells, BUB1 mutations have been identified [31]
that facilitate the transformation of cells that lack the
breast cancer susceptibility gene, BRCA2 [32]. Recent
studies by Michel et al. demonstrate that MAD2 haploinsufficiency significantly elevates the rate of lung tumor
development in MAD2þ/2 mice compared with agematched wild-type mice [33].
Therapeutic manipulation of cell-cycle checkpoints
Preclinical studies indicate that cells with defective
checkpoint function are more vulnerable to some anticancer agents. Thus, research efforts are focused on
identifying compounds that disrupt cell-cycle checkpoints.
These investigations include: (1) the development of
chemical inhibitors through structure-based, rational,
drug design; (2) the use of high-throughput screening
assays; and (3) the manipulation of genetic-based screening technologies to identify novel anticancer therapies.
Chemical approaches
Because the activity of CDKs is often deregulated in
tumors, compounds that inhibit CDK function might be
effective anticancer agents. Flavopiridol, a chemical
CDKI, arrests cancer cells at the G1 –S and G2 –M
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transitions by inhibiting CDK2, CDK4 and CDK1 [34].
Flavopiridol has potent antiproliferative activity in several human cancer cell lines, and xenograft tumor studies
in mice indicate that it acts synergistically with other
anticancer agents [34]. Flavopiridol produced favorable
clinical responses in Phase 1 and Phase 2 studies of
patients with renal, colorectal, gastric, lung and esophageal carcinomas, and current clinical trials are evaluating
the drug in non-Hodgkin’s lymphoma, breast and prostate
cancers [19]. The clinical tests of flavopiridol and related,
chemical CDKIs has spawned further research efforts to
design mechanism-based CDKIs through manipulation of
the phosphorylation and cyclin-binding sites of CDK
proteins. However, the specificity of chemical CDKIs
remains a limiting factor because patients in Phase 1
and Phase 2 studies experienced severe side-effects.
Several studies suggest that flavopiridol might act
through cell-cycle-independent mechanisms because it
binds to and inactivates cytosolic aldehyde dehydrogenase
and glycogen phosphorylase [35,36] and inhibits transcription globally [37]. Recent studies by Knockaert et al.
addressed the issue of the specificity of chemical CDKIs
using an affinity chromatography approach in which
cellular extracts are passed over chemical CDKIs immobilized on a matrix. Microsequencing was then used to
identify the cellular proteins that bind the chemical CDKIs
[38,39]. Studies such as these will help determine the
specificity of an inhibitor and identify other targets that
might be either beneficial or antagonistic to therapeutic
strategies with newly developed compounds.
Numerous studies indicate that the chemotherapeutic
efficacy of agents such as ionizing radiation and cisplatin
can be enhanced by the abrogation of the DNA-damageinduced G2 arrest in cancer cells. Tumor cells treated with
either caffeine or pentoxifylline, compounds that disrupt
the G2 checkpoint, are sensitized to ionizing radiation
[40,41]. Caffeine inhibits ATM and ATR kinases, which
prevents activation of Chk2 and Chk1 [8]. Caffeine also
inhibits homologous recombination, which provides an
additional mechanism by which it abrogates G2 block [42].
The effectiveness of targeting Chk1 to ablate the G2
checkpoint is exemplified by the use of the Chk1 inhibitors
UCN01 (7-hydroxystaurosporine) and SB2180708 (a
staurosporine-related compound; see Chemical names) to
increase the cytotoxic effect of DNA-damaging agents in
tumor cells [43,44]. Promising preclinical results that show
that pentoxifylline and UCN01 inhibit tumor growth in
vivo have prompted clinical trials to evaluate the efficacy of
these compounds against a variety of tumors [45– 47].
As with chemical CDKIs, UCN01 might disrupt tumor
growth by multiple mechanisms. For example, several
recent studies link mitogenic signaling to abrogation of the
G1 cell-cycle checkpoint in breast cancers [48– 50]. These
studies demonstrate that protein kinase B (PKB) phosphorylates p27 and causes it to accumulate in the
cytoplasm. PKB is a downstream target of the phosphatidylinositol 3-kinase (PI 3-kinase) signaling pathway and
phosphorylation and activation of PKB after PI 3-kinase
signaling is mediated by the 3-phosphoinositide-dependent protein kinase 1 (PDK1) [51]. A study by Sato et al.
shows that inhibition of PDK1 by UCN01 induces
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apoptosis by preventing the phosphorylation and activation of PKB [52]. Thus, in addition to modulating the
activity of Chk1, UCN01 might inhibit the survival signals
generated by kinases such as PDK1.
Although many anticancer drugs target kinases that
are involved in checkpoint signaling pathways, others
regulate checkpoint function by inhibiting either histone
deacetylases or proteasome-dependent ubiquitination.
Histone deacetylase inhibitors alter chromatin structure
and gene expression, which produces G2 checkpoint arrest
in normal human cells and mitotic catastrophe in tumor
cells [53]. In transformed cells inhibitors of histone
deacetylase can induce either differentiation or apoptosis,
but the precise mechanisms by which histone deacetylase
inhibitors induce growth arrest, differentiation and
apoptosis is a focus of current research [54,55]. The
histone deacetylase inhibitors FR901228 and MS27275
have potent anticancer activity in vitro [56] and in vivo
[57], and FR901228 has demonstrated efficacy against T-cell
lymphoma in clinical trials [58]. The ubiquitin – proteasome pathway is also an attractive target for manipulation
by anticancer drugs because it mediates the degradation of
cyclins and CDKIs [2]. PS341 is a proteasome-specific
inhibitor with significant in vitro cytotoxicity against a
variety of human tumor cell lines that has shown favorable
patient responses in Phase 2 clinical trials for melanoma,
lung cancer and sarcomas [59].
Screens for new compounds
Several screening strategies have been employed to
identify novel anticancer agents. In one such effort, the
National Cancer Institute (NCI) evaluated the anticancer
activity of 70 000 compounds against a panel of 60 cell
lines from human tumors [60]. Subsequent studies found
that the p53 status of these tumor cell lines was a crucial
determinant of cellular sensitivity to chemotherapeutic
agents because the growth of cell lines with mutant p53
was inhibited less than those with wild-type [61]. Recently,
Amundson et al. used the NCI cell lines to evaluate the basal
expression of transcripts of genes associated with checkpoint
pathways and correlated these with the sensitivity of the
cells to standard chemotherapy agents [62]. Similarly, cDNA
microarray analyses have been used to study the geneexpression profiles of these cell lines in response to standard
chemotherapeutic drugs [63]. Such studies provide
valuable insight into the correlation between the
expression of specific genes and drug sensitivity.
High-throughput screens have also been used to
identify novel compounds that disrupt checkpoint function. In one study, breast cancer cells that express mutant
p53 were grown in microtiter plates, irradiated to induce
G2 arrest, and then cotreated with the microtubule
inhibitor nocodazole and extracts from marine invertebrates [64]. This assay identified isogranulatimide, a novel
G2 inhibitor that has synergistic cytotoxicity in combination therapy with ionizing radiation [64]. A similar
microtiter-plate assay was used recently to screen
24 000 extracts from marine invertebrates and terrestrial
plants for novel antimitotic agents. This identified eight
novel chemicals with antimitotic activity [65]. In another
study, isogenic human colorectal cancer cell lines that
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143
differ only at the K-Ras locus were stably transfected with
an expression vector for either a yellow or a blue
fluorescent protein [66]. These isogenic cell lines were
used to screen 30 000 compounds to identify compounds
that are selectively toxic to the mutant Ras genotype. The
latter approach has identified a novel cytidine nucleoside
analog that is selective to tumor xenografts that contain
mutant Ras [66]. Recently, Bykov et al. screened a library
of low-molecular-weight compounds to identify agents that
restore wild-type function to mutant p53. The investigators
isolated the compound p53 reactivation and induction of
massive apoptosis (PRIMA-1), a 2,2-bis(hydroxy-methy)-1azabicyclo [2,2,2]octan-3-one that restores sequence-specific
DNA binding and an ‘active’ conformation to p53 derived
from tumors. In mice, PRIMA-1 has antitumor effects with
little toxicity [67]. The identification of small molecules
that either inhibit or restore biochemical activity of key,
cell-cycle-regulatory proteins opens exciting possibilities
for the future of cancer therapy.
