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1
*
Celgene Corporation, Warren, NJ 07059; and
Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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mediates both protective and detrimental manifestations of
the host immune response. Our previous work has shown thalidomide to be
a relatively selective inhibitor of TNF- production in vivo and in
vitro. Additionally, we have recently reported that thalidomide exerts
a costimulatory effect on T cell responses. To develop thalidomide
analogues with increased anti-TNF- activity and reduced or
absent toxicities, novel TNF- inhibitors were designed and
synthesized. When a selected group of these compounds was examined for
their immunomodulatory activities, different patterns of cytokine
modulation were revealed. The tested compounds segregated into two
distinct classes: one class of compounds, shown to be potent
phosphodiesterase 4 inhibitors, inhibited TNF- production, increased
IL-10 production by LPS-induced PBMC, and had little effect on T cell
activation; the other class of compounds, similar to thalidomide, were
not phosphodiesterase 4 inhibitors and markedly stimulated T cell
proliferation and IL-2 and IFN-
production. These compounds
inhibited TNF-, IL-1ß, and IL-6 and greatly increased IL-10
production by LPS-induced PBMC. Similar to thalidomide, the effect of
these agents on IL-12 production was dichotomous; IL-12 was inhibited
when PBMC were stimulated with LPS but increased when cells were
stimulated by cross-linking the TCR. The latter effect was associated
with increased T cell CD40 ligand expression. The distinct
immunomodulatory activities of these classes of thalidomide analogues
may potentially allow them to be used in the clinic for the treatment
of different immunopathological disorders. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, a highly
pleiotropic cytokine produced primarily by monocytes and macrophages,
plays a central role in the host protective immune response to
bacterial and viral infections. For example, TNF- is essential for
granuloma formation and the control of bacterial dissemination in
experimental tuberculosis in mice (1, 2). In addition,
TNF- added to infected cells in vitro inhibits the replication of
both DNA and RNA viruses (3, 4). However, the cytokine may
also play a role in the pathogenesis of disease. Perhaps the best
evidence for this is the dramatic reduction in disease activity
observed in rheumatoid arthritis and inflammatory bowel disease after
treatment of patients with neutralizing anti-TNF- Abs (5, 6). Additionally, elevated levels of TNF- have been
associated with the fevers, malaise, and weight loss that accompany
chronic infections (7), and reductions in TNF- levels
have been linked with an amelioration of clinical symptoms in a number
of disease states (8, 9, 10, 11).
Our previous work has shown thalidomide to be a relatively selective
inhibitor of TNF- production by human monocytes in vivo and in
vitro. Leprosy patients with erythema nodosum leprosum treated with
thalidomide, experience a reduction of serum TNF- levels with a
concomitant abrogation of clinical symptoms (9). In
patients with tuberculosis, with or without HIV infection, thalidomide
lowers plasma TNF- protein levels and leukocyte TNF- mRNA levels
in association with an accelerated weight gain (8). In
vitro, thalidomide has been shown to selectively partially (50–70%)
inhibit TNF- produced by monocytes and macrophages stimulated with
LPS (12).
Recently, we have reported the ability of thalidomide to costimulate T
cells in vitro (13). Thus, in addition to its monocyte
cytokine-inhibitory activity, thalidomide exerts a costimulatory or
adjuvant effect on T cell responses that includes increased production
of IL-2 and IFN-. This effect may contribute to the
immune-modulating effects of the drug.
To obtain drugs that are more efficient TNF- inhibitors than
thalidomide, structural analogues of the parent molecule have been
synthesized and examined for inhibition of TNF- production.
Recently, some of these thalidomide analogues have been described
(12, 14, 15, 47). On a molar basis, these reported
compounds are up to 50,000-fold more potent than thalidomide at
inhibiting TNF- production by PBMC in vitro. In this study, we have
selected six of these compounds and evaluated them for their effects on
the production of other monocyte cytokines, as well as their
immunomodulatory effects on T cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PBMC were isolated from the blood of healthy volunteers by Ficoll-Hypaque (Pharmacia, Piscataway, NJ) density centrifugation as previously described (12). T lymphocytes were purified from PBMC by rosetting with neuraminidase-treated sheep erythrocytes and subsequent incubation of erythrocyte-rosetting cells on a nylon wool column. Nonadherent cells eluted from the column were >93% CD3 Ag positive by flow cytometry (FACStar, Becton Dickinson, San Jose, CA). Leukocytes were cultured in RPMI medium (Life Technologies, Grand Island, NY) supplemented with 10% AB+ human serum, 2 mM L-glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin (Life Technologies).
