Differential regulation by thalidomide and dexamethasone of cytokine expression in human peripheral blood mononuclear cells

Rowland, Tom L; McHugh, SM; Deighton, John; Dearman, Rebecca J.; Ewan, P. W.; Kimber, Ian

doi:10.1016/s0162-3109(98)00010-1

Cited by 116 publications

(63 citation statements)

References 27 publications

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“…In addition, thalidomide may have mitigated some IFN related side effects probably by suppressing IFN mediated cytokine expression as previously shown in murine granulomatous tissue 24 or isolated human macrophages, 25 enabling patients to stay longer on maintenance treatment. Survival after discontinuation of maintenance therapy was remarkably long and did not differ significantly between the maintenance groups ( Figure 3B).…”

Section: Discussionmentioning

confidence: 91%

Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma

Ludwig¹,

Adam²,

Tóthová³

et al. 2010

Haematologica

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BackgroundThalidomide maintenance therapy after stem cell transplantation resulted in increased progression-free survival and overall survival in a few trials, but its role in non-transplant eligible patients with multiple myeloma remains unclear. This study assessed the impact of thalidomide-interferon in comparison to interferon maintenance therapy in elderly patients with multiple myeloma. Design and MethodsOf 289 elderly patients with multiple myeloma who were randomized to thalidomide-dexamethasone or melphalan-prednisolone induction therapy, 137 finally completed 9 cycles of induction therapy with stable disease or better and thereby qualified for maintenance treatment. Of these, 128 have been randomized to either thalidomide-interferon or interferon alone. Primary study endpoints were progression-free survival and response rates; secondary endpoints were overall survival, toxicity and quality of life. ResultsThalidomide-interferon maintenance therapy led to a significantly longer progression-free survival compared to interferon (27.7 vs. 13.2 months, P=0.0068), but overall survival was similar in both groups (52.6 vs. 51.4 months, P=0.81) and did not differ between patients aged 75 years or older, or younger patients (P=0.39). Survival after disease progression tended to be shorter in patients on thalidomide-interferon maintenance therapy (P=0.056). Progression-free survival and overall survival tended to be shorter in patients with adverse cytogenetic (FISH) findings compared to the standard risk group but differences were not significant (P=0.084 and P=0.082, respectively). Patients on thalidomide-interferon presented with more neuropathy (P=0.0015), constipation (P=0.0004), skin toxicity (P=0.0041) and elevated creatinine (P=0.026). ConclusionsThalidomide plus interferon maintenance therapy increased progression-free survival but not overall survival and was associated with slightly more toxicity than maintenance with interferon alone. (ClinicalTrials.gov Identifier: NCT00205751).Key words: thalidomide, thalidomide-interferon, progression-free survival, overall survival. Haematologica 2010;95(9):1548-1554. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Ludwig H, Adam Z, Tóthová E, Hajek R, Labar B, Egyed M, Spicka I, Gisslinger H, Drach J, Kuhn I, Hinke A, and Zojer N.Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma.Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma

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Section: Discussionmentioning

confidence: 91%

Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma

Ludwig¹,

Adam²,

Tóthová³

et al. 2010

Haematologica

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“…In vitro experiments demonstrated that thalidomide is a potent inhibitor of TNF-a synthesis in monocytes [36] and macrophages [20]. Thalidomide also inhibits the production of IL-6 and TNF-a in peripheral blood mononuclear cell culture [35], and decreases TNF-a synthesis in CD4+ and CD8+ T cells [22]. Thalidomide abolishes the endