© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 5, 376-387,
March 1, 2000
© 2000 Oxford University Press
REVIEW |
Preclinical and Clinical Development of Cyclin-Dependent Kinase Modulators
Affiliation of authors: DTP Clinical Trials Unit, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD.
Correspondence to: Adrian M. Senderowicz, M.D., National Institutes of Health, Bldg. 10, Rm. 6N113, Bethesda, MD 20892 (e-mail: sendero{at}helix. nih.gov).
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ABSTRACT |
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 Top Abstract Introduction to Cell Cycle...Targets for Intervention in...Indirect cdk ModulatorsDirect cdk Modulators (Small...Consequences of cdk InhibitionPreclinical Pharmacology of...Human Clinical Trials of...Preclinical Pharmacology of UCN...Phase I Clinical Trials...SummaryNotesReferences |
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In the last decade, the discovery and cloning of the cyclin-dependent kinases (cdks), key regulators of cell cycle progression, have led to the identification of novel modulators of cdk activity. Initial experimental results demonstrated that these cdk modulators are able to block cell cycle progression, induce apoptotic cell death, promote differentiation, inhibit angiogenesis, and modulate transcription. Alteration of cdk activity may occur indirectly by affecting upstream pathways that regulate cdk activity or directly by targeting the cdk holoenzyme. Two direct cdk modulators, flavopiridol and UCN-01, are showing promising results in early clinical trials, in which the drugs reach plasma concentrations that can alter cdk activity in vitro. Although modulation of cdk activity is a well-grounded concept and new cdk modulators are being assessed for clinical testing, important scientific questions remain to be addressed. These questions include whether one or more cdks should be inhibited, how cdk inhibitors should be combined with other chemotherapy agents, and which cdk substrates should be used to assess the biologic effects of these drugs in patients. Thus, modulation of cdk activity is an attractive target for cancer chemotherapy, and several agents that modulate cdk activity are in or are approaching entry into clinical trials.
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INTRODUCTION TO CELL CYCLE REGULATION |
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TopAbstractIntroduction to Cell Cycle...Targets for Intervention in...Indirect cdk ModulatorsDirect cdk Modulators (Small...Consequences of cdk InhibitionPreclinical Pharmacology of...Human Clinical Trials of...Preclinical Pharmacology of UCN...Phase I Clinical Trials...SummaryNotesReferences |
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After activation of several mitogenic signaling cascades, cells traverse the cell cycle in several tightly controlled phases (Fig. 1). G1 phase separates M and S phases. In this period, cells commit to enter the cell cycle and prepare to duplicate their DNA (1). After G1 phase, cells enter S phase, the period of DNA synthesis (genome duplication). After S phase, cells enter G2 phase, the period in which cells can repair errors that might occur during DNA duplication and thus prevent passing these errors to daughter cells. During G2 phase, cells prepare to enter M phase, the period in which chromatids and then daughter cells separate. After M phase, cells can enter G1 phase again or enter G0 phase, a replicatively quiescent phase. In G0 phase, the cells usually have a diploid amount of DNA, which represents the differentiated functioning cell not committed to the cell cycle.
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The progression of cells from G1 to S phase is accompanied by the phosphorylation of the retinoblastoma gene product (Rb protein), a tumor suppressor gene active in the control of G1 phase (2,3). Phosphorylation of Rb protein by serine/threonine kinases known as cyclin-dependent kinases (cdks) inactivates Rb (4). The cdks, key regulators of the cell cycle, consist of catalytic subunits that form complexes with proteins known as cyclins. There are at least nine cdks (cdk1-cdk9) (4-7). The cdks that are clearly involved in cell cycle control are cdk1 through cdk7. Although structurally related to cdk1 through cdk7, cdk8 and cdk9 are important transcriptional regulators (5,6). There are at least 15 cyclins (cyclin A through cyclin T) (8-10). Cyclin expression varies during the cell cycle, and indeed the periodic expression of different cyclins defines the start of each phase of the cell cycle and also marks the transitions between the various phases. Cyclins and their cognate cdk catalytic subunits noncovalently form 1 : 1 complexes to produce the cdk holoenzyme. The holoenzyme is activated by the phosphorylation of specific residues in the cdk catalytic subunit. This phosphorylation can be catalyzed by cdk7/cyclin H, which is also known as the cdk-activating kinase (11,12).
Specific cdks operate in distinct phases of the cell cycle. Complexed with their respective D-type cyclin partners, cdk4 and cdk6 are responsible for the cell's progression through G1 phase (Fig. 1). A complex of cdk2 and cyclin E is responsible for the cell's progression from G1 phase to S phase. A complex of cdk2 and cyclin A is required for the cell's progression through S phase, and a complex of cdk1 (also known as cdc2) and cyclin B is required for mitosis (1). These complexes are in turn regulated by a stoichiometric combination with small inhibitory proteins called endogenous cdk inhibitors. The INK4 (inhibitor of cdk4) family includes p16ink4a, p15ink4b, p18ink4c, and p19ink4d, and its members specifically inhibit cyclin D-associated kinases. Members of the kinase inhibitor protein family p21waf1, p27Kip1, and p57kip2 bind and inhibit the activity of complexes of cyclin E and cdk2 and complexes of cyclin A and cdk2 (13-15). Although members of the kinase inhibitor protein family were initially thought to exclusively regulate G1 and S phases, several reports (16-18) demonstrated that these proteins can also regulate the G2/M-phase transition.
DNA synthesis (S phase) begins with the cdk4- and/or cdk6-mediated phosphorylation of Rb protein (which is complexed with the transcriptional factor E2F). Phosphorylated Rb is released from its complex with E2F. The released E2F then promotes the transcription of numerous genes required for the cell to progress through S phase, including thymidylate synthase and dihydrofolate reductase, among others (2,19,20). Additional information about cell cycle regulation can be found in several reviews (21-24).
The vast majority of human cancers have abnormalities in some component of the Rb pathway (Fig. 2) because of hyperactivation of cdks resulting from the overexpression of positive cofactors (cyclins/cdks) or a decrease in negative factors (endogenous cdk inhibitors) or Rb gene mutations (Fig. 2). Therefore, a pharmacologic cdk inhibitor that could be used in "mechanism-based therapy" would be of great theoretical interest as a treatment for many neoplasms (25). This possibility is intriguing because, for cancer patients, the loss of endogenous cdk inhibitors confers poor prognosis. For example, loss of p27kip1 protein predicts a poor outcome in patients with breast, prostate, lung, colon, or gastric carcinoma [reviewed in (26)]. Loss of p16ink4a is clearly associated with poor prognosis in patients with non-small-cell lung cancer or melanoma (26). However, the results with p21waf1 are inconclusive; loss of p21 may be prognostic in certain cancers, but inconsistent results were obtained for breast cancer (26). If validated in larger clinical studies, these markers could be incorporated in the routine pathologic examination of many tumors to determine prognosis.
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TARGETS FOR INTERVENTION IN THE CELL CYCLE |
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TopAbstractIntroduction to Cell Cycle...Targets for Intervention in...Indirect cdk ModulatorsDirect cdk Modulators (Small...Consequences of cdk InhibitionPreclinical Pharmacology of...Human Clinical Trials of...Preclinical Pharmacology of UCN...Phase I Clinical Trials...SummaryNotesReferences |
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Several strategies for therapeutic intervention could modulate cdk activity (Fig. 3). These strategies are divided into direct efforts that target the catalytic cdk subunit or indirect efforts that target the regulatory pathways that govern cdk activity. Compounds that directly target the catalytic cdk subunit are chemical inhibitors (small molecule cdk inhibitors); these compounds provide the opportunity for rational design of drugs that interact specifically with the adenosine 5'-triphosphate (ATP)-binding site of cdks (27-29). Compounds may inhibit cdk activity by targeting the regulatory pathways that modulate the activity of cdks; by altering the expression and synthesis of the cdk/cyclin subunits or the cdk inhibitory proteins; by modulating the phosphorylation of cdks; by targeting cdk-activating kinase (cdk7); by affecting cdc25 and wee1/myt1 (Fig. 3); or by manipulating the proteolytic machinery that regulates the catabolism of cdk/cyclin complexes or their regulators.
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INDIRECT CDK MODULATORS |
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TopAbstractIntroduction to Cell Cycle...Targets for Intervention in...Indirect cdk ModulatorsDirect cdk Modulators (Small...Consequences of cdk InhibitionPreclinical Pharmacology of...Human Clinical Trials of...Preclinical Pharmacology of UCN...Phase I Clinical Trials...SummaryNotesReferences |
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cdk Inhibition by Overexpression of Endogenous cdk Inhibitors
When the cdk inhibitor p16ink4A was introduced into a lung cancer cell line with defective endogenous p16ink4A, the cells were arrested in G1 phase (30). This effect occurs only in cells with functional Rb (31). When both p53 and p16ink4a were introduced into cells, apoptotic cell death followed (32). When p21waf1 or p27kip1 were introduced, in vitro and in vivo antitumor effects and G1/S arrest were observed (33,34). When p27 was introduced in several preclinical tumor models, apoptotic cell death was induced, but the relationship between the putative cdk inhibition of p27kip1 and its induction of apoptotic cell death is unclear (35,36).
Several small molecule chemical inhibitors of cdks appear to modulate the expression of cdk inhibitors. For example, lovastatin blocks cells in G1 phase by induction of p21waf1and p27kip1, which leads to the loss of cdk activity (37,38). Rapamycin blocks lymphocytes in G1 phase by preventing the interleukin 2-stimulated degradation of p27kip1 (39). However, it is unclear whether the cell cycle inhibitory effects of these small molecule chemical inhibitors can be solely explained by the induction of p27kip1.
cdk Inhibition by Peptidomimetic-Based Approaches
Another strategy to block cell cycle progression by loss of cdk activity is to use small peptides that mimic the effects of endogenous cdk inhibitors. Several carriers have been tested that introduce peptides into cells, including a 16-residue segment derived from the Drosophila antenappedia protein. When this 16-residue transmembrane carrier was linked to the third ankyrin repeat of the p16ink4A protein and inserted into cells, Rb-dependent G1 arrest and cell senescence were observed (40). Hybrids containing the antenappedia peptide and different p21waf1 peptides were constructed. In a breast-derived cell line, the chimera containing the carboxyl-terminal peptide of p21, amino acids 141-160, had a higher specificity for cdk4/cyclin D than for cdk2/cyclin E and arrested the cells in G1 phase (41). In contrast, in vitro the chimera containing amino-terminal peptides of p21, amino acids 17-33 and 63-77, inhibited both cdk1 and cdk2, and cells transduced with this chimera were arrested in all phases of the cell cycle (42).
Another approach to inhibiting cdk activity is to develop peptides that bind to cdks and inhibit cdk kinase activity (43,44). Colas et al. (43) demonstrated that a 20-amino acid peptide, identified by use of a combinatorial library, specifically binds cdk2 and inhibits its activity at low nanomolar concentrations in vitro. This peptide could act by blocking the interaction of the catalytic subunit with substrates or cyclin cofactors (43). Chen et al. (44) have shown that 8-amino acid peptides derived from the putative cyclin-cdk2-binding region of p21waf1 (PVKRRLFG) and E2F1 (PVKRRLDL) linked to N-terminal residues derived from human immunodeficiency virus Tat protein or antennapedia protein can block cells in S phase. This effect was associated with a loss of cdk2 activity. Although all of the cells tested with these chimeras showed clear evidence of G1/S-phase arrest, immortalized/transformed cells were more prone to apoptotic cell death.
cdk Inhibition by Depletion in cdk/Cyclin Subunits
Antisense technology has been used to deplete messenger RNAs (mRNAs) for cdk and/or cyclins (45-47). When cyclin D1 was depleted from tumor cell lines, a substantial antiproliferative effect was observed that was synergistic with different standard chemotherapeutic agents (45).
Several compounds can inhibit tumor progression by the modulation of cdk/cyclin subunits. In breast carcinoma cell lines, antiestrogens, such as tamoxifen, inhibit the expression of cyclin D and other cell cycle-related proteins and inhibit cdk activity (48). In breast carcinoma cell lines, retinoids, such as all-trans-retinoic acid and 9-cis-retinoic acid, inhibit the expression of multiple cell cycle regulators, including cyclin D1, cyclin D3, cdk2, and cdk4 (49). In some model systems, rapamycin, an inhibitor of FKBP (FK-506-binding protein)/mTOR (mammalian target of rapamycin), was also associated with a decline in cyclin D1 protein (39). Although treatment of cells with any of these compounds may lead to the decline of cyclin proteins and the perturbation of other cell cycle-related proteins, it is unclear how these compounds act. Perhaps the changes result from a direct interaction between the drug and the pathways that regulate the production of cyclin/cdk or result from the G1-phase arrest and/or Rb dephosphorylation, which are observed with these compounds.
cdk Inhibition by Modulation of Proteasomal Machinery
Sequential turnover of certain cell cycle regulators, including cyclins and p27kip1, is mediated by the 20S proteasome, which promotes proteolytic degradation through the ubiquitin/proteasome pathway. Increased turnover of cyclins with the associated loss of cdk activity may lead to cell cycle arrest with or without apoptotic cell death. Inhibiting 20S proteasome-mediated degradation could lead to accumulation of cdk inhibitors, such as p27ink4a, and to cell cycle arrest with or without apoptotic cell death (50). An important unresolved issue is the net effect and/or specificity of modulating proteasomal pathways. Nonspecific proteasome modulation could alter many signaling pathways (by the accumulation of proteins that activate or inhibit cdks) and thus could have a final effect on cells that is difficult to predict.
cdk Activation by Modulation of Upstream Phosphatases/Kinases
The abrogation (overriding) of intact cell cycle checkpoints by
upstream phosphatases and/or kinases could induce the "inappropriate
acceleration" of certain phases of the cell cycle. For example, when
the G2-phase checkpoint is activated by genotoxic stress
(i.e., 
-irradiation), the G2 period is extended to allow
DNA repair. In the presence of agents that abrogate (override) this
checkpoint, premature mitosis occurs, resulting in apoptotic cell death
(51). Thus, abolishing the G2 checkpoint might
sensitize cells to agents that would normally cause cells to pause or
arrest in G2 phase (51,52).
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DIRECT CDK MODULATORS (SMALL MOLECULAR CDK INHIBITORS) |
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TopAbstractIntroduction to Cell Cycle...Targets for Intervention in...Indirect cdk ModulatorsDirect cdk Modulators (Small...Consequences of cdk InhibitionPreclinical Pharmacology of...Human Clinical Trials of...Preclinical Pharmacology of UCN...Phase I Clinical Trials...SummaryNotesReferences |
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Chemical (small molecular) cdk inhibitors can be subdivided into the following eight families (Fig. 4): 1) purine derivatives (isopentenyladenine, 6-dimethylaminopurine, olomoucine, roscovitine, CVT-313, and purvalanol and its derivatives), 2) butyrolactone I, 3) flavopiridols (flavopiridol and deschloroflavopiridol), 4) staurosporines (staurosporine and UCN-01), 5) toyocamycin, 6) 9-hydroxyellipticine, 7) polysulfates (suramin), and 8) paullones. Not all small molecular cdk inhibitors are specific for cdks. In fact, staurosporine, UCN-01, suramin, 6-dimethylaminopurine, and isopentenyladenine are relatively nonspecific protein kinase inhibitors. In contrast, flavopiridol, butyrolactone I, olomoucine, roscovitine, CVT-313, paullones, and purvalanol derivatives are clearly more selective for cdks. Butyrolactone I, olomoucine, roscovitine, CVT-313, purvalanol, and paullone derivatives are relatively selective for cdk1 and cdk2 but are relatively inactive for cdk4 and cdk6. Flavopiridol can inhibit all cdks tested (53-55)
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Olomoucine, Roscovitine, and Other Purine Derivatives
The first cdk inhibitor discovered was dimethylaminopurine (56). This compound was initially shown to inhibit mitosis in sea urchin embryos without inhibiting protein synthesis. Later, dimethylaminopurine was shown to inhibit cdk1 activity (IC50 [concentration that inhibits activity by 50%] = 120 µM) but to be relatively nonspecific (27). Isopentenyladenine, a derivative of dimethylaminopurine, was somewhat more potent and selective for the cdks (IC50 = 55 µM) (57). Other active purine derivatives have been identified in screening campaigns for more specific and potent cdk inhibitors. Olomoucine potently inhibited cdk1 and cdk2 activities (IC50 = 7 µM) (27,57). Roscovitine, a derivative of olomoucine, is a more potent cdk inhibitor (IC50 values for cdk1/cdk2 = 0.7 µM) (27).
The crystal structures of cdk2 complexed with isopentenyladenine, olomoucine, or roscovitine showed that all three inhibitors bind to the ATP site (29,58). CVT-313, another purine analogue, was identified by use of a combinatorial library strategy and the crystal structure of cdk2. Similar to previous analogues, CVT-313 was specific for cdk1 and cdk2 with IC50 values of 4.2 and 1.5 µM, respectively (59).