Genetic approaches
Saccharomyces cerevisiae provides an attractive model
system to evaluate chemotherapeutic agents because of
the conservation of cell-checkpoint processes between
yeast and mammals, the availability of yeast genomic
sequences [68] and the ease of genetic manipulation in
yeast. In a recent study, anticancer drugs were screened
using a panel of isogenic strains of S. cerevisiae that
contain defined mutations in cell-cycle-checkpoint pathways [69]. The toxicity profiles of several chemotherapeutic agents and ionizing radiation differed between
strains, which indicates that the particular mutation in
DNA repair and cell-cycle-checkpoint systems in individual tumors might influence the outcome of a particular
chemotherapeutic regimen. Similarly, Schizosaccharomyces
pombe has been employed to select peptide inhibitors and
identify novel cellular targets for anticancer drugs [70]. In
this study, peptides were selected using phenotypic
analyses, followed by genetic dissection of candidate target
pathways to identify putative targets of the selected
inhibitors [70]. The identification of Ydr517w, a previously
unknown component of the spindle checkpoint, exemplifies the power of genetic approaches for identifying novel
components of known biological pathways that are
potential targets for drug discovery. Yeast genomics can
also be combined with analyses of cDNA microarrays to
examine genome-wide changes in gene expression after
treatment with anticancer regimens [71]. In a recent
study, this approach generated a database of expression
profiles from cell-cycle mutants of S. cerevisiae treated
with a panel of chemotherapeutic compounds and ionizing
radiation [72], and analysis of these profiles revealed novel
components of cell-cycle-signaling pathways.
Concluding remarks
Identifying the molecular differences between cancer cells
and normal cells is crucial for the continued development
of anticancer agents that preferentially target cancer cells
and minimize the toxicity to normal tissues. Information
generated from genomic and proteomic studies of
prokaryotes and eukaryotes will continue to reveal
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Chemical names
FR901228 (FK228 or depsipeptide): ðEÞ-ð1S; 4S; 10S; 21RÞ7-½ðZÞ-ethylidene-4; 21-diisopropyl-2-oxa-12; 13-dithia-5; 8;
20; 23-tetraazabicyclo-½8; 7; 6-tricos-16-ene-3; 6; 9; 19; 22pentanone
MS27275:
N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)aminomethyl]benzamide
PS341: N-pyrazinecarbonyl-L-phenylalanine-L-leucine boronic acid
SB2180708:
9,10,11,12-tetrahydro-9,12-epoxy-1H-diindolo[1,2,3-fg:30 ,20 ,10 -kl]pyrrolo[3,4-i][1,6]benzodiazocine-1,3(2H)dione
UCN01: 7-hydroxystaurosporine
new cell-cycle-regulatory molecules. As our knowledge of
cell-cycle checkpoints increases, novel signaling molecules
will be identified that can be targeted for rational drug
design. This will allow mechanism-based approaches to
cancer treatment that exploit the molecular defects in
tumors. To fully realize this potential, we need to continue
to develop technologies that define precisely the cell-cyclecheckpoint defects in individual tumors, and treatment
regimens that are tailored to the cell-cycle phenotypes of
tumors.
Acknowledgements
Supported by National Institutes of Health Institutional Training Grant
GM07347 (Z.A.S.), US Army Grant DAMD17 – 01 – 1 – 0439 (M.D.W.),
National Institutes of Health Grant CA70856 (J.A.P.) and US Army Grant
DAMD17 – 99 – 1 – 9422 (J.A.P.).
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Articles of interest in other Trends and Current Opinion journals
A polygenic basis for late-onset disease
Alan Wright et al., Trends in Genetics 19, 97 – 106
Trace amine receptors as targets for novel therapeutics: legend, myth and fact
Theresa A. Branchek and Thomas P. Blackburn, Current Opinion in Pharmacology 3, 90 – 97
Chemical proteomics and its application to drug discovery
Douglas A. Jeffery and Matthew Bogyo, Current Opinion in Biotechnology 2, 14, 87– 95
Determinant spreading and tumor responses after peptide-based cancer immunotherapy
Antoni Ribas et al., Trends in Immunology 24, 58 – 61
Molecular modeling of ion channels: structural predictions
Alejandro Giorgetti and Paolo Carloni, Current Opinion in Chemical Biology 7, 150 – 156
Resistance in the anti-angiogenic era: nay-saying or a word of caution?
Christopher J. Sweeney et al., Trends in Molecular Medicine 9, 24 – 29
The Yin and Yang of NMDA receptor signalling
Giles E. Hardingham and Hilmar Bading, Trends in Neurosciences 26, 81– 89
Pharmacology of traumatic brain injury
N.C. Royo et al., Trends in Endocrinology and Metabolism 13, 451 – 457
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