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MiDs: A Novel Class of Immunomodulatorsobert Knight

IMiDs are structural and functional analogues of thalidomide that represent a promisingnew class of immunomodulators for treatment of a variety of inflammatory, autoimmune,and neoplastic diseases. The discovery of the antiangiogenic and T-cell co-stimulatoryfunctions of IMiD compounds has led to the investigation of these agents for treatment ofhematologic neoplasms such as multiple myeloma and myelodysplastic syndromes, as wellas certain solid tumors. The second-generation IMiDs, such as lenalidomide and CC-4047,exhibited a greatly enhanced potency for immunomodulation and antiangiogenesis innonclinical studies when compared with the parent compound, thalidomide. In clinicalstudies, the IMiDs appear to have reduced sedative and neurotoxicity effects, which areoften associated with long-term thalidomide dosing. The precise mechanism of action ofIMiDs in the treatment of specific diseases is not entirely clear and may differ for variousdiseases depending on their underlying pathobiologies. Although IMiDs have similareffects on inflammatory cytokine secretion, T-cell modulation, angiogenesis, and expres-sion of adhesion molecules, each IMiD has a unique potency profile for these activities,which may ultimately indicate selective applicability of specific IMiDs for distinct diseasesand conditions. Clinical trials of lenalidomide, the primary second-generation IMiD, haveshown clinical benefits in both myelodysplastic syndrome and multiple myeloma and abetter safety profile than that of thalidomide, with no evidence of teratogenicity. It isanticipated that lenalidomide and other IMiD compounds will become important alterna-tives to thalidomide because of their more potent anti-inflammatory and anticancer prop-erties, as well as their improved side-effect profiles.Semin Oncol 32(suppl 5):S24-S30 © 2005 Elsevier Inc. All rights reserved.

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he IMiDs are a series of unique, orally bioavailable com-pounds that have been developed using the parent IMiD

ompound, thalidomide, as a structural template. They werepecifically designed to create new compounds with in-reased immunomodulating and anticancer properties, yetith less toxicity than thalidomide.1 In preclinical studies,

MiD compounds exhibit a wide range of biologic activitieselieved to have applicability for the treatment of variousisease conditions. The distinct IMiD compounds have sim-

lar effects on inflammatory cytokine expression, immuneell modulation (ie, T cells, monocytes, macrophages, andendritic cells), adhesion molecules, and angiogenesis. How-ver, each IMiD has a distinct relative potency and safetyrofile. Currently, several second-generation IMiD com-ounds are under investigation in clinical trials of treatmentor various neoplastic and inflammatory diseases.

linical Research and Development - Oncology, Celgene Corporation, Sum-mit, NJ.

upported by an unrestricted educational grant from Celgene Corporation.ddress reprint requests to Robert Knight, MD, Celgene Corporation, 86

tMorris Ave, Summit, NJ 07901.

24 0093-7754/05/$-see front matter © 2005 Elsevier Inc. All rights reserved.doi:10.1053/j.seminoncol.2005.06.018

ationale for IMiD Compoundshalidomide was originally marketed in Europe for its seda-

ive and antiemetic activities.1 However, the association ofhalidomide with birth defects and neuropathies eventuallyed to its withdrawal from the market in the early 1960s. Itas later discovered that thalidomide exhibits anti-inflam-atory properties applicable to the treatment of patients with

cute erythema nodosum leprosum, an inflammatory com-lication of lepromatous leprosy. Thalidomide is now ap-roved in the United States to treat erythema nodosum lep-osum and is used clinically to treat a variety of autoimmunend inflammatory disease states.