A combinatorial approach was then used to modify the purine scaffold of 2-fluoro-6-chloropurine, and several compounds that potently and specifically inhibited cdc2 and cdk2 were identified. Four novel compounds (purvalanol-A, purvalanol-B, compound 52, and compound 52E) were characterized through a battery of in vitro kinases experiments (60). The crystal structure of purvalanol-B complexed with cdk2 showed that purvalanol-B bound to the ATP-binding site resembles the binding of olomoucine to cdk2. The more membrane-permeable purvalanol-A was tested on the National Cancer Institute's (NCI's) 60-cell-line anticancer drug screen panel. The average IC50 value of purvalanol-A was 2 µM, demonstrating that it was a more active antiproliferative agent than purvalanol-B (60). Cell cycle studies of purvalanol-A on human fibroblasts showed that it arrested cells in G1/S phase and G2/M phase, compatible with the putative inhibitory properties in cdk1 and cdk2, respectively (60).
Paullones
With the use of the antiproliferative in vitro profile of flavopiridol in NCI's anticancer drug screen panel and the computational algorithm COMPARE, several members of the paullone family were identified (61). Kenpaullone (NSC 664704) potently inhibited cdk1/cyclin B (IC50 = 0.4 µM), cdk2/cyclin A (IC50 = 0.68 µM), cdk2/cyclin E (IC50 = 7.5 µM), and cdk5/p35 (IC50 = 0.85 µM) but had much lower activity toward other kinases (28). Kenpaullone competitively inhibits the binding of ATP, with an apparent Ki (i.e., inhibitory constant) for cdk1/cyclin B of about 2.5 µM. Molecular modeling studies demonstrated that kenpaullone may bind to the ATP-binding site with residue contacts similar to other cdk2 inhibitors (28). Cell cycle effects of kenpaullone were characterized with the MCF10A breast epithelial cell line. Cells were synchronized in G0/G1 phase by serum starvation and then stimulated to re-enter the cell cycle in the presence of vehicle or kenpaullone at its approximate IC50 concentration (30 µM). Twenty hours later, vehicle-treated cells entered S phase. However, cells exposed to kenpaullone were arrested at the G1/S boundary. A similar effect was obtained with another paullone analogue, 10-bromo-paullone (NSC 672234) (28).
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CONSEQUENCES OF CDK INHIBITION |
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TopAbstractIntroduction to Cell Cycle...Targets for Intervention in...Indirect cdk ModulatorsDirect cdk Modulators (Small...Consequences of cdk InhibitionPreclinical Pharmacology of...Human Clinical Trials of...Preclinical Pharmacology of UCN...Phase I Clinical Trials...SummaryNotesReferences |
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Cell Cycle Arrest
Initial cell cycle studies by van den Heuvel and Harlow (62) demonstrated that ectopic expression of cdk1-dominant negative alleles was able to block U2OS osteosarcoma cell lines at the G2/M-phase boundary. In contrast, expression of dominant negative alleles of cdk2 or cdk3 blocked cells in S phase (62). Thus, roles for each cdk in human cell cycle began to be assigned.
Ectopic expression of endogenous cdk inhibitors (such as p16, p21, or p27) or peptidomimetics derived from p21, p16, or E2F1, as described above in detail, demonstrates the feasibility of using this method to arrest cells in the cell cycle.
As described above, several small molecular cdk inhibitors, including roscovitine, olomoucine, purvalanol, and flavopiridol, arrest cells at either the G1/S- or the G2/M-phase boundaries (53,59,60,63,64). It is unclear why these agents arrest some cells in G1/S phase and other cells in G2/M phase or both.
Apoptotic Cell Death
The antiproliferative effects of olomoucine, flavopiridol, and roscovitine were accompanied by the induction of apoptotic cell death in certain cell types (64-66). In one study (66), the ability of flavopiridol and olomoucine to induce apoptotic cell death varied, depending on the growth status of the cells. That is, flavopiridol or olomoucine protected postmitotic nondividing PC12 neuronal cells from apoptotic cell death after the withdrawal of nerve growth factor. However, flavopiridol did not protect cycling PC12 cells from apoptotic cell death after the withdrawal of nerve growth factor (66). Similarly, cdk4 and cdk6 proteins from dominant negative alleles, but not cdk2 or cdk3 proteins from dominant negative alleles, protected neurons from apoptotic cell death after the withdrawal of nerve growth factor (67). Thus, susceptibility of PC12 cells to flavopiridol- and olomucine-induced apoptotic cell death may vary, depending on the growth state of the cells.
HeLa cervical carcinoma cells treated with staurosporine and tumor necrosis factor-
were protected from apoptotic cell death by cdc2, cdk2, or cdk3 encoded by dominant negative
alleles. However, only cdk2 encoded by a dominant negative allele protected cells from apoptotic
cell death induced by ectopic expression of topoisomerase-II (68).
Finally, certain apoptotic stimuli induce the caspase-mediated cleavage in endogenous cdk
inhibitors (p21/p27) or cdk-inhibitory proteins (wee1 and cdc27) leading to activation of cdks (69-71). Thus, cell cycle arrest and/or apoptosis induced by the inhibition
of cdks depends on several factors, including the mechanism of inhibition, the type of cells, and
the proliferation status of the cells.
Differentiation
During differentiation, cells exit the cell cycle and lose cdk2 activity. Lee et al. (72) tested whether the chemical cdk2 inhibitors flavopiridol and roscovitine could induce a differentiated phenotype by exposing NCI-H358 lung carcinoma cells to a cdk2 antisense construct, flavopiridol, or roscovitine. They observed that all three cdk2 inhibitors could induce mucinous differentiation with the loss of cdk2 activity.
When U937 myelomonocytic leukemia cells were treated with aminopurvalanol, the cells acquired a phenotype characteristic of differentiated macrophages. Moreover, aminopurvalanol, a potent inhibitor of cdk1 and cdk2, appeared to arrest cells at the G2/M boundary and then to induce apoptotic cell death (73). Other investigators (74) observed a similar phenomenon; ectopic expression of p21waf1 or p27kip1 resulted in a "differentiated phenotype" with cells arrested in G1 or G2 phases and a 4N amount of DNA.
Transcriptional Effects
To compare the effects of several chemical cdk inhibitors on the expression of complementary DNA in yeast cells, Gray et al. (60) incubated Saccharomyces cerevisiae with compound 52 and flavopiridol (each at 25 µM ) for 2 hours and measured mRNA by oligonucleotide array methods. Two percent to 3% of the 6200 yeast genes examined showed a greater than twofold change in transcript levels in the presence of these agents. Moreover, almost 50% of affected transcripts were affected by both compound 52 and flavopiridol. These genes fell into distinct groups, including genes that regulate progression of cell cycle, genes that regulate phosphate and cellular energy metabolism, and genes that regulate guanosine 5'-triphosphate (GTP)- or ATP-binding proteins. However, more than 40% of the changes in mRNA were not concordant between flavopiridol and compound 52. These discrepancies might be explained 1) by the broad cdk-inhibitory activity of flavopiridol compared with the selective cdk2/cdk1-inhibitory activities of compound 52, 2) by the different intracellular concentrations achieved by these inhibitors, 3) by the distinctive molecular structures of these inhibitors, or 4) from their putative effects on other cellular targets.
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PRECLINICAL PHARMACOLOGY OF FLAVOPIRIDOL |
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TopAbstractIntroduction to Cell Cycle...Targets for Intervention in...Indirect cdk ModulatorsDirect cdk Modulators (Small...Consequences of cdk InhibitionPreclinical Pharmacology of...Human Clinical Trials of...Preclinical Pharmacology of UCN...Phase I Clinical Trials...SummaryNotesReferences |
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Of the cdk inhibitors, flavopiridol has advanced the farthest toward clinical applications.
Mechanism of Action
Flavopiridol, also known as L86-8275 or HMR 1275, is a semisynthetic
flavonoid derived from rohitukine, an alkaloid isolated from a plant
indigenous to India (Fig. 4). Table 1
contains a
summary of the most important preclinical in vitro effects of
flavopiridol. Initially, flavopiridol displayed modest activity in
vitro as an inhibitor of tyrosine kinase of the epidermal growth
factor receptor and an inhibitor of protein kinase A (IC50 =
21 and 122 µM, respectively) (75). However, when
flavopiridol was tested in the NCI's 60-cell-line anticancer drug
screen panel, its IC50 was 66 nM. This concentration
is about 1000 times lower than the concentration required to inhibit
protein kinase A and the tyrosine kinase of the epidermal growth factor
receptor (75). The antiproliferative effect was not associated
with the presence of the epidermal growth factor receptor
(75,76). Flavopiridol was shown to arrest cells in
G1 phase or at the G2/M boundary, raising the
possibility that flavopiridol may inhibit cdk2 and cdk1 (76).
