Thalidomide induces imbalances in T-lymphocyte sub-populations in the circulating blood of healthy males

Sm, Gad; Ej, Shannon; Wa, Krotoski; Rc, Hastings

doi:10.5935/0305-7518.19850006

Cited by 48 publications

(34 citation statements)

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“…33,34 Although the underlying mechanism remains unclear, the effects may be related to its immunomodulatory effects on T cell function. 9,10 This same patient also tolerated concomitant IFN maintenance without exacerbation of his GVHD, which was a potential concern as IFN may exacerbate GVHD. 35,36 Thus, we would now not consider chronic GVHD a contraindication to thalidomide and IFN in selected patients.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy of thalidomide therapy for extramedullary relapse of myeloma following allogeneic transplantation

Biagi

Mileshkin

Grigg

et al. 2001

Bone Marrow Transplant

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Summary:Treatment options for patients with myeloma who relapse after allogeneic stem cell transplantation are limited. Thalidomide, an antineoplastic agent, has been shown to be effective in multiple myeloma through proposed mechanisms that may include angiogenesis inhibition. Herein we report successful thalidomide treatment of four patients who relapsed following allogeneic transplantation, three of whom had predominantly extramedullary relapse. Thalidomide was well tolerated in all patients; in two patients interferon-␣ was subsequently added to thalidomide as maintenance therapy without worsening graft-versus-host disease. We suggest that extramedullary myeloma is particularly sensitive to thalidomide, speculating that growth biology may in part be dependent on angiogenesis. Bone Marrow Transplantation (2001) 28, 1145-1150. Keywords: myeloma; thalidomide; transplantation; extramedullary; allogeneic; graft-versus-host disease Management options for multiple myeloma (MM) include autologous stem cell transplantation (autoSCT) and allogeneic bone marrow/stem cell transplantation (alloBMT). [1][2][3] Following alloBMT, a graft-versus-myeloma (GVM) effect is well recognized and may contribute to sustained molecular remission. 4-6 However, treatment options for relapse following alloBMT are often limited by concomitant graft-versus-host disease (GVHD), hematologic cytopenias or poor performance status.Thalidomide has antineoplastic properties, through proposed mechanisms that include angiogenesis inhibition, immunomodulation, apoptotic mechanisms, and modulation of T cell function. [7][8][9][10] In myeloma, angiogenesis as measured by microvessel density (MVD) has correlated with disease activity and outcome. [11][12][13] There is also recent evidence that thalidomide is active in vitro against MM cell lines resistant to standard chemotherapy. 14 Recently pub- lished studies have demonstrated activity of thalidomide in relapsed or refractory MM, 15-17 including patients who had had autoSCT. 18 To date there are no published data specifically examining the role of thalidomide for relapse after alloBMT.Trials investigating the role of interferon-␣ (IFN) in induction and maintenance phases of disease have yielded conflicting results. A recent meta-analysis demonstrated a survival advantage in this setting, suggesting that maintenance therapy may be of benefit. 19 We have concluded a clinical trial evaluating the efficacy of thalidomide, with IFN as maintenance treatment, in the management of relapsed or refractory MM. Four of the 75 patients accrued relapsed after HLA-identical sibling alloBMT. Herein we report successful thalidomide treatment in these four patients, three of whom had predominantly extramedullary (EM) relapse. Furthermore, we describe two of these patients who have proceeded to IFN maintenance therapy while on thalidomide. Issues related to EM relapse and the effects of the combination of thalidomide and IFN on disease control and GVHD are discussed. Study design of thalidomide trialPatients were pro...

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Section: Discussionmentioning

confidence: 99%

“…[7][8][9][10] In myeloma, angiogenesis as measured by microvessel density (MVD) has correlated with disease activity and outcome. [11][12][13] There is also recent evidence that thalidomide is active in vitro against MM cell lines resistant to standard chemotherapy.…”

mentioning

confidence: 99%

Efficacy of thalidomide therapy for extramedullary relapse of myeloma following allogeneic transplantation

Biagi

Mileshkin

Grigg

et al. 2001

Bone Marrow Transplant

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“…The drug also increases the primary CD8+ cytotoxic T cell response induced by allogeneic dendritic cells in the absence of CD4+ T cells. In healthy male volunteers given 200 mg/day for 4 days, it significantly decreased the circulating T-helper to T-suppressor cell ratio [25]. It also induces T helper cell type 2 (Th2) cytokine production in human peripheral blood mononuclear cell cultures, while concomitantly inhibiting T helper cell type 1 (Th1) cytokine production.…”