The immunomodulating effects of thalidomide are due inart to its selective inhibition of tumor necrosis factor-�TNF-�) production by lipopolysaccharide (LPS)-activateduman monocytes.2 TNF-� is a proinflammatory, proapop-otic cytokine that has an important role in the pathogenesisf many inflammatory diseases and certain cancers, andherefore represents an important therapeutic target.1,3,4 Theeduction in serum TNF-� levels and concomitant abroga-

ion of symptoms in erythema nodosum leprosum patients

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reated with thalidomide directly shows the importance ofhis mechanism of action.1,5

The subsequent discovery of thalidomide’s antiangio-enic6 and T-cell co-stimulatory activities7 led to clinical in-estigation of thalidomide for treatment of certain cancers. Inlinical trials, thalidomide treatment of patients with relapsednd refractory multiple myeloma (MM) has resulted in re-ponse rates of approximately 30%.8 Thalidomide has alsohown efficacy in the treatment of myelodysplastic syn-romes (MDS), which are clonal hematologic malignanciesharacterized by refractory cytopenias and increased risk ofransformation to acute myeloid leukemia.3,4,9-11 Severalmall and large clinical studies have shown the capacity ofhalidomide to induce hematologic improvement and trans-usion independence in a substantial percentage of patientsith MDS.4 However, thalidomide was associated with side

ffects that resulted in discontinuation of treatment in manyatients.4 Common side effects of treatment included fatigue,omnolence, constipation, rash, dizziness, shortness ofreath, nausea, fluid retention, and neuropathy.8,10 Given theast clinical potential for thalidomide in an increasing varietyf inflammatory and neoplastic disease conditions, strategiesere undertaken to synthesize analogues of thalidomide thatave greater potency and better tolerability.During the mid-1990s, a series of IMiD compounds were

reated by introducing chemical modifications to the struc-ural backbone of thalidomide.1 The initial goal in designinghe analogues was to enhance the potency of TNF-� inhibi-ion, believed to be the major mechanism of thalidomidection in vivo, while reducing the toxicity of the parent com-ound. Among these analogues, the most potent were mem-ers of a series of 4-amino analogues in which an aminoroup was added to the fourth carbon of the phthaloyl ring ofhalidomide. In this way, increased TNF-� inhibition initro–up to 50,000 times greater than that of thalidomide–as realized.1,12 Extensive preclinical testing of the pharma-

ology, pharmacokinetics, and toxicity profiles of theseompounds has led to the identification of lenalidomide (CC-013, Revlimid; Celgene Corp; Summit, NJ) as the primaryMiD for investigation in clinical trials (Fig 1).1,13,14 Lenalido-ide is currently in the advanced stages of development for

reatment of MDS and MM and in early clinical trials forreatment of certain solid malignancies, including androgen-ndependent prostate cancer and renal cell carcinoma.ompared with thalidomide, lenalidomide is a more potent

nhibitor of TNF-� secretion from activated monocytes (ap-roximately 2,000-fold), has an improved side-effect profile,nd shows no evidence of teratogenicity or mutagenesis inreclinical models.1,12 A closely related analogue, CC-4047,lso has potent activity against TNF-� secretion and has onlyecently entered clinical study.1

iologic Activityf IMiD Compounds

he multifaceted activities of the IMiD compounds, although

ot completely defined, have been shown in in vitro and I

nimal models and are being explored in clinical trials. Thenticancer, anti-inflammatory, and prohematopoietic prop-rties of IMiD compounds may be accounted for by a numberf mechanisms and may depend on the pathobiology of thepecific disease as well as the immune status of individualatients.

nhibition of Monocyte-Derived Cytokineshe anti-inflammatory activities of IMiD compounds are pri-arily mediated by the inhibition of proinflammatory cyto-

ine secretion from activated monocytes, macrophages, andther cell types.15-17 In addition to TNF-�, other cytokinesnhibited by the IMiD compounds include cyclooxygenase-2;ransforming growth factor �; and interleukins-1�, -6, and12 (IL-1�, IL-6, and IL-12). Conversely, increased secretionf the anti-inflammatory cytokine IL-10 from LPS-activatederipheral blood mononuclear cells was shown in one studyf closely related thalidomide analogues.16 Figure 2 shows

igure 1 Pharmacologic evolution of lenalidomide (CC-5013, Rev-imid; Celgene Corp). Lenalidomide is a 4-amino-glutamyl ana-ogue of thalidomide that is more potent than the parent compoundn its inhibitory actions both on the synthesis of TNF-� by activated

onocytes and on angiogenesis. Lenalidomide also appears to aug-ent the cytotoxicity of natural-killer cells leading directly to lysis ofM cells. Unlike thalidomide, no significant constipation, neurop-

thy, or sedation has been associated with lenalidomide treatment.mportantly, lenalidomide was nonteratogenic in a rabbit toxicologyodel traditionally used to detect drug teratogenicity.1,13,14

igure 2 Modulatory effects of IMiDs on cytokine production. Theseompounds markedly stimulate T-cell proliferation and IL-2 andnterferon-� production. IMiDs were also shown to inhibit TNF-�,L-1�, and IL-12. Production of IL-10 by LPS-induced peripherallood mononuclear cells was greatly increased by treatment with

MiD compounds. IL, interleukin; TNF, tumor necrosis factor.16

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he differential cytokine modulation under these conditionsy a representative IMiD, at its inhibitory concentration of0% (IC50) for TNF-� .16 In contrast to other known inhibi-ors of TNF-�, thalidomide and its 4-amino analogues do notnhibit phosphodiesterase isozyme 4 activity.16 Thalidomidenhibition of TNF-� from LPS-activated peripheral blood

ononuclear cells was shown to be mediated by enhancedegradation of TNF-� messenger RNA.15 However, the pre-ise molecular target of thalidomide and its analogues duringnhibition of other monocyte-derived cytokines is still undernvestigation.

Because treatment with thalidomide also results in theownmodulation of leukocyte adhesion molecules that me-iate cell migration and function (eg, integrins, intracellulardhesion molecule-1),18 these activities may represent an-ther potential anti-inflammatory mechanism of IMiD com-ounds. Adhesion molecules on noninflammatory cell typeseg, endothelial cells, stromal cells, and cancer cells) are alsoubject to downregulation by IMiDs, and this activity mayave profound effects on disease pathology.1

Immunologic mechanisms are believed to have a majorole in the pathogenesis of MDS.9 The aberrant expressionnd activities in the bone marrow microenvironment ofroinflammatory, proapoptotic cytokines contribute to inef-ective hematopoiesis and marrow failure.3,4,9 The efficacy ofreatment with thalidomide and its IMiD analogues in restor-ng hematopoiesis in patients with MDS is likely to be due ateast partly to inhibition of these cytokines. Similarly, inhibi-ion of IL-6 and TNF-� in the bone marrow milieu of MMatients could contribute to the anticancer effects of theseompounds, as these same cytokines mediate growth and

Figure 3 Differential co-stimulation of T-cell subsets by IMwith immobilized anti-CD3 in the absence or presence owas measured by [3H]-thymidine incorporation and celinto the CD8� and CD4� subsets. Results showed thproliferation of the CD8� subset, with a smaller effectsubset was the predominant T-cell type. (A) Proliferati(Reprinted with permission.21)

urvival of MM cells.17

-Cell Co-stimulationhe immunomodulatory activities of thalidomide and theMiD analogues also include potent T-cell co-stimulatory ac-ivity. These compounds have the capacity to provide therucial co-stimulatory second signal to T cells that have beenartially activated by the T-cell receptor.1,4,7,16,19 In the ab-ence of this secondary antigen-independent signal, medi-ted by accessory molecules on both the T cell and the anti-en-presenting cell, T-cell unresponsiveness (anergy)ccurs.1 IMiD compounds have been shown to substitute forhe secondary signal when it is not present, and to potentiatehe signal when it is present.20,21

Consequences of T-cell co-stimulation include increasedecretion of the T-cell lymphokines interferon-�, and IL-2,hich stimulate clonal T-cell proliferation and natural killer

ell activity.1,16,19,21 Other effects, which would seem to be atdds with the inhibitory action of IMiDs on inflammatoryytokines, are the increased secretion of cytokines such asNF-� and IL-12 from T-cell–activated antigen-presentingells (eg, monocytes/macrophages and dendritic cells).16

iven this mechanistic profile, it is reasonable to expect thathe effects of IMiD treatment may vary in individual patientsepending on the nature of the immunologic contribution toheir disease pathology.