Studies using purified cdks showed that flavopiridol inhibits the
activities of cdk1, cdk2, and cdk4; this inhibition is competitively
blocked by ATP, with a Ki of 41 nM
(53,54,76-78). The crystal structure of the complex of
deschloroflavopiridol and cdk2 showed that flavopiridol binds to
the ATP-binding pocket, with the benzopyran occupying the same region
as the purine ring of ATP (79). This observation was
concordant with our earlier biochemical studies with flavopiridol
(54). Flavopiridol inhibits all cdks thus far examined
(IC50 = approximately 100 nM), but it inhibits cdk7
(cdk-activating kinase) less potently (IC50 = approximately
300 nM) (53,54,77).
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In addition to directly inhibiting cdks, flavopiridol causes a decrease in the level of cyclin D1, an oncogene that is overexpressed in many human neoplasias. Neoplasms that overexpress cyclin D1 have a poor prognosis (80-82). When MCF-7 human breast carcinoma cells were incubated with flavopiridol, levels of cyclin D1 protein decreased within 3 hours (83). This effect was followed by a decline in the levels of cyclin D3 with no alteration in the levels of cyclin D2 and cyclin E, the remaining G1 cyclins, and then 2 hours later, loss of cdk4 activity occurred. Thus, depletion of cyclin D1 appears to lead to the loss of cdk4 activity (83). The depletion of cyclin D1 is caused by depletion of cyclin D1 mRNA, not by shortening the half-life of the protein. Depletion of cyclin D1 mRNA was associated with a specific decline in cyclin D1 promoter, measured by a luciferase reporter assay (83). The transcriptional repression of cyclin D1 observed after treatment with flavopiridol is consistent with the effects of flavopiridol on yeast cells (see above) and underscores the conserved effect of flavopiridol on eukaryotic cyclin transcription (60). In summary, flavopiridol can induce cell cycle arrest by at least three mechanisms: 1) by direct inhibition of cdk activities by binding to the ATP-binding site; 2) by prevention of the phosphorylation of cdks at threonine-160/161 by inhibition of cdk7/cyclin H (77,78); and 3) for G1-phase arrest, by a decrease in the amount of cyclin D1, an important cofactor for cdk4 and cdk6 activation.
Another important action of flavopiridol is the selective induction of apoptotic cell death. Hematopoietic cell lines are often quite sensitive to flavopiridol-induced apoptotic cell death (65,84-86), but the mechanism(s) by which flavopiridol induces apoptosis have not yet been elucidated. Flavopiridol does not modulate topoisomerase I/II activity (65). In certain hematopoietic cell lines, neither BCL-2/BAX nor p53 appeared to be affected (65,85), whereas, in other systems, BCL-2 may be inhibited (86). It is unclear whether the putative flavopiridol-induced inhibition of cdk activity is required for induction of apoptosis.
Cell cycle arrest, but again with clear evidence of apoptotic cell death, was observed with a
panel of head and neck squamous cell carcinoma cell lines, including a cell line (HN30) that is
refractory to several DNA-damaging agents, such as -irradiation and bleomycin (87). The apoptotic effect was independent of p53 status and was
associated with the depletion of cyclin D1 (87). These findings have been
corroborated in other preclinical models (88-90). Efforts to understand
flavopiridol-induced apoptosis are under way.
To determine whether flavopiridol has antiangiogenic properties, Brusselbach et al. (91) incubated human umbilical vein endothelial cells (HUVECs) with flavopiridol and observed apoptotic cell death even in cells that were not cycling. In another report, Kerr et al. (92) tested flavopiridol in an in vivo angiogenesis model and found that flavopiridol decreased blood vessel formation in the mouse Matrigel model of angiogenesis. Melillo et al. (93) demonstrated that, at low nanomolar concentrations, flavopiridol blunted the induction of vascular endothelial growth factor (VEGF) by hypoxia in human monocytes. This effect was caused by a decreased stability of VEGF mRNA, which paralleled the decline in VEGF protein. Thus, the antitumor activity of flavopiridol may be supplemented by antiangiogenic effects. Whether the various antiangiogenic actions of flavopiridol result from its interaction with a cdk target or other targets requires further study.
To test for synergistic effects with other compounds, cytotoxic assays of flavopiridol in
combination with standard chemotherapeutic agents were performed (94,95). Synergistic effects in A549 lung carcinoma cells were demonstrated when
treatment with flavopiridol followed treatment with paclitaxel, cytarabine, topotecan,
doxorubicin, or etoposide. In contrast, a synergistic effect was observed with 5-fluorouracil only
when cells were treated with flavopiridol for 24 hours before addition of 5-fluorouracil.
Synergistic effects with cisplatin were not schedule dependent (95).
However, Chien et al. (88) failed to demonstrate a synergistic effect
between flavopiridol and cisplatin and/or -irradiation in bladder carcinoma models.
Several questions about the antiproliferative activity of flavopiridol remain unanswered. Why does treatment with flavopiridol cause some cells to arrest at the G1/S-phase boundary and other cells to arrest at the G2/M-phase boundary? What role does the depletion of D-type cyclins play in flavopiridol-induced G1/S arrest? What is the relationship between cdk inhibition and apoptotic cell death, and what are the targets for flavopiridol-induced apoptotic cell death?
Antitumor Effect in Preclinical Models
Experiments using colorectal (Colo205) and prostate (LnCap/DU-145) carcinoma xenograft models in which flavopiridol was administered frequently over a protracted period demonstrated that flavopiridol is cytostatic (75). This demonstration led to clinical trials in humans of flavopiridol administered as a 72-hour continuous infusion every 2 weeks (96) (see below).
Subsequent studies in some models of human leukemia/lymphoma xenografts demonstrated that flavopiridol administered intravenously as a bolus rendered animals tumor free, whereas flavopiridol administered as an infusion only delayed tumor growth (84). In head and neck (HN-12) xenografts, when flavopiridol was administered as an intraperitoneal bolus daily at 5 mg/kg for 5 days, a substantial growth delay was observed (87). Again, apoptotic cell death and cyclin D1 depletion were observed in tissues from xenografts treated with flavopiridol at peak plasma concentrations of 5-8 µM (84). Based on these results, the feasibility of a phase I trial with the administration of flavopiridol as a 1-hour infusion is currently being explored at the NCI (see below).
Preclinical Pharmacokinetics and Toxicology
Murine plasma concentration-time profiles for flavopiridol
exhibited biexponential behavior with mean and ß half-lives of
16.4 and 201.0 minutes, respectively. The mean total-body plasma
clearance was 22.6 mL/minute per kg, and the mean oral bioavailability
after bolus intragavage was approximately 20%. Pharmacokinetic studies
in dogs (75) had very similar results.
The metabolism of flavopiridol was investigated in isolated liver perfusion models. Flavopiridol was glucuronidated in the liver, and then this flavopiridol metabolite excreted in the biliary tract. This property underlies flavopiridol's propensity to undergo enterohepatic circulation (97,98). Preclinical pharmacologic and toxicologic evaluations have identified dose-limiting toxic effects as reversible hematopoietic and gastrointestinal effects.
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HUMAN CLINICAL TRIALS OF FLAVOPIRIDOL |
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TopAbstractIntroduction to Cell Cycle...Targets for Intervention in...Indirect cdk ModulatorsDirect cdk Modulators (Small...Consequences of cdk InhibitionPreclinical Pharmacology of...Human Clinical Trials of...Preclinical Pharmacology of UCN...Phase I Clinical Trials...SummaryNotesReferences |
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Two clinical trials of flavopiridol given as a 72-hour continuous infusion every 2 weeks have been completed (96,99). In the NCI phase I trial of infusional flavopiridol, 76 patients were treated. Dose-limiting toxicity was secretory diarrhea with a maximal tolerated dose of 50 mg/m2 per day for 3 days.
In the presence of antidiarrheal prophylaxis (a combination of cholestyramine and loperamide), patients tolerated higher doses, defining a second maximal tolerated dose, 78 mg/m2 per day for 3 days. The dose-limiting toxicity observed at the higher dose level was reversible hypotension and a substantial proinflammatory syndrome (fever, fatigue, local tumor pain, and modulation of acute-phase reactants) (96).
Tumors in one patient with non-Hodgkin's lymphoma, one patient with colon cancer, and one patient with kidney cancer decreased in size (minor responses = shrinkage of <50%) for more than 6 months. Moreover, one patient with refractory renal cancer achieved a partial response (shrinkage of >50% of masses) (96). Of 14 patients who received flavopiridol for more than 6 months, five patients received flavopiridol for more than 1 year and one patient received flavopiridol for more than 2 years (96). This potential "disease stabilization," which may have been noted in this trial, is consistent with preclinical models, where tumor stasis is observed. Appropriate measurements of cytostatic effects are necessary to confirm that cdk inhibition might be related to this clinical outcome. Plasma concentrations of 300-500 nM flavopiridol, which inhibit cdk activity in vitro, were safely achieved during our trial (96).
In a complementary phase I trial also exploring the use of a 72-hour continuous infusion of flavopiridol every 2 weeks, Thomas et al. (99) found that the dose-limiting toxicity is diarrhea, corroborating the experience of the NCI. Moreover, plasma concentrations of 300-500 nM flavopiridol were also observed. It is interesting that there was one patient in this trial with refractory gastric cancer that had metastasized to the liver who was initially treated surgically and subsequently failed to respond to one treatment regimen of 5-fluorouracil. When treated with flavopiridol, this patient achieved a sustained complete response without any evidence of disease for more than 2 years after treatment was completed.
In September 1998, we began the first phase I trial of a daily 1-hour infusion of flavopiridol for 5 consecutive days every 3 weeks. This dose schedule was based on our antitumor results observed in leukemia/lymphoma and head and neck xenografts treated with flavopiridol (see above). At this time, 27 patients have been treated in this phase I trial. The recommended phase II dose is 37.5 mg/m2 per day for 5 consecutive days. Dose-limiting toxic effects observed at 52.5 mg/m2 per day are nausea/vomiting, neutropenia, fatigue, and diarrhea. Other (non-dose-limiting) side effects are "local tumor pain" and anorexia (Senderowicz AM: unpublished results). To reach higher flavopiridol concentrations, the protocol was amended to administer flavopiridol for 3 days only. Higher peak plasma flavopiridol concentrations (approximately 4 µM) may be obtained with this schedule (Senderowicz AM: unpublished results).
A phase I trial testing the combination of paclitaxel and flavopiridol demonstrated good tolerability with a dose-limiting pulmonary toxicity (100).
Phase II trials of flavopiridol given as a 72-hour continuous infusion to patients with chronic lymphocytic leukemia, non-small-cell lung cancer, non-Hodgkin's lymphoma, or colon, prostate, gastric, head and neck, or kidney cancer, etc., and phase I trials of flavopiridol administered on novel schedules and in combination with standard chemotherapeutic agents are being explored (101-104).
Several important clinical questions remain to be answered in these trials. Is flavopiridol an "effective" anticancer agent? Which is the best schedule for flavopiridol monotherapy? What is the best method to combine flavopiridol and other agents? Which is the most reliable pharmacodynamic parameter to follow in patients? How should "stable disease" be defined in phase II trials?
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PRECLINICAL PHARMACOLOGY OF UCN-01 |
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TopAbstractIntroduction to Cell Cycle...Targets for Intervention in...Indirect cdk ModulatorsDirect cdk Modulators (Small...Consequences of cdk InhibitionPreclinical Pharmacology of...Human Clinical Trials of...Preclinical Pharmacology of UCN...Phase I Clinical Trials...SummaryNotesReferences |
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Staurosporine is a nonspecific protein kinase inhibitor that arrests cell cycle progression in transformed and nontransformed cells at 1-100 nM (105). At similar concentrations, staurosporine inhibits many protein and tyrosine kinases (105). Several analogues of staurosporine have been evaluated to identify compounds with greater specificity for protein kinases.
Mechanism of Action
One staurosporine analogue, UCN-01 (7-hydroxystaurosporine; Fig. 4), has potent activity against several protein kinase C isoenzymes, particularly the Ca2+-dependent protein kinase C with an IC50 of about 30 nM. UCN-01 has lower potency against the novel Ca2+-independent protein kinases C (IC50 = approximately 500 nM) and no effect against the atypical protein kinases C (106-108), similar to the activity of staurosporine. In addition to its effects on protein kinase C, UCN-01 has antiproliferative activity in several human tumor cell lines (109-113). In contrast, another highly selective potent protein kinase C inhibitor, GF 109203X, has a modest antiproliferative activity, despite a similar capacity to inhibit protein kinase C in vitro (110). Thus, these results suggest that the antiproliferative activity of UCN-01 is probably not explained solely by inhibition of protein kinase C. UCN-01 moderately inhibited the activity of immunoprecipitated cdk1 (cdc2) and cdk2 (IC50 = 300-600 nM). However, when intact cells were exposed to UCN-01, "inappropriate activation" of the same kinases occurred (110).
Experimental evidence suggests that DNA damage leads to cell cycle arrest to allow DNA repair. In cells where the G1-phase checkpoint is not active because of p53 inactivation, irradiated cells accumulate in G2 phase because the G2 checkpoint is mediated by the inactivation of cyclin B/cdc2 by wee1 kinase (Fig. 5, A). In contrast, UCN-01 (Fig. 5, B) induces the activation of cdc2/cyclin B and thus promotes cells to enter early mitosis with the onset of apoptotic cell death. These effects could be partially explained by the inactivation of wee1, the kinase that negatively regulates the G2/M-phase transition or activation of cdc25 phosphatase (114). Thus, although UCN-01 at high concentrations can directly inhibit cdks in vitro, UCN-01 can modulate cellular upstream regulators at much lower concentration, leading to inappropriate cdc2 activation by acting on targets that remain to be defined. DNA-damaging agents not only can activate the G2-phase checkpoint but also can activate the S-phase checkpoint (115). Studies from other groups suggest that UCN-01 not only is able to abrogate the G2 checkpoint induced by DNA-damaging agents but also, in some circumstances, is able to abrogate the DNA damage-induced S-phase checkpoint (115).
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Another pharmacologic feature of UCN-01 is the increased cytotoxicity in cells containing mutated p53 genes (51). In CA-46 Burkitt's lymphoma and HT-29 colon carcinoma cell lines carrying mutated p53 genes, cytotoxicity results when these cells are exposed to UCN-01. Compared with the isogenic wild-type MCF-7 cell line, the MCF-7 cell line with no endogenous p53 because of the ectopic expression of E6, a human papillomavirus type-16 protein, showed enhanced cytotoxicity when treated with a DNA-damaging agent, such as cisplatin, and UCN-01. The synergistic effect of UCN-01 is enhanced with many chemotherapeutic agents, including mitomycin C, 5-fluorouracil, carmustine, and camptothecin, among others (116-122). Therefore, it is possible that combining UCN-01 with these and other agents could improve its therapeutic index.
Another interesting aspect of UCN-01 is its ability to arrest cells in G1 phase of the cell cycle (109,112,113,123-125). Human epidermoid carcinoma A431 cells contain mutated p53. When incubated with UCN-01, these cells were arrested in G1 phase, Rb was hypophosphorylated, and p21waf1 and p27kip1 accumulated (113). However, in another report (125), the antiproliferative effect of UCN-01 was not dependent on the functional status of Rb. Thus, the G1 arrest observed with UCN-01 is apparently independent of the status of p53 and Rb. Further studies on the putative target(s) for UCN-01 in the G1-phase arrest of cells are under way.
Courage et al. (126) found that UCN-01-resistant A549 lung
carcinoma cells were sensitive to two other protein kinase C inhibitors, CGP 41251 and Ro
31-8220, and were marginally resistant (about twofold) to etoposide. These UCN-01-resistant
cells had lost several protein kinase C isoenzymes, protein kinase C , 
, and |gv.
However, the levels of these isoenzymes returned to baseline when these resistant cells were
cultured in UCN-01-free medium. Thus, as described above, it is unlikely that the protein kinase
C family of signaling proteins is the only target for UCN-01 cytotoxicity (110,126).
Although many important questions have been answered, several questions remain. What is the real target for UCN-01 in G1/S phase-arrested cells? Does protein kinase C play any role in UCN-01-induced cell cycle arrest and/or apoptotic cell death? What is the real target for the G2 checkpoint abrogation?
Spectrum of In Vivo Antitumor Activity
UCN-01 administered by an intravenous or intraperitoneal route displayed antitumor activity in xenograft model systems with breast carcinoma (MCF-7), renal carcinoma (A498), and leukemia (MOLT-4 and HL-60) cell lines (Senderowicz AM: unpublished results). The antitumor effect was greater when UCN-01 was given over a longer period. This requirement for a longer period of treatment was also observed in in vitro models, with highest antitumor activity observed when UCN-01 was present for 72 hours (109). Thus, a clinical trial using a 72-hour continuous infusion every 2 weeks was conducted (described below).
Preclinical Pharmacokinetics and Toxicology
Pharmacokinetics and toxicologic studies using several schedules were done in rats and dogs. When beagle dogs were given a 72-hour continuous infusion of UCN-01, local (site of injection) and gastrointestinal toxic effects were dose-limiting and a steady-state plasma concentration of 330 nM UCN-01 was achieved. Pharmacokinetic parameters were a volume of distribution (6.09 L/kg), a total clearance of 0.6 L/kg per hour with a ß half-life of about 12 hours (127).