Thalidomide and analogues
Thalidomide and analogues (Celgene, Warren, NJ) were dissolved in DMSO (Sigma, St. Louis, MO); further dilutions were made in culture medium immediately before use. The final DMSO concentration in all assays was 0.25%. The following structural analogues were used: CII-A is compound 3a (14) and CC-1069 (12); CII-B is compound CC-3052 (16) with the carboxymethyl group replaced by an amide moiety; CII-C is an amino-substituted analogue of compound 4b (14); compounds CI-A, CI-B, and CI-C are amino-substituted analogues of thalidomide. CI-A is 5a, CI-B is 8a and CI-C is 14 (47).
PBMC stimulation by LPS
PBMC (2 x 105 cells) incubated in 96-well
flat-bottom polystyrene Costar tissue culture plates (Corning, Corning,
NY) were stimulated by 1 µg/ml LPS from Salmonella
minnesota R595 (List Biological Labs, Campbell, CA) for the induction
of TNF- , IL-1ß, IL-6, IL-8, IL-10, and IL-12 (12).
Cells were incubated with or without thalidomide or analogues for
20 h, and supernatants were collected for the determination of
cytokine levels by ELISA.
PBMC stimulation by anti-CD3 Ab
PBMC (1 x 106 cells) were stimulated by
cross-linking of the TCR by immobilized monoclonal mouse anti-human
CD3 (Orthoclone OKT3, a kind gift of Dr. R. Zivin, Orthobiotech,
Raritan, NJ) as previously described (13). The
anti-CD3 Ab was diluted to 10 µg/ml in 100 µl PBS and coated
onto 48-well flat-bottom polystyrene Falcon tissue culture plates
(Becton Dickinson, Franklyn Lakes, NJ) by overnight incubation at
4°C. Appropriate dilutions of thalidomide and analogues were added at
the start of the cell cultures. Supernatants were collected at 24, 48,
and 72 h and assayed for IL-10, IL-12, and TNF- levels. Cells
were collected at 48 h for evaluation of CD40 ligand
(CD40L)3 and CD3
surface expression by two-color flow cytometry (anti-CD40L,
PharMingen, San Diego, CA; anti-CD3, Becton Dickinson, San
Jose, Ca).
T cell stimulation and proliferation assays
Purified T cells (2 x 105 cells/well) in
96-well Costar tissue culture plates (Corning) previously coated with
anti-CD3 mAb (as above) were treated daily with thalidomide or
analogues for up to 120 h. Supernatants were harvested for IFN-
assay at 72 h. T cell-proliferative responses were assayed by
measuring [3H]thymidine (NEN Products, Boston,
MA) incorporation during the last 18 h of 120-h cultures. DNA was
harvested onto fiber mats with an automatic cell harvester (Skatron,
Stirling, VA), and [3H]thymidine incorporation
was measured with a LKB 1205 Betaplate liquid scintillation counter
(Wallac, Gaithersburg, MD)
Phosphodiesterase 4 (PDE4) inhibition assay
PDE4 inhibition was evaluated in purified extracts of promonocytic U937 cells using a modified method of Hill and Mitchell (17) as previously described (14). Cells (1 x 109) were washed in PBS and lysed in cold homogenization buffer (20 mM Tris-HCl, pH 7.1; 3 mM 2-ME; 1 mM MgCl; 0.1 mM EGTA, 1 µM PMSF, 1 µg/ml leupeptin). After homogenization with a Dounce homogenizer, the supernatant was collected by centrifugation and loaded onto a Sephacryl S-200 column equilibrated with homogenization buffer. PDE4 was eluted in homogenization buffer, and enzyme activity was determined in 50 mM Tris-HCl, pH 7.5, 5 mM MgCl2, and 1 µM cAMP (of which 1% was [3H]cAMP) as described in detail by Thompson et al. (18). Reactions were performed at 30°C for 30 min and terminated by boiling for 2 min. Briefly, cyclic 3',5'-[3H]AMP was converted to 5'-[3H]AMP by phosphodiesterase. The separation of 5'-[3H]AMP from 3',5'-[3H]AMP was achieved by enzymatically converting 5'-[3H]AMP to [3H]adenosine with nucleotidase present in snake venom (Sigma, V-0376), 1 mg/ml at 30°C for 15 min. Adenosine was separated from the unreacted cyclic substrate by addition of 200 µl of AG1-X8 resin (Bio-Rad, Hercules, CA) that absorbs cyclic 3',5'-[3H]AMP. Samples were then spun at 3000 rpm for 5 min, and 50 µl of the aqueous phase were taken for counting of adenosine radioactivity by liquid scintillation techniques. Enzyme activity was determined in the presence of varying concentrations of compounds. IC50 values were determined from dose-responses curves derived from at least three independent experiments done in duplicate. IC50 values were calculated by nonlinear regression analysis (variable slope) using Prism by GraphPad Software (San Diego, CA).
Cytokine assays
Culture supernatants were harvested at indicated times and
frozen immediately at -70°C until assayed in triplicate or
duplicate. TNF- , IL-1ß, IL-2, IL-6, IL-8, IL-10, IL-12 (p40 and
p70), and IFN- levels were measured by ELISA (Endogen, Cambridge,
MA) as described by the manufacturer.
Statistical analysis
Data were evaluated by the Friedman test, a nonparametric ANOVA, in view of the small sample size. The SPSS computer program was used. Significance was set at p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A group of thalidomide analogues were selected for their capacity
to inhibit TNF- production by LPS-stimulated PBMC. Their
IC50 values for TNF- (the concentration at
which each compound was able to inhibit TNF- levels by 50%) were
established when screening these agents (Table
I). Although all compounds were efficient
TNF- inhibitors, their dose-response curves were not identical (data
not shown). For some compounds, dose-response curves were the classical
sigmoidal curves seen for pharmacological antagonists (class II
compounds, see below) (12). Other compounds, however,
showed a flatter, thalidomide–like dose response (class I compounds,
see below) (12). Subsequent experiments were conducted
with the compounds at three concentrations: their approximate TNF-
IC50; 3 times the TNF-
IC50; and 10 times the TNF-
IC50. Rolipram, a known TNF- inhibitor
(19), was used as a control. The effect of these drugs on
other LPS-induced cytokines was also investigated. Compounds were added
at the mentioned concentrations to LPS-stimulated human PBMC, and
cytokine secretion into the culture supernatant was evaluated. Fig. 1
shows the effect of the drugs on the
production of TNF- , IL-1ß, IL-6, IL-8, IL-10, and IL-12.
Compounds clearly segregated into two different classes according to
their effects on LPS-induced IL-1ß, IL-6, IL-10, and IL-12 cytokines.
One class of compounds (class I) showed significant inhibition of
IL-1ß, at their TNF- IC50, and almost
complete inhibition at higher concentrations, whereas compounds from
class II had a more modest inhibitory effect, albeit significant at the
higher concentrations (Fig. 1). Similarly, class I compounds
significantly inhibited IL-6 levels, whereas class II compounds did not
affect IL-6 production (Fig. 1). IL-8 levels were not significantly
affected by either class of compounds, although class I showed a very
minor trend toward inhibition of IL-8 production (Fig. 1).
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).
LPS-induced IL-12 levels were significantly inhibited by both classes
of compounds at the higher concentrations, but class I compounds were
more potent (Fig. 1). Thus, in summary, compounds from class I caused a
more pronounced inhibition of LPS-induced IL-1ß and IL-12 in addition
to the inhibition of IL-6 and a much greater stimulation of IL-10.
Class II compounds showed significant inhibitory activities against
LPS-induced IL-1ß and IL-12 but only at concentrations above their
TNF- IC50 values. A modest but consistent
stimulation of IL-10 was observed for class II compounds CII-A and
CII-B. Rolipram, used as a control, showed cytokine-modulatory profiles
comparable with those of class II compounds (Fig. 1).
Effect of class I and class II compounds on T cell-proliferative responses to immobilized anti-CD3 mAb
Optimal T cell activation requires two types of signals (20). Signal 1 is delivered by clustering of the T cell Ag receptor-CD3 complex through engagement of specific foreign peptides bound to MHC molecules on the surface of an APC. Signal 1 can be mimicked by cross-linking the TCR complexes with anti-CD3 mAb. Signal 2 (or costimulation) is Ag independent and may be provided by cytokines or by surface ligands on the APC that interact with their receptors on the T cell. Costimulatory signals are essential to induce maximal T cell proliferation and secretion of cytokines including IL-2 which ultimately drives T cell clonal expansion (20).
Thalidomide was recently reported to provide a costimulatory signal to
T cells receiving primary stimulation via the TCR, resulting in
increased cytokine production and proliferation (13). We
now examined the effect of the two classes of thalidomide analogues on
the proliferative responses of purified T cells stimulated by
anti-CD3 mAb. Two compounds from each class were tested in these
assays. Again, the two classes of compounds showed differential
activities. Compounds from class II exerted a modest inhibition of T
cell proliferation in response to immobilized anti-CD3, significant
for only one of the two compounds (Fig. 2). Class I compounds, however, were
potent costimulators of T cells and increased cell proliferation
significantly in a dose-dependent manner. As expected, thalidomide was
also significantly costimulatory in this assay but not as potent. There
was no proliferative response to these drugs in the absence of
anti-CD3, indicating that these drugs are not mitogenic per se but
provide a secondary, costimulatory signal (data not shown).
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Effect of class I and class II compounds on T cell cytokine production
We next evaluated the effect of the two classes of compounds on
production of the T cell cytokines IL-2 and IFN-. Class I compounds
induced significant concentration-dependent increases in IFN- at
72 h [peak of the production of this cytokine in this system
(13)] (Fig. 3). Class II
compounds, on the other hand, either had no effect or slightly
inhibited IFN- production at higher drug concentrations. As reported
previously, thalidomide significantly stimulated IFN- production,
although it required higher dosages (2–3 logs of magnitude) for
activity.
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). Thalidomide stimulated IL-2
production significantly but only at higher doses.
Thus, class I compounds were found to be efficient T cell costimulators
leading to the augmented production of the T cell cytokines IL-2 and
IFN-.
Effect of class I and class II compounds on PDE4 activity
PDE4 is one of the major phosphodiesterase isoenzymes found in
human myeloid and lymphoid lineage cells. The enzyme plays a crucial
role in regulating cellular activity by degrading the ubiquitous second
messenger cAMP and maintaining it at low intracellular levels
(21). Inhibition of PDE4 and the consequent increased cAMP
levels result in the modulation of LPS-induced cytokines including
inhibition of TNF-. As previously reported, class II compounds,
similarly to rolipram, are potent PDE4 inhibitors (14).
Therefore, we examined the effect of class I compounds on PDE4 activity
in purified fractions of the monocytic cell line U937. These compounds
did not show significant PDE4 inhibitory activity at up to 100 µM
(Table I). These results strongly suggest that the molecular target of
the class I compounds is not PDE4. Thus, class I compounds constitute a
new class of immunomodulators. These compounds are efficient TNF-
inhibitors but do not act as PDE4 inhibitors. Unlike PDE4 inhibitors,
which usually decrease T cell activity, class I compounds are potent
stimulators of T cell proliferation and IFN- and IL-2
production.
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IL-12 is produced primarily by APC (monocytes/macrophages and
dendritic cells) and is regulated by both T cell-dependent and T
cell-independent pathways. LPS induction of IL-12 is an example of the
T cell-independent pathway. In the T cell-dependent pathway, on the
other hand, the production of IL-12 is induced primarily by the
interaction of CD40L on activated T cells with CD40 on IL-12-producing
APC (22, 23). To study the effect of thalidomide and class
I compounds on cytokine production in a T cell-dependent system, PBMC
were stimulated through the TCR with immobilized anti-CD3 mAb, and
IL-12, TNF-, and IL-10 were measured. In this system, both
thalidomide and the class I compound CI-A induced significant increases
in IL-12 production (Fig. 4). However,
thalidomide did not affect the production of TNF- and IL-10 by
anti-CD3. On the other hand, the class I drug CI-A slightly
stimulated TNF- production but significantly inhibited IL-10
production in this system.
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).
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, and IL-10 levels were determined.
LPS-induced IL-12 and TNF- levels were significantly inhibited by
thalidomide and by the class I drug CI-A, whereas IL-10 was
significantly stimulated (Fig. 4). Similar results were obtained with
another class I compound, CI-B (data not shown). Thus, class I
compounds modulate IL-12, TNF-, and IL-10 production differently in
cells from the same donor depending on whether the stimulus is directed
at the monocytes/macrophages (LPS) or T cells (anti-CD3). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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potency and reduced or absent teratogenic potential, a
program to identify improved TNF- inhibitors was initiated. Here we
report that when a selected group of these TNF--inhibitory compounds
was further characterized, a dichotomous pattern in cytokine modulation
activities was revealed. Although all tested compounds were much more
potent TNF- inhibitors than the parent drug thalidomide, they
differed in the slope of their dose-response curves as well as in the
modulation of other monocyte and lymphocyte cytokines. Members of one
class of compounds, referred to here as class I, were broad inhibitors
of the LPS-induced proinflammatory monocyte cytokines TNF- ,
IL-1ß, IL-6, and IL-12 while potently augmenting the secretion of the
antiinflammatory cytokine IL-10. Class II compounds, on the other hand,
inhibited both TNF- and IL-12 in LPS-stimulated PBMC but had little
effect on the production of other LPS-induced monocyte cytokines such
as IL-1ß, IL-6, or IL-8. The latter drugs also produced a modest
stimulation of LPS-induced IL-10 levels. In all of these effects, class
II compounds closely resemble thalidomide (12).
Recently, we reported that thalidomide provides a costimulatory signal
to T cells, resulting in increased T cell proliferation and augmented
IL-2 and IFN- production (13). Resting T cells require
a costimulus in addition to the primary signal mediated by the T cell
Ag receptor to achieve optimal activation (20). Such a
costimulus alone will not activate the T cell. Similarly to
thalidomide, class I compounds also exhibited T cell costimulatory
properties but were far more potent than the parent molecule in this
respect. Thus, these compounds caused marked increases in proliferation
and secretion of IL-2 and IFN- by anti-CD3-stimulated T cells.
In the absence of the TCR-mediated stimulus, however, the drugs had no
activating effect. Costimulation by class I compounds also resulted in
increased CD40L expression on T cells, associated with enhanced T
cell-dependent IL-12 production. These findings show that in addition
to their strong antiinflammatory properties, class I compounds
efficiently costimulate T cells, achieving both effects with 100 to
1000 times the potency of thalidomide.
The different cytokine-modulatory profiles of the two classes of
compounds are likely to be related to their molecular targets. Class II
compounds are potent inhibitors of PDE4 (14). PDE4
inhibition leads to increases in intracellular cAMP levels resulting in
the suppression of TNF- and IL-12 production and increased
production of the antiinflammatory cytokine IL-10 (24, 25). IL-6 and IL-8, on the other hand, are not directly
regulated by cAMP (25, 26). IL-1ß is only partially
affected by inhibition of PDE4 (26, 27). Thus, PDE4
inhibitors appear to have a selective antiinflammatory action. It is
also well established that raising cAMP levels in T cells during the
early phase of mitogen or Ag activation results in a decrease in
proliferative potential (28, 29). Indeed, class II
compounds modestly but consistently inhibited T cell proliferation and
T cell cytokine production, in accord with rolipram and other known
PDE4 inhibitors (29, 30). In addition, class II compounds
either inhibited or had no effect on CD40L expression on T cells.
Although there are no reports on the effects of PDE4 inhibitors on
CD40L expression, other cAMP-elevating agents have been shown to be
unable to induce CD40L expression on T lymphocytes (31).
All these results are consistent with the notion that the class II
compounds described here act via PDE4 inhibition.
In contrast, thalidomide and class I compounds do not have activity against PDE4 at concentrations below 100 µM. The possibility that metabolites or degradation products of these drugs may weakly inhibit PDE4 has not been ruled out. However, because PDE4 inhibition is not associated with increased T cell activation, thalidomide and class I compounds must have another molecular target. The molecular mechanism of action of thalidomide and class I compounds is currently under investigation.
Thalidomide has been reported to inhibit IL-12 production by LPS-stimulated monocytes (32), and here we have confirmed this effect. In vivo, however, thalidomide treatment has been found to increase IL-12 levels in the plasma of tuberculosis and HIV-infected patients (Ref. 48 and our manuscript in preparation). The dual and opposite effects of thalidomide on IL-12 production may be explained by the present findings. Whereas thalidomide inhibits LPS-induced monocyte IL-12 production, the drug stimulates the production of this cytokine in T cell-dependent systems. Thus, the effect of the drug on IL-12 varies according to the nature of the stimulus and the cell type being stimulated. Indeed, this Janus-faced attribute of thalidomide can explain the coincidence of seemingly opposite effects in some clinical situations. For example, in the management of the Behçet syndrome, thalidomide is very effective in healing the debilitating orogenital ulceration (antiinflammatory effect), while simultaneously inducing or exacerbating erythema nodosum (possible T cell-costimulatory effect) in these patients (33).
The analogues studied here appear to have "inherited" different properties from the parent drug. The distinct immunomodulatory activities of two classes of thalidomide analogues suggest that they may have differing applications in different immunopathologic disorders. Therapeutic elevation of intracellular cAMP levels by PDE4 inhibitors has antiinflammatory effects, with consequent benefits in a variety of diseases such as asthma (34), rheumatoid arthritis (35), and atopic dermatitis (36). However, in general, the efficacy of PDE4 inhibitors in clinical trials has been disappointing because of dose-limiting side effects, most prominently nausea and vomiting (37). Preliminary results with thalidomide-derived PDE4 inhibitors in animals have not shown any evidence of emesis.
In addition to their potential use as antiinflammatory drugs, class I
compounds could also be useful in clinical settings where there is a
defect in T cell function or IL-12 responses, as in HIV disease
(38). IL-12 has been shown to restore HIV-specific
cell-mediated immunity in vitro (39). In addition, IL-12
has been shown to exhibit potent antitumor activity in murine tumor
models through various mechanisms including the stimulation of NK cells
(40), CD8+ cytotoxic T cells
(41), and IFN--mediated antiangiogenesis
(42). Our recent finding of the preferential costimulation
of CD8+ T cells by thalidomide (13)
and the observation that thalidomide and class I compounds induce T
cell-dependent IL-12 production suggest possible applications of
these drugs in the control of viral infections (43, 44) or
in boosting antitumor immunity (45, 46).
In conclusion, through the design and selection of analogues more
active than thalidomide in inhibiting LPS-induced TNF- production,
we have identified two different classes of immunomodulators that share
with thalidomide its anti-TNF- activity. However, the two
classes of compounds possess different properties. Preliminary results
indicate that at least some of these new compounds are nontoxic and
nonteratogenic (Ref. 16 and unpublished observations). These compounds
with distinct immunomodulatory effects will be used as investigational
tools in animal disease models to define mechanisms of pathogenesis and
to continue to elucidate the mechanism of action of thalidomide.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to L. G. Corral, Laboratory of Cellular Physiology and Immunology, Rockefeller University, 1230 York Avenue, New York, NY 10021. E-mail address:
3 Abbreviations used in this paper: CD40L, CD40 ligand; PDE4, phosphodiesterase 4.
Received for publication December 23, 1998. Accepted for publication April 22, 1999.
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References |
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 A. Thornburg, R. Abonour, P. Smith, K. Knox, and H. L. Twigg III Hypersensitivity Pneumonitis-Like Syndrome Associated With the Use of Lenalidomide Chest, May 1, 2007; 131(5): 1572 - 1574. [Abstract] [Full Text] [PDF]
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 D. Verhelle, L. G. Corral, K. Wong, J. H. Mueller, L. Moutouh-de Parseval, K. Jensen-Pergakes, P. H. Schafer, R. Chen, E. Glezer, G. D. Ferguson, et al. Lenalidomide and CC-4047 Inhibit the Proliferation of Malignant B Cells while Expanding Normal CD34+ Progenitor Cells Cancer Res., January 15, 2007; 67(2): 746 - 755. [Abstract] [Full Text] [PDF]
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 A. Yndestad, L. E. Vinge, R. Bjornerheim, T. Ueland, J. E. Wang, S. S. Froland, H. Attramadal, P. Aukrust, and E. Oie Thalidomide attenuates the development of fibrosis during post-infarction myocardial remodelling in rats Eur J Heart Fail, December 1, 2006; 8(8): 790 - 796. [Abstract] [Full Text] [PDF]
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A. Tefferi, J. Cortes, S. Verstovsek, R. A. Mesa, D. Thomas, T. L. Lasho, W. J. Hogan, M. R. Litzow, J. B. Allred, D. Jones, et al. Lenalidomide therapy in myelofibrosis with myeloid metaplasia Blood, August 15, 2006; 108(4): 1158 - 1164. [Abstract] [Full Text] [PDF]
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 M. Kiaei, S. Petri, K. Kipiani, G. Gardian, D.-K. Choi, J. Chen, N. Y. Calingasan, P. Schafer, G. W. Muller, C. Stewart, et al. Thalidomide and Lenalidomide Extend Survival in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis J. Neurosci., March 1, 2006; 26(9): 2467 - 2473. [Abstract] [Full Text] [PDF]
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 P.-K. Li, B. Pandit, D. L. Sackett, Z. Hu, J. Zink, J. Zhi, D. Freeman, R. W. Robey, K. Werbovetz, A. Lewis, et al. A thalidomide analogue with in vitro antiproliferative, antimitotic, and microtubule-stabilizing activities. Mol. Cancer Ther., February 1, 2006; 5(2): 450 - 456. [Abstract] [Full Text] [PDF]
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 L. Gullestad, T. Ueland, J. G. Fjeld, E. Holt, T. Gundersen, K. Breivik, M. Folling, A. Hodt, R. Skardal, J. Kjekshus, et al. Effect of Thalidomide on Cardiac Remodeling in Chronic Heart Failure: Results of a Double-Blind, Placebo-Controlled Study Circulation, November 29, 2005; 112(22): 3408 - 3414. [Abstract] [Full Text] [PDF]
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A. Tefferi Pathogenesis of Myelofibrosis With Myeloid Metaplasia J. Clin. Oncol., November 20, 2005; 23(33): 8520 - 8530. [Abstract] [Full Text] [PDF]
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F. J. Hernandez-Ilizaliturri, N. Reddy, B. Holkova, E. Ottman, and M. S. Czuczman Immunomodulatory Drug CC-5013 or CC-4047 and Rituximab Enhance Antitumor Activity in a Severe Combined Immunodeficient Mouse Lymphoma Model Clin. Cancer Res., August 15, 2005; 11(16): 5984 - 5992. [Abstract] [Full Text] [PDF]
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A. Vacca, C. Scavelli, V. Montefusco, G. Di Pietro, A. Neri, M. Mattioli, S. Bicciato, B. Nico, D. Ribatti, F. Dammacco, et al. Thalidomide Downregulates Angiogenic Genes in Bone Marrow Endothelial Cells of Patients With Active Multiple Myeloma J. Clin. Oncol., August 10, 2005; 23(23): 5334 - 5346. [Abstract] [Full Text] [PDF]
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 A. List, S. Kurtin, D. J. Roe, A. Buresh, D. Mahadevan, D. Fuchs, L. Rimsza, R. Heaton, R. Knight, and J. B. Zeldis Efficacy of Lenalidomide in Myelodysplastic Syndromes N. Engl. J. Med., February 10, 2005; 352(6): 549 - 557. [Abstract] [Full Text] [PDF]
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H. Kaufmann, M. Raderer, S. Wohrer, A. Puspok, A. Bankier, C. Zielinski, A. Chott, and J. Drach Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma Blood, October 15, 2004; 104(8): 2269 - 2271. [Abstract] [Full Text] [PDF]
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S.A. Schey, P. Fields, J.B. Bartlett, I.A. Clarke, G. Ashan, R.D. Knight, M. Streetly, and A.G. Dalgleish Phase I Study of an Immunomodulatory Thalidomide Analog, CC-4047, in Relapsed or Refractory Multiple Myeloma J. Clin. Oncol., August 15, 2004; 22(16): 3269 - 3276. [Abstract] [Full Text] [PDF]
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T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson Advances in biology of multiple myeloma: clinical applications Blood, August 1, 2004; 104(3): 607 - 618. [Abstract] [Full Text] [PDF]
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 S. V. Rajkumar Thalidomide: Tragic Past and Promising Future Mayo Clin. Proc., July 1, 2004; 79(7): 899 - 903. [PDF]
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R. LeBlanc, T. Hideshima, L. P. Catley, R. Shringarpure, R. Burger, N. Mitsiades, C. Mitsiades, P. Cheema, D. Chauhan, P. G. Richardson, et al. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway Blood, March 1, 2004; 103(5): 1787 - 1790. [Abstract] [Full Text] [PDF]
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M. S. Gee, S. Makonnen, K. al-Kofahi, B. Roysam, F. Payvandi, H.-W. Man, G. W. Muller, and W. M. F. Lee Selective Cytokine Inhibitory Drugs with Enhanced Antiangiogenic Activity Control Tumor Growth through Vascular Inhibition Cancer Res., December 1, 2003; 63(23): 8073 - 8078. [Abstract] [Full Text] [PDF]
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M. A. Dimopoulos, A. Anagnostopoulos, and D. Weber Treatment of Plasma Cell Dyscrasias With Thalidomide and Its Derivatives J. Clin. Oncol., December 1, 2003; 21(23): 4444 - 4454. [Abstract] [Full Text] [PDF]
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 P. H. Schafer, A. K. Gandhi, M. A. Loveland, R. S. Chen, H.-W. Man, P. P. M. Schnetkamp, G. Wolbring, S. Govinda, L. G. Corral, F. Payvandi, et al. Enhancement of Cytokine Production and AP-1 Transcriptional Activity in T Cells by Thalidomide-Related Immunomodulatory Drugs J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 1222 - 1232. [Abstract] [Full Text] [PDF]
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 M. Weeber, R. Vos, H. Klein, L. T.W. de Jong-van den Berg, A. R. Aronson, and G. Molema Generating Hypotheses by Discovering Implicit Associations in the Literature: A Case Report of a Search for New Potential Therapeutic Uses for Thalidomide J. Am. Med. Inform. Assoc., May 1, 2003; 10(3): 252 - 259. [Abstract] [Full Text] [PDF]
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 J N Gordon and P M Goggin Thalidomide and its derivatives: emerging from the wilderness Postgrad. Med. J., March 1, 2003; 79(929): 127 - 132. [Abstract] [Full Text] [PDF]
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J. B. Marriott, I. A. Clarke, A. Czajka, K. Dredge, K. Childs, H.-W. Man, P. Schafer, S. Govinda, G. W. Muller, D. I. Stirling, et al. A Novel Subclass of Thalidomide Analogue with Anti-Solid Tumor Activity in Which Caspase-dependent Apoptosis is Associated with Altered Expression of bcl-2 Family Proteins Cancer Res., February 1, 2003; 63(3): 593 - 599. [Abstract] [Full Text] [PDF]
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 G. Mufti, A. F. List, S. D. Gore, and A. Y.L. Ho Myelodysplastic Syndrome Hematology, January 1, 2003; 2003(1): 176 - 199. [Abstract] [Full Text] [PDF]
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P. G. Richardson, R. L. Schlossman, E. Weller, T. Hideshima, C. Mitsiades, F. Davies, R. LeBlanc, L. P. Catley, D. Doss, K. Kelly, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma Blood, October 16, 2002; 100(9): 3063 - 3067. [Abstract] [Full Text] [PDF]
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G. Vescovo, B. Ravara, A. Angelini, M. Sandri, U. Carraro, C. Ceconi, and L. D. Libera Effect of thalidomide on the skeletal muscle in experimental heart failure Eur J Heart Fail, August 1, 2002; 4(4): 455 - 460. [Abstract] [Full Text] [PDF]
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R. P. Baughman, M. A. Judson, A. S. Teirstein, D. R. Moller, and E. E. Lower Thalidomide for Chronic Sarcoidosis* Chest, July 1, 2002; 122(1): 227 - 232. [Abstract] [Full Text] [PDF]
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 L. Tsenova, B. Mangaliso, G. Muller, Y. Chen, V. H. Freedman, D. Stirling, and G. Kaplan Use of IMiD3, a Thalidomide Analog, as an Adjunct to Therapy for Experimental Tuberculous Meningitis Antimicrob. Agents Chemother., June 1, 2002; 46(6): 1887 - 1895. [Abstract] [Full Text] [PDF]
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N. Mitsiades, C. S. Mitsiades, V. Poulaki, D. Chauhan, P. G. Richardson, T. Hideshima, N. C. Munshi, S. P. Treon, and K. C. Anderson Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications Blood, May 29, 2002; 99(12): 4525 - 4530. [Abstract] [Full Text] [PDF]
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K. Dredge, J. B. Marriott, S. M. Todryk, G. W. Muller, R. Chen, D. I. Stirling, and A. G. Dalgleish Protective Antitumor Immunity Induced by a Costimulatory Thalidomide Analog in Conjunction with Whole Tumor Cell Vaccination Is Mediated by Increased Th1-Type Immunity J. Immunol., May 15, 2002; 168(10): 4914 - 4919. [Abstract] [Full Text] [PDF]
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 S J H van Deventer Small therapeutic molecules for the treatment of inflammatory bowel disease Gut, May 1, 2002; 50(90003): iii47 - 53. [Abstract] [Full Text] [PDF]
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M. A. Hussein Nontraditional Cytotoxic Therapies for Relapsed/Refractory Multiple Myeloma Oncologist, April 1, 2002; 7(90001): 20 - 29. [Abstract] [Full Text] [PDF]
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A. F. List New Approaches to the Treatment of Myelodysplasia Oncologist, April 1, 2002; 7(90001): 39 - 49. [Abstract] [Full Text] [PDF]
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S. Majumdar, B. Lamothe, and B. B. Aggarwal Thalidomide Suppresses NF-{kappa}B Activation Induced by TNF and H2O2, But Not That Activated by Ceramide, Lipopolysaccharides, or Phorbol Ester J. Immunol., March 15, 2002; 168(6): 2644 - 2651. [Abstract] [Full Text] [PDF]
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 A Wozniacka, A Carter, and D P Mccauliffe Antimalarials in cutaneous lupus erythematosus: mechanisms of therapeutic benefit Lupus, February 1, 2002; 11(2): 71 - 81. [Abstract] [PDF]
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K. Neben, T. Moehler, G. Egerer, A. Kraemer, J. Hillengass, A. Benner, A. D. Ho, and H. Goldschmidt High Plasma Basic Fibroblast Growth Factor Concentration Is Associated with Response to Thalidomide in Progressive Multiple Myeloma Clin. Cancer Res., September 1, 2001; 7(9): 2675 - 2681. [Abstract] [Full Text] [PDF]
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B. Barlogie, R. Desikan, P. Eddlemon, T. Spencer, J. Zeldis, N. Munshi, A. Badros, M. Zangari, E. Anaissie, J. Epstein, et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients Blood, July 15, 2001; 98(2): 492 - 494. [Abstract] [Full Text] [PDF]
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F. E. Davies, N. Raje, T. Hideshima, S. Lentzsch, G. Young, Y.-T. Tai, B. Lin, K. Podar, D. Gupta, D. Chauhan, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma Blood, July 1, 2001; 98(1): 210 - 216. [Abstract] [Full Text] [PDF]
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W. S. Dalton, P. L. Bergsagel, W. M. Kuehl, K. C. Anderson, and J. L. Harousseau Multiple Myeloma Hematology, January 1, 2001; 2001(1): 157 - 177. [Abstract] [Full Text] [PDF]
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R. J. Klasa, A. F. List, and B. D. Cheson Rational Approaches to Design of Therapeutics Targeting Molecular Markers Hematology, January 1, 2001; 2001(1): 443 - 462. [Abstract] [Full Text] [PDF]
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T. Hideshima, D. Chauhan, Y. Shima, N. Raje, F. E. Davies, Y.-T. Tai, S. P. Treon, B. Lin, R. L. Schlossman, P. Richardson, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy Blood, November 1, 2000; 96(9): 2943 - 2950. [Abstract] [Full Text] [PDF]
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A. Verbon, N. P. Juffermans, P. Speelman, S. J. H. van Deventer, I. J. M. ten Berge, H.-J. Guchelaar, and T. van der Poll A Single Oral Dose of Thalidomide Enhances the Capacity of Lymphocytes to Secrete Gamma Interferon in Healthy Humans Antimicrob. Agents Chemother., September 1, 2000; 44(9): 2286 - 2290. [Abstract] [Full Text]
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K. C. Anderson, R. A. Kyle, W. S. Dalton, T. Landowski, K. Shain, R. Jove, L. Hazlehurst, and J. Berenson Multiple Myeloma: New Insights and Therapeutic Approaches Hematology, January 1, 2000; 2000(1): 147 - 165. [Abstract] [Full Text] [PDF]
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N. Raje and K. Anderson Thalidomide -- A Revival Story N. Engl. J. Med., November 18, 1999; 341(21): 1606 - 1609. [Full Text]
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 J. A. Keifer, D. C. Guttridge, B. P. Ashburner, and A. S. Baldwin Jr. Inhibition of NF-kappa B Activity by Thalidomide through Suppression of Ikappa B Kinase Activity J. Biol. Chem., June 15, 2001; 276(25): 22382 - 22387. [Abstract] [Full Text] [PDF]
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