The IMiD analogues are also far more potent than thalid-mide at co-stimulating T cells.16 There is conflicting infor-ation in the literature regarding preferential activation of

pecific T-cell subsets by IMiD compounds,7,20 although fur-her studies with IMiD compounds have shown greater stim-lation of CD8� cytotoxic T cells relative to CD4� helper Tells (Fig 3).21

mpounds. Purified T cells were cultured and stimulateddicated concentration of IMiD compound. Proliferationanalyzed with a cell sorter to determine incorporationco-stimulatory effect of the IMiDs was mainly in theCD4� subset. In the presence of an IMiD, the CD8�-cell subsets. (B) CD4/CD8 ratios in unsorted T cells.

iD cof the inls wereat theon theon of T

The ability of IMiD compounds to enhance activator pro-

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IMiDs: A novel class of immunomodulators S27

ein 122 and transcription factor NF-�-B19 activity in antigen-ctivated T cells has been proposed as a mechanism for the-cell co-stimulatory activity of IMiDs. Whatever the preciseechanism, augmentation of the T-cell arm of the immune

esponse (in conjunction with natural killer cell activation)y IMiDs may provide a novel mechanism for direct antitu-or activity, and for clonal suppression of preleukemic

lones in MDS.

ngiogenesis Inhibitionhe antiangiogenic activities of IMiD compounds have beenhown in a number of in vitro assays6,13,23 and in mouseodels of human tumors.13,23 The primary IMiD analogues

re more potent antiangiogenic agents than thalidomide, al-hough the exact mechanism in each circumstance is stillnder investigation. Figure 4 illustrates the approximately00-fold increased antiangiogenic potency of the IMiD ana-

ogue IMiD 1 relative to thalidomide in a human umbilicalrtery explant assay. 1,13,14 Although inhibition of endothelialell proliferation by IMiDs has not been shown, direct inhi-ition of angiogenic growth factor-mediated neovasculariza-ion in these in vitro systems may be mediated by suppres-ion of trophic signaling.6,13 Specifically, the antiangiogenicctivity exhibited by IMiD compounds may be secondary toheir inhibition of secretion of two angiogenic cytokines, vas-ular endothelial growth factor (VEGF) and basic fibroblastrowth factor, from tumor and stromal cells. Preclinical stud-es have shown the capacity of IMiD compounds to preventhe upregulation of VEGF and IL-6 secretion from co-cul-ures of bone marrow stromal cells and MM cells.24 Thisunction has been proposed to be a potential mechanism for

Figure 4 Inhibition of angiogenesis by IMiD compoundsthalidomide and the IMiD analogues inhibit angiogenesisvitro compared with thalidomide.1,13

he anti-MM activity of IMiD compounds in clinical studies.25 t

n addition, IMiD compounds inhibit cytokine-stimulatedndothelial cell migration and adhesion in some experimen-al systems, possibly due in part to downregulation of endo-helial cell integrins.13

The importance of angiogenesis and angiogenic factors inhe pathobiology of hematologic malignancies (including

DS) is increasingly recognized.3,26,27 Bone marrow mi-rovessel density, a measure of neovascularization, is oftenigher in MDS, acute myeloid leukemia, and MM patientshan in healthy patients and correlates with a poorer progno-is.24,26 As such, the antiangiogenic activity of IMiD com-ounds is likely to be a very important mechanism of action

n these patients.The ability of IMiD compounds to inhibit VEGF secretion

nd activity is likely to have diverse protective effects beyondeduction of neovascularization. VEGF is a potent angiogeniceptide with a range of biologic activities that extends be-ond stimulation of endothelial cell proliferation.27 For ex-mple, VEGF regulates embryonic and hematopoietic stemell development, extracellular matrix remodeling, and localeneration of inflammatory cytokines. Reciprocal regulationf VEGF and IL-6 secretion was shown in cultures of bonearrow stromal cells,24 indicating that inhibition of VEGF by