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PHASE I CLINICAL TRIALS OF UCN-01 |
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TopAbstractIntroduction to Cell Cycle...Targets for Intervention in...Indirect cdk ModulatorsDirect cdk Modulators (Small...Consequences of cdk InhibitionPreclinical Pharmacology of...Human Clinical Trials of...Preclinical Pharmacology of UCN...Phase I Clinical Trials...SummaryNotesReferences |
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We recently completed the first phase I trial of UCN-01 in humans (128). Clinical features of UCN-01 observed included the unexpectedly long half-life (approximately 30 days). This half-life was 100 times longer than the half-life observed in preclinical models, which was probably caused by the avid binding of UCN-01 to
1-acid glycoprotein (129,130). Other clinical
features were the relative lack of myelotoxicity or gastrointestinal
toxicity (prominent side effects observed in animal models), despite
very high plasma concentrations achieved (35-50 µM)
(128-131). Dose-limiting toxic effects were nausea/vomiting
(amenable to standard antiemetic treatments), symptomatic hyperglycemia
associated with an insulin-resistance state, and pulmonary toxicity
characterized by substantial hypoxemia without obvious radiologic
changes. The recommended phase II dose of UCN-01 given on a 72-hour
continuous infusion schedule was 42.5 mg/m2 per day
(131). One patient with refractory metastatic melanoma
developed a partial response that lasted 8 months. Tumors in a few
patients with leiomyosarcoma, non-Hodgkin's lymphoma, or lung cancer
were stabilized (
6 months) (131). The concentration of
"free" UCN-01 was assessed in saliva. At the recommended phase II
dose, concentrations of free UCN-01 that may cause G2
checkpoint abrogation can be achieved.Table 2
compares important clinical and pharmacologic features of the cdk
modulators flavopiridol and UCN-01. Future trials are being explored in
which UCN-01 would be given by infusion for shorter periods
(132) and/or in combination with DNA-damaging agents.
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SUMMARY |
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TopAbstractIntroduction to Cell Cycle...Targets for Intervention in...Indirect cdk ModulatorsDirect cdk Modulators (Small...Consequences of cdk InhibitionPreclinical Pharmacology of...Human Clinical Trials of...Preclinical Pharmacology of UCN...Phase I Clinical Trials...SummaryNotesReferences |
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With knowledge of the role of cdks in cell cycle regulation and the discovery that approximately 90% of all neoplasias are associated with "cdk hyperactivation" leading to the inactivation of the Rb pathway (2), novel cdk inhibitors are being developed. The first two modulators of cdk function tested in clinical trials, flavopiridol and UCN-01, have been observed to reach plasma concentrations that can modulate cdk-related functions. Future clinical trials should determine what is the best schedule for administering chemical cdk inhibitors, should determine what is the best combination of chemical cdk inhibitors and standard chemotherapeutic agents, and should demonstrate cdk modulation in tumor samples from patients treated with cdk inhibitors.
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NOTES |
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Editor's note: E. A. Sausville is a participant in the National Cancer Institute's Cooperative Research and Development Agreement with Hoechst Marian Rousell that manufactures flavopiridol.
We are indebted to colleagues from the Laboratory of Biological Chemistry and Developmental Therapeutics Program Clinical Trials Unit, National Cancer Institute, for all the encouragement and heavy work provided for these projects. We also want to acknowledge the National Cancer Institute and the National Institutes of Health staff for their contributions in these clinical trials. Finally, we want to acknowledge the patients and their relatives for their willingness to participate in our clinical trials and contribute to the advancement of medicine.
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Manuscript received June 15, 1999; revised December 7, 1999; accepted December 15, 1999.
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R. I. Haddad, L. J. Weinstein, T. J. Wieczorek, N. Bhattacharya, H. Raftopoulos, M. W. Oster, X. Zhang, V. M. Latham Jr., R. Costello, J. Faucher, et al. A Phase II Clinical and Pharmacodynamic Study of E7070 in Patients with Metastatic, Recurrent, or Refractory Squamous Cell Carcinoma of the Head and Neck: Modulation of Retinoblastoma Protein Phosphorylation by a Novel Chloroindolyl Sulfonamide Cell Cycle Inhibitor Clin. Cancer Res., July 15, 2004; 10(14): 4680 - 4687. [Abstract] [Full Text] [PDF]
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X. Lu, W. E. Burgan, M. A. Cerra, E. Y. Chuang, M.-H. Tsai, P. J. Tofilon, and K. Camphausen Transcriptional signature of flavopiridol-induced tumor cell death Mol. Cancer Ther., July 1, 2004; 3(7): 861 - 872. [Abstract] [Full Text] [PDF]
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G. I. Shapiro Preclinical and Clinical Development of the Cyclin-Dependent Kinase Inhibitor Flavopiridol Clin. Cancer Res., June 15, 2004; 10(12): 4270S - 4275S. [Abstract] [Full Text] [PDF]
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M. M. Facchinetti, A. De Siervi, D. Toskos, and A. M. Senderowicz UCN-01-Induced Cell Cycle Arrest Requires the Transcriptional Induction of p21waf1/cip1 by Activation of Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase/Extracellular Signal-Regulated Kinase Pathway Cancer Res., May 15, 2004; 64(10): 3629 - 3637. [Abstract] [Full Text] [PDF]
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 D. Gherardi, V. D'Agati, T.-H. T. Chu, A. Barnett, A. Gianella-Borradori, I. H. Gelman, and P. J. Nelson Reversal of Collapsing Glomerulopathy in Mice with the Cyclin-Dependent Kinase Inhibitor CYC202 J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1212 - 1222. [Abstract] [Full Text] [PDF]
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S.-H. Chao, J. N. Harada, F. Hyndman, X. Gao, C. G. Nelson, S. K. Chanda, and J. S. Caldwell PDX1, a Cellular Homeoprotein, Binds to and Regulates the Activity of Human Cytomegalovirus Immediate Early Promoter J. Biol. Chem., April 16, 2004; 279(16): 16111 - 16120. [Abstract] [Full Text] [PDF]
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 A. Sodhi, S. Montaner, V. Patel, J. J. Gomez-Roman, Y. Li, E. A. Sausville, E. T. Sawai, and J. S. Gutkind Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor PNAS, April 6, 2004; 101(14): 4821 - 4826. [Abstract] [Full Text] [PDF]
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K. Camphausen, K. J. Brady, W. E. Burgan, M. A. Cerra, J. S. Russell, E. E.A. Bull, and P. J. Tofilon Flavopiridol enhances human tumor cell radiosensitivity and prolongs expression of {gamma}H2AX foci Mol. Cancer Ther., April 1, 2004; 3(4): 409 - 416. [Abstract] [Full Text] [PDF]
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 M. E. M. Noble, J. A. Endicott, and L. N. Johnson Protein Kinase Inhibitors: Insights into Drug Design from Structure Science, March 19, 2004; 303(5665): 1800 - 1805. [Abstract] [Full Text] [PDF]
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 Y.-M. Ham, K.-J. Choi, S.-Y. Song, Y.-H. Jin, M.-W. Chun, and S.-K. Lee Xylocydine, a Novel Inhibitor of Cyclin-Dependent Kinases, Prevents the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptotic Cell Death of SK-HEP-1 Cells J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 814 - 819. [Abstract] [Full Text] [PDF]
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Y. Takada and B. B. Aggarwal Flavopiridol Inhibits NF-{kappa}B Activation Induced by Various Carcinogens and Inflammatory Agents through Inhibition of I{kappa}B{alpha} Kinase and p65 Phosphorylation: ABROGATION OF CYCLIN D1, CYCLOOXYGENASE-2, AND MATRIX METALLOPROTEASE-9 J. Biol. Chem., February 6, 2004; 279(6): 4750 - 4759. [Abstract] [Full Text] [PDF]