Section: Effect On T Lymphocytesmentioning

confidence: 99%

Thalidomide as an anti‐cancer agent

Kumar

Witzig

Rajkumar

2002

J Cellular Molecular Medi

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Thalidomide is a glutamic acid derivative initially introduced as a sedative hypnotic nearly forty years ago. It was withdrawn following numerous reports linking it to a characteristic pattern of congenital abnormalities in babies born to mothers who used the drug for morning sickness. It has gradually been re-introduced into clinical practice over the past two decades, albeit under strict regulation, since it was found to be useful in the management of erythema nodosum leprosum and HIV wasting syndrome. Recognition of its anti-angiogenic effect led to its evaluation in the treatment of various malignancies, where angiogenesis has been shown to play an important role. Numerous clinical trials done over the past four years have confirmed the significant anti-myeloma activity of this drug. It has also shown promise in preliminary trials in the treatment of a variety of different malignant diseases. The mechanisms of its antineoplastic effects continue to be the focus of ongoing research. It has become clear that even though its anti angiogenic effects play a significant role in the anti-tumor activity, there are other properties of this drug which are responsible as well. It also possesses anti-TNF alpha activity, which has led to its evaluation in several inflammatory states. In this concise review, we briefly describe the historical background and pharmacological aspects of this drug. We have concisely reviewed the current knowledge regarding mechanisms of its anti-neoplastic activity and the results of various clinical trials in oncology. Keywords:

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“…La talidomide è capace di ridurre la quota circolante dei linfociti T CD4+ e quindi il rapporto CD4/CD8 (7)(8)(9). Favorisce l'aumento del numero delle cellule Natural Killer (NK) (10) e dei linfociti T helper 2 rispetto ai linfociti T helper 1.…”

Section: Meccanismo D'azioneunclassified

Thalidomide in treatment of connective diseases and vasculities

Maruotti¹,

Cantatore²,

Ribatti³

2011

Reumatismo

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MECCANISMO D'AZIONEI meccanismi attraverso cui si esplicano le attività immunomodulatoria, antinfiammatoria e antiangiogenica della talidomide appaiono interconnessi, anche se non ancora completamente chiariti. La talidomide è capace di ridurre la quota circolante dei linfociti T CD4+ e quindi il rapporto CD4/CD8 (7-9). Favorisce l'aumento del numero delle cellule Natural Killer (NK) (10) e dei linfociti T helper 2 rispetto ai linfociti T helper 1. Inoltre, la talidomide inibisce la proliferazione di linfociti T attivati e la chemiotassi leucocitaria (9, 11, 12) ed è responsabile di modificazioni nella espressione delle integrine e del CD44 e dell'Intercellular Cell Adhesion Molecule-1 (ICAM-1). La talidomide può inoltre bloccare il ciclo cellulare in G1 nelle cellule tumorali per l'induzione di p21, favorendo l'apoptosi (11, 13). Molti studi dimostrano che la talidomide inibisce la produzione del tumor necrosis factor α (TNFα) attraverso un'aumentata degradazione del mRNA del TNFα e il legame dell'α-1glicoproteina acida (9,14). La talidomide inoltre blocca l'attività del fattore di trascrizione L a talidomide, introdotta sul mercato nel 1956 come farmaco sedativo-ipnotico usato anche come antiemetico e per il trattamento della nausea in gravidanza, fu successivamente ritirata dal commercio nel 1962 a causa dei seri effetti teratogeni come sordità, difetti facciali e del palato, focomelia in bambini nati da donne che avevano assunto anche una sola dose di talidomide durante la gestazione (1, 2). Tuttavia, a partire dal 1965 è stata riutilizzata, talvolta con discreto successo, in molte patologie, tra cui l'eritema nodoso associato alla lebbra, il morbo di Crohn, l'insufficienza cardiaca congestizia avanzata, sarcoidosi cutanee, ulcere orali e cachessia associate ad infezione da HIV e svariati tipi di tumori solidi ed ematologici. In questa sede verrà descritto in modo più approfondito l'utilizzo della talidomide nel trattamento del lupus eritematoso sistemico e della sindrome di Behçet (3-6). Reumatismo, 2006; 58(3):187-190 TNFα, SUMMARY Thalidomide is an immunomodulatory, anti-inflammatory and anti-angiogenic drug. Thalidomide exerts its effects by decreasing circulating CD4 positive T-cells and stimulating CD8 positive T-cells, by increasing the number of Natural Killer cells and T-helper 2 cells. Thalidomide also inhibits proliferation of stimulated T-cells and leukocyte chemotaxis. It modifies a number of integrin receptors and other leukocytic surface receptors and down-modulates cell-adhesion molecules involved in leukocyte migration. It has been demonstrated that thalidomide inhibits

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Thalidomide induces imbalances in T-lymphocyte sub-populations in the circulating blood of healthy males

Cited by 48 publications

References 1 publication

Efficacy of thalidomide therapy for extramedullary relapse of myeloma following allogeneic transplantation

Efficacy of thalidomide therapy for extramedullary relapse of myeloma following allogeneic transplantation

Thalidomide as an anti‐cancer agent

Thalidomide in treatment of connective diseases and vasculities

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