MiD would also inhibit IL-6 generation. Inhibition of VEGFecretion and activity in the setting of MDS would also bexpected to suppress leukemia progenitor self-renewal andromote erythroid progenitor growth and maturation.27

roerythropoiesishalidomide and the IMiD lenalidomide potentiate erythro-oiesis at several levels, which has important implications for

own here in the human umbilical artery explant assay,lidomide exhibits more potent antiangiogenic activity in

. As sh. Lena

reatment of MDS.4 In patients with MDS responding to tha-

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idomide, a progressive increase in both fetal hemoglobin andndogenous serum erythropoietin was observed, suggestingctivation of physiologic compensatory mechanisms.4 Mi-roarray analysis of the changes in gene expression resultingrom treatment with lenalidomide has shown selective in-reases in expression of erythropoiesis-related genes (ie,hose related to various hemoglobins and glycophorins afterdays, relative to control treatment). In clinical trials of tha-

idomide and lenalidomide, some patients with MDS whoere previously dependent on frequent red blood cell trans-

usions for management of their disease became transfusionndependent following treatment with thalidomide or lena-idomide.10

ntitumor and Apoptosis Activitiesenalidomide treatment has also shown direct antiprolifera-ive activity against MDS and MM cells, in the absence ofccessory immune cells.1,28 The observed effects (G0/G1 cellycle arrest or promotion of apoptosis) are likely to be medi-ted by modulation of the relevant cytokines and suppressionf specific signaling pathways, including apoptotic pathwayseg, Akt). IMiD compounds have been shown to directlyotentiate apoptosis of MM cells at several levels, includingnhanced caspase-8 activation, increased sensitivity to Fasnduction, inhibition of expression of the cellular inhibitor ofpoptosis protein-2, and potentiation of the activities of otherpoptosis inducers such as TNF-related apoptosis-inducingigand (TRAIL).29 Preclinical data show that an MDS cell lineith the 5q- deletion (MUTZ-1) is particularly sensitive to

he antiproliferative/cytotoxic effects of IMiDs (Table 1).28

ecent clinical results have confirmed these preclinical find-ngs.31

Finally, another IMiD anticancer mechanism in MM is thenhibition of adhesion of MM cells to bone marrow stromalells,17,25 which has been shown to be mediated by down-odulation of cell adhesion molecules such as intracellular

dhesion molecule-1.18 This interaction of tumor and “host”tromal cells in turn upregulates the production of VEGF andL-6, which is necessary for MM cell survival and prolifera-ion, as well as angiogenesis.17,25

In summary, IMiD compounds can affect gene expression,

able 1 Sensitivity of 5q Mutant Cells to IMiD Compounds

Cell line MUTZ-1

ype B-cell precursorrigin MDSq status Del 5

halidomide ��100enalidomide (CC-5013) 2.5C-4047 0.12C-11006 2.3

bbreviations: ALL, acute lymphocytic leukemia; AML, acute myelosyndromes.

ata from Gandhi et al.28

uppress or potentiate specific signal transduction pathways, t

alt proliferation and/or promote apoptosis, inhibit inflam-atory cytokine production, and augment T-cell–mediated

ytotoxic killing in a variety of experimental and clinical set-ings. In subsets of MM and patients with MDS, these seem-ngly disparate functions collectively promote the killing of

alignant cells and restore the normal bone marrow milieuith minimal toxicity in normal, healthy cells.

linicalevelopment of Lenalidomide

esults of Phase Iost data on metabolic and pharmacologic properties of

MiD compounds to date has been obtained with lenalido-ide. Metabolism studies of lenalidomide in vitro and in

nimals have shown no effect on cytochrome P-450 activity,nd no in vitro phase I and II metabolism by human livericrosomes/supersomes or by isolated human hepatocytes.

n both rats and monkeys, 50% is excreted unchanged, andhe other 50% is metabolized to hydrolysis metabolites, in-luding N-acetyl and glucose conjugates. Pharmacologictudies of lenalidomide in healthy volunteers show an overallavorable safety profile with no adverse renal effects, al-hough some adverse immunologic events (eg, rash/pruritusnd decreased lymphocytes) were noted. Other findingsrom studies in volunteers include the following:

● Multiple dosing did not alter the pharmacokinetic pro-file.