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 C. Monnerat, R. Henriksson, T. Le Chevalier, S. Novello, P. Berthaud, S. Faivre, and E. Raymond Phase I study of PKC412 (N-benzoyl-staurosporine), a novel oral protein kinase C inhibitor, combined with gemcitabine and cisplatin in patients with non-small-cell lung cancer Ann. Onc., February 1, 2004; 15(2): 316 - 323. [Abstract] [Full Text] [PDF]
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G. Liu, D. R. Gandara, P. N. Lara Jr., D. Raghavan, J. H. Doroshow, P. Twardowski, P. Kantoff, W. Oh, K. Kim, and G. Wilding A Phase II Trial of Flavopiridol (NSC #649890) in Patients with Previously Untreated Metastatic Androgen-Independent Prostate Cancer Clin. Cancer Res., February 1, 2004; 10(3): 924 - 928. [Abstract] [Full Text] [PDF]
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A. De Siervi, M. Marinissen, J. Diggs, X.-F. Wang, G. Pages, and A. Senderowicz Transcriptional Activation of p21waf1/cip1 by Alkylphospholipids: Role of the Mitogen-Activated Protein Kinase Pathway in the Transactivation of the Human p21waf1/cip1 Promoter by Sp1 Cancer Res., January 15, 2004; 64(2): 743 - 750. [Abstract] [Full Text] [PDF]
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C. Hamdouchi, H. Keyser, E. Collins, C. Jaramillo, J. E. De Diego, C. D. Spencer, J. A. Dempsey, B. D. Anderson, T. Leggett, N. B. Stamm, et al. The discovery of a new structural class of cyclin-dependent kinase inhibitors, aminoimidazo[1,2-a]pyridines Mol. Cancer Ther., January 1, 2004; 3(1): 1 - 9. [Abstract] [Full Text]
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D. S. Sappal, A. K. McClendon, J. A. Fleming, V. Thoroddsen, K. Connolly, C. Reimer, R. K. Blackman, C. E. Bulawa, N. Osheroff, P. Charlton, et al. Biological characterization of MLN944: A potent DNA binding agent Mol. Cancer Ther., January 1, 2004; 3(1): 47 - 58. [Abstract] [Full Text]
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Y.-S. Seong, C. Min, L. Li, J. Y. Yang, S.-Y. Kim, X. Cao, K. Kim, S. H. Yuspa, H.-H. Chung, and K. S. Lee Characterization of a Novel Cyclin-Dependent Kinase 1 Inhibitor, BMI-1026 Cancer Res., November 1, 2003; 63(21): 7384 - 7391. [Abstract] [Full Text] [PDF]
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J. Jiang, C. B. Matranga, D. Cai, V. M. Latham Jr., X. Zhang, A. M. Lowell, F. Martelli, and G. I. Shapiro Flavopiridol-Induced Apoptosis during S Phase Requires E2F-1 and Inhibition of Cyclin A-Dependent Kinase Activity Cancer Res., November 1, 2003; 63(21): 7410 - 7422. [Abstract] [Full Text] [PDF]
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J. Litz, P. Carlson, G. S. Warshamana-Greene, S. Grant, and G. W. Krystal Flavopiridol Potently Induces Small Cell Lung Cancer Apoptosis during S Phase in a Manner That Involves Early Mitochondrial Dysfunction Clin. Cancer Res., October 1, 2003; 9(12): 4586 - 4594. [Abstract] [Full Text] [PDF]
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J. A. Shabbits, Y. Hu, and L. D. Mayer Tumor Chemosensitization Strategies Based on Apoptosis Manipulations Mol. Cancer Ther., August 1, 2003; 2(8): 805 - 813. [Full Text] [PDF]
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U. Raju, E. Nakata, K. A. Mason, K. K. Ang, and L. Milas Flavopiridol, a Cyclin-dependent Kinase Inhibitor, Enhances Radiosensitivity of Ovarian Carcinoma Cells Cancer Res., June 15, 2003; 63(12): 3263 - 3267. [Abstract] [Full Text] [PDF]
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C. Yu, M. Rahmani, Y. Dai, D. Conrad, G. Krystal, P. Dent, and S. Grant The Lethal Effects of Pharmacological Cyclin-dependent Kinase Inhibitors in Human Leukemia Cells Proceed through a Phosphatidylinositol 3-Kinase/Akt-dependent Process Cancer Res., April 15, 2003; 63(8): 1822 - 1833. [Abstract] [Full Text] [PDF]
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S.-H. Chao, J. R. Walker, S. K. Chanda, N. S. Gray, and J. S. Caldwell Identification of Homeodomain Proteins, PBX1 and PREP1, Involved in the Transcription of Murine Leukemia Virus Mol. Cell. Biol., February 1, 2003; 23(3): 831 - 841. [Abstract] [Full Text]
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S. Wittmann, P. Bali, S. Donapaty, R. Nimmanapalli, F. Guo, H. Yamaguchi, M. Huang, R. Jove, H. G. Wang, and K. Bhalla Flavopiridol Down-Regulates Antiapoptotic Proteins and Sensitizes Human Breast Cancer Cells to Epothilone B-induced Apoptosis Cancer Res., January 1, 2003; 63(1): 93 - 99. [Abstract] [Full Text] [PDF]
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Y. Ma, W. D. Cress, and E. B. Haura Flavopiridol-induced Apoptosis Is Mediated through Up-Regulation of E2F1 and Repression of Mcl-1 Mol. Cancer Ther., January 1, 2003; 2(1): 73 - 81. [Abstract] [Full Text] [PDF]
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J. E. Karp, D. D. Ross, W. Yang, M. L. Tidwell, Y. Wei, J. Greer, D. L. Mann, T. Nakanishi, J. J. Wright, and A. D. Colevas Timed Sequential Therapy of Acute Leukemia with Flavopiridol: In Vitro Model for a Phase I Clinical Trial Clin. Cancer Res., January 1, 2003; 9(1): 307 - 315. [Abstract] [Full Text] [PDF]
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S. R. D. Johnston, J. Head, S. Pancholi, S. Detre, L.-A. Martin, I. E. Smith, and M. Dowsett Integration of Signal Transduction Inhibitors with Endocrine Therapy: An Approach to Overcoming Hormone Resistance in Breast Cancer Clin. Cancer Res., January 1, 2003; 9(1): 524S - 532S. [Abstract] [Full Text] [PDF]
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 L. M. Schang Cyclin-dependent kinases as cellular targets for antiviral drugs J. Antimicrob. Chemother., December 1, 2002; 50(6): 779 - 792. [Abstract] [Full Text] [PDF]
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R. S. DiPaola To Arrest or Not To G2-M Cell-Cycle Arrest : Commentary re: A. K. Tyagi et al., Silibinin Strongly Synergizes Human Prostate Carcinoma DU145 Cells to Doxorubicin-induced Growth Inhibition, G2-M Arrest, and Apoptosis. Clin. Cancer Res., 8: 3512-3519, 2002. Clin. Cancer Res., November 1, 2002; 8(11): 3311 - 3314. [Full Text] [PDF]
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I. Gojo, B. Zhang, and R. G. Fenton The Cyclin-dependent Kinase Inhibitor Flavopiridol Induces Apoptosis in Multiple Myeloma Cells through Transcriptional Repression and Down-Regulation of Mcl-1 Clin. Cancer Res., November 1, 2002; 8(11): 3527 - 3538. [Abstract] [Full Text] [PDF]
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V. Patel, T. Lahusen, C. Leethanakul, T. Igishi, M. Kremer, L. Quintanilla-Martinez, J. F. Ensley, E. A. Sausville, J. S. Gutkind, and A. M. Senderowicz Antitumor Activity of UCN-01 in Carcinomas of the Head and Neck Is Associated with Altered Expression of Cyclin D3 and p27KIP1 Clin. Cancer Res., November 1, 2002; 8(11): 3549 - 3560. [Abstract] [Full Text] [PDF]
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A. R. Tan, D. Headlee, R. Messmann, E. A. Sausville, S. G. Arbuck, A. J. Murgo, G. Melillo, S. Zhai, W. D. Figg, S. M. Swain, et al. Phase I Clinical and Pharmacokinetic Study of Flavopiridol Administered as a Daily 1-Hour Infusion in Patients With Advanced Neoplasms J. Clin. Oncol., October 1, 2002; 20(19): 4074 - 4082. [Abstract] [Full Text] [PDF]
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E. Raymond, W.W. ten Bokkel Huinink, J. Taieb, J.H. Beijnen, S. Faivre, J. Wanders, M. Ravic, P. Fumoleau, J.P. Armand, and J.H.M. Schellens Phase I and Pharmacokinetic Study of E7070, a Novel Chloroindolyl Sulfonamide Cell-Cycle Inhibitor, Administered as a One-Hour Infusion Every Three Weeks in Patients With Advanced Cancer J. Clin. Oncol., August 15, 2002; 20(16): 3508 - 3521. [Abstract] [Full Text] [PDF]
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 M. L. Rodriguez-Puebla, P. L. Miliani de Marval, M. LaCava, D. S. Moons, H. Kiyokawa, and C. J. Conti cdk4 Deficiency Inhibits Skin Tumor Development but Does Not Affect Normal Keratinocyte Proliferation Am. J. Pathol., August 1, 2002; 161(2): 405 - 411. [Abstract] [Full Text] [PDF]
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 A. F.W. Frijhoff, C. J. Conti, and A. M. Senderowicz Second Symposium of Novel Molecular Targets for Cancer Therapy Oncologist, August 1, 2002; 7(90003): 1 - 3. [Full Text] [PDF]
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A. M. Senderowicz The Cell Cycle as a Target for Cancer Therapy: Basic and Clinical Findings with the Small Molecule Inhibitors Flavopiridol and UCN-01 Oncologist, August 1, 2002; 7(90003): 12 - 19. [Abstract] [Full Text] [PDF]
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C. G. Ferreira, M. Epping, F. A. E. Kruyt, and G. Giaccone Apoptosis: Target of Cancer Therapy Clin. Cancer Res., July 1, 2002; 8(7): 2024 - 2034. [Abstract] [Full Text] [PDF]
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B. Zhang, I. Gojo, and R. G. Fenton Myeloid cell factor-1 is a critical survival factor for multiple myeloma Blood, March 15, 2002; 99(6): 1885 - 1893. [Abstract] [Full Text] [PDF]
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V. Patel, T. Lahusen, T. Sy, E. A. Sausville, J. S. Gutkind, and A. M. Senderowicz Perifosine, a Novel Alkylphospholipid, Induces p21WAF1 Expression in Squamous Carcinoma Cells through a p53-independent Pathway, Leading to Loss in Cyclin-dependent Kinase Activity and Cell Cycle Arrest Cancer Res., March 1, 2002; 62(5): 1401 - 1409. [Abstract] [Full Text] [PDF]
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C. B. Matranga and G. I. Shapiro Selective Sensitization of Transformed Cells to Flavopiridol-induced Apoptosis following Recruitment to S-Phase Cancer Res., March 1, 2002; 62(6): 1707 - 1717. [Abstract] [Full Text] [PDF]
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M. Filipits, U. Jaeger, G. Pohl, T. Stranzl, I. Simonitsch, A. Kaider, C. Skrabs, and R. Pirker Cyclin D3 Is a Predictive and Prognostic Factor in Diffuse Large B-cell Lymphoma Clin. Cancer Res., March 1, 2002; 8(3): 729 - 733. [Abstract] [Full Text] [PDF]
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T. Yamauchi, M. J. Keating, and W. Plunkett UCN-01 (7-Hydroxystaurosporine) Inhibits DNA Repair and Increases Cytotoxicity in Normal Lymphocytes and Chronic Lymphocytic Leukemia Lymphocytes Mol. Cancer Ther., February 1, 2002; 1(4): 287 - 294. [Abstract] [Full Text] [PDF]
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T. Sandal Molecular Aspects of the Mammalian Cell Cycle and Cancer Oncologist, February 1, 2002; 7(1): 73 - 81. [Abstract] [Full Text] [PDF]
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P. M. Clare, R. A. Poorman, L. C. Kelley, K. D. Watenpaugh, C. A. Bannow, and K. L. Leach The Cyclin-dependent Kinases cdk2 and cdk5 Act by a Random, Anticooperative Kinetic Mechanism J. Biol. Chem., December 14, 2001; 276(51): 48292 - 48299. [Abstract] [Full Text] [PDF]
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H. Wang, J. Guan, H. Wang, A. R. Perrault, Y. Wang, and G. Iliakis Replication Protein A2 Phosphorylation after DNA Damage by the Coordinated Action of Ataxia Telangiectasia-Mutated and DNA-dependent Protein Kinase Cancer Res., December 1, 2001; 61(23): 8554 - 8563. [Abstract] [Full Text] [PDF]
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P. J. Nelson, I. H. Gelman, and P. E. Klotman Suppression of HIV-1 Expression by Inhibitors of Cyclin-Dependent Kinases Promotes Differentiation of Infected Podocytes J. Am. Soc. Nephrol., December 1, 2001; 12(12): 2827 - 2831. [Abstract] [Full Text] [PDF]
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Y. A. Elsayed and E. A. Sausville Selected Novel Anticancer Treatments Targeting Cell Signaling Proteins Oncologist, December 1, 2001; 6(6): 517 - 537. [Abstract] [Full Text] [PDF]
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 D. Wang, C. de la Fuente, L. Deng, L. Wang, I. Zilberman, C. Eadie, M. Healey, D. Stein, T. Denny, L. E. Harrison, et al. Inhibition of Human Immunodeficiency Virus Type 1 Transcription by Chemical Cyclin-Dependent Kinase Inhibitors J. Virol., August 15, 2001; 75(16): 7266 - 7279. [Abstract] [Full Text] [PDF]
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Y. Hirose, M. S. Berger, and R. O. Pieper Abrogation of the Chk1-mediated G2 Checkpoint Pathway Potentiates Temozolomide-induced Toxicity in a p53-independent Manner in Human Glioblastoma Cells Cancer Res., August 1, 2001; 61(15): 5843 - 5849. [Abstract] [Full Text] [PDF]
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M. V. Blagosklonny and A. B. Pardee Exploiting Cancer Cell Cycling for Selective Protection of Normal Cells Cancer Res., June 1, 2001; 61(11): 4301 - 4305. [Abstract] [Full Text] [PDF]
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 R. Weissleder and U. Mahmood Molecular Imaging Radiology, May 1, 2001; 219(2): 316 - 333. [Abstract] [Full Text]
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 B. Hagenauer, A. Salamon, T. Thalhammer, O. Kunert, E. Haslinger, P. Klingler, A. M. Senderowicz, E. A. Sausville, and W. Jäger In Vitro Glucuronidation of the Cyclin-Dependent Kinase Inhibitor Flavopiridol by Rat and Human Liver Microsomes: Involvement of UDP-Glucuronosyltransferases 1A1 and 1A9 Drug Metab. Dispos., April 1, 2001; 29(4): 407 - 414. [Abstract] [Full Text]
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 A. Kubo and F. J. Kaye Searching for Selective Cyclin-Dependent Kinase Inhibitors to Target the Retinoblastoma/p16 Cancer Gene Pathway J Natl Cancer Inst, March 21, 2001; 93(6): 415 - 417. [Full Text] [PDF]
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H. Dosaka-Akita, F. Hommura, T. Mishina, S. Ogura, M. Shimizu, H. Katoh, and Y. Kawakami A Risk-Stratification Model of Non-Small Cell Lung Cancers Using Cyclin E, Ki-67, and ras p21: Different Roles of G1 Cyclins in Cell Proliferation and Prognosis Cancer Res., March 1, 2001; 61(6): 2500 - 2504. [Abstract] [Full Text]
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M. E. S. Kahn, A. Senderowicz, E. A. Sausville, and K. E. Barrett Possible Mechanisms of Diarrheal Side Effects Associated with the Use of a Novel Chemotherapeutic Agent, Flavopiridol Clin. Cancer Res., February 1, 2001; 7(2): 343 - 349. [Abstract] [Full Text]
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R. W. Robey, W. Y. Medina-Pérez, K. Nishiyama, T. Lahusen, K. Miyake, T. Litman, A. M. Senderowicz, D. D. Ross, and S. E. Bates Overexpression of the ATP-binding Cassette Half-Transporter, ABCG2 (MXR/BCRP/ABCP1), in Flavopiridol-resistant Human Breast Cancer Cells Clin. Cancer Res., January 1, 2001; 7(1): 145 - 152. [Abstract] [Full Text]
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X. Chen, M. Lowe, T. Herliczek, M. J. Hall, C. Danes, D. A. Lawrence, and K. Keyomarsi Protection of Normal Proliferating Cells Against Chemotherapy by Staurosporine-Mediated, Selective, and Reversible G1 Arrest J Natl Cancer Inst, December 20, 2000; 92(24): 1999 - 2008. [Abstract] [Full Text] [PDF]
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M. Omura-Minamisawa, M. B. Diccianni, A. Batova, R. C. Chang, L. J. Bridgeman, J. Yu, Esther de Wit, F. H. Kung, J. D. Pullen, and A. L. Yu In Vitro Sensitivity of T-Cell Lymphoblastic Leukemia to UCN-01 (7-Hydroxystaurosporine) Is Dependent on p16 Protein Status: A Pediatric Oncology Group Study Cancer Res., December 1, 2000; 60(23): 6573 - 6576. [Abstract] [Full Text]
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F. Innocenti, W. M. Stadler, L. Iyer, J. Ramírez, E. E. Vokes, and M. J. Ratain Flavopiridol Metabolism in Cancer Patients Is Associated with the Occurrence of Diarrhea Clin. Cancer Res., September 1, 2000; 6(9): 3400 - 3405. [Abstract] [Full Text]
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A. M. Senderowicz and E. A. Sausville RESPONSE: Re: Preclinical and Clinical Development of Cyclin-Dependent Kinase Modulators J Natl Cancer Inst, July 19, 2000; 92(14): 1185 - 1185. [Full Text] [PDF]
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S.-H. Chao, K. Fujinaga, J. E. Marion, R. Taube, E. A. Sausville, A. M. Senderowicz, B. M. Peterlin, and D. H. Price Flavopiridol Inhibits P-TEFb and Blocks HIV-1 Replication J. Biol. Chem., September 8, 2000; 275(37): 28345 - 28348. [Abstract] [Full Text] [PDF]
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S.-H. Chao and D. H. Price Flavopiridol Inactivates P-TEFb and Blocks Most RNA Polymerase II Transcription in Vivo J. Biol. Chem., August 17, 2001; 276(34): 31793 - 31799. [Abstract] [Full Text] [PDF]
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