● Steady-state plasma levels were reached within 4 days.● Sixty-seven percent was excreted unchanged in urine

(less than 24 hours).● Renal clearance was greater than glomerular filtration

rate.● Peak concentration was reached at 0.9 hours post dose.● Mean t1/2 was 8 hours.

Clinical trials of lenalidomide in patients with relapsed andefractory MM have shown that treatment can overcome drugesistance, including thalidomide resistance. In addition,hen compared with thalidomide, lenalidomide was well

Proliferation IC50 M

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IMiDs: A novel class of immunomodulators S29

0, 25, and 50 mg/d) trial of lenalidomide in 27 patients withelapsed and refractory MM, no dose-limiting toxicity wasbserved at any dose level within the first 28 days; after 28ays, myelosuppression at the highest dose level resulted in aose reduction to 25 mg/d, thereby establishing 25 mg as theaximum tolerated dose. None of the sedation, constipation,

r neuropathy observed with thalidomide was seen in theseatients, although other adverse events included grades 1nd 2 rash, fatigue, lightheadedness, and leg cramps. Lena-idomide had activity in patients who were no longer re-ponding to thalidomide, and stable disease or better wasbserved in 19 of 24 patients (79%) after treatment.25 Medianime to best response was 2 months (range, 1 to 11 months)nd median duration of response was 6 months (range, 2 to4 months).A multicenter, randomized phase II study was conducted

o evaluate efficacy and safety of two lenalidomide dose reg-mens used alone or in combination with dexamethasone forhe treatment of relapsed/refractory MM.30 The preliminaryesults showed that 71 of 83 evaluable patients (85%) withrogressive disease experienced a reduction in, or stabiliza-ion of, their M-protein levels. Thrombocytopenia and neu-ropenia were seen in 18% and 28% of patients, respectively.ignificant somnolence, constipation, or neuropathy was noteen at either of the two doses tested. Two identical phase IIIrials, one in the United States and one outside the Unitedtates, are comparing treatment with lenalidomide plusexamethasone with treatment with placebo plus dexameth-sone.1,14 These trials are powered to detect improvement inurvival, and the primary end point is the time to diseaserogression (ie, skeletal related event).Results from phase I and II clinical trials of both thalido-ide and lenalidomide in patients with MDS have shown

rythroid responses, hematologic improvements, and trans-usion independence, primarily in lower-risk patients withewer pretherapy blasts.4,10,11,31 In clinical trials of lenalido-ide in MDS, the major drug-related adverse events were

ranulocytopenia and thrombocytopenia, both of whichere associated with dose or duration of treatment and were

eversible and manageable.31

ummaryhe precise mechanisms of action of thalidomide and sec-nd-generation IMiD analogues in various clinical settingsre still incompletely understood, and their effects are likelyo vary with disease stage and the immunologic status ofndividual patients. Data from nonclinical studies are shed-ing light on the diverse and multifaceted activities of theseompounds that are relevant to specific inflammatory andeoplastic disorders. However, validation of these activities

n the context of clinical disease is ongoing and will likelymerge from exploratory end points included in clinical trialsf these agents.Progress to date indicates that lenalidomide, the primary

MiD compound in clinical development, is an orally bio-vailable agent that is more potent than thalidomide and does

ot result in the adverse events associated with thalidomide 1

reatment (ie, sedation, major constipation, peripheral neu-opathy, teratogenicity in animals). Beneficial activity haseen achieved in clinical trials of lenalidomide in both MMnd MDS. Treatment with lenalidomide has already shownignificant activity in patients with relapsed and refractoryM and in patients with MDS who have red blood cell trans-

usion-dependent anemia. The US Food and Drug Adminis-ration has granted fast-track status to lenalidomide for thereatment of both of these diseases, and it is anticipated thatenalidomide, alone or in combination with other agents, willhow promise for the treatment of certain solid tumors asell.Future-generation analogues may enable each IMiD ana-

ogue to more potently target specific mechanisms of actiono optimize their activity yet further. Although there is stilluch to be learned about the molecular mechanisms of spe-

ific IMiD compounds in different disease situations, themerging results from clinical investigations warrant the con-inued clinical development of these compounds and under-core their promise for treatment of diseases for which betterherapeutic options are urgently needed.

eferences1. Bartlett JB, Dredge K, Dalgleish AG: The evolution of thalidomide and

its IMiD derivatives as anticancer agents. Nat Rev Cancer 4:314-322,2004

2. Sampaio EP, Sarno EN, Galilly R, et al: Thalidomide selectively inhibitstumor necrosis factor � production by stimulated human monocytes. JExp Med 173:699-703, 1991

3. List AF: New approaches to the treatment of myelodysplasia. Oncolo-gist 7:39-49, 2002 (suppl 1)

4. Musto P: Thalidomide therapy for myelodysplastic syndromes: Currentstatus and future perspectives. Leuk Res 28:325-332, 2004

5. Sampaio EP, Kaplan G, Miranda A, et al: The influence of thalidomideon the clinical and immunologic manifestation of erythema nodosumleprosum. J Infect Dis 168:408-414, 1993

6. D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is an inhibitorof angiogenesis. Proc Natl Acad Sci U S A 91:4082-4085, 1994

7. Haslett PA, Corral LG, Albert M, et al: Thalidomide costimulates pri-mary human T lymphocytes, preferentially inducing proliferation, cy-tokine production, and cytotoxic responses in the CD8� subset. J ExpMed 187:1885-1892, 1998

8. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomidein refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999

9. Rosenfeld C, List A: A hypothesis for the pathogenesis of myelodysplas-tic syndromes: Implications for new therapies. Leukemia 14:2-8, 2000

0. Raza A, Meyer P, Dutt D, et al: Thalidomide produces transfusionindependence in long-standing refractory anemias of patients with my-elodysplastic syndromes. Blood 98:958-965, 2001

1. Strupp C, Germing U, Aivado M, et al: Thalidomide for the treatment ofpatients with myelodysplastic syndromes. Leukemia 16:1-6, 2002

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8. Nogueira AC, Neubert R, Helge H, et al: Thalidomide and the immunesystem. 3. Simultaneous up- and down-regulation of different integrinreceptors on human white blood cells. Life Sci 55:77-92, 1994

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0. Marriott JB, Clarke IA, Dredge K, et al: Thalidomide and its analogueshave distinct and opposing effects on TNF-� and TNFR2 during co-stimulation of both CD4� and CD8� T cells. Clin Exp Immunol 130:75-84, 2002

1. Stirling D: Thalidomide: A novel template for anticancer drugs. SeminOncol 28:602-606, 2001

2. Schafer PH, Gandhi AK, Loveland MA, et al: Enhancement of cytokineproduction and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. J Pharmacol Exp Ther 305:1222-1232, 2003

3. Lentzsch S, Rogers MS, LeBlanc R, et al: S-3-amino-phthalimido-glu-tarimide inhibits angiogenesis and growth of B-cell neoplasias in mice.

Cancer Res 62:2300-2305, 2002

4. Gupta D, Treon SP, Shima Y, et al: Adherence of multiple myeloma cells tobone marrow stromal cells upregulates vascular endothelial growth factorsecretion: therapeutic applications. Leukemia 15:1950-1961, 2001

5. Richardson PG, Schlossman RL, Weller E, et al: Immunomodulatorydrug CC-5013 overcomes drug resistance and is well tolerated in pa-tients with relapsed multiple myeloma. Blood 100:3063-3067, 2002

6. Pruneri G, Bertolini F, Soligo D, et al: Angiogenesis in myelodysplasticsyndromes. Br J Cancer 81:1398-1401, 1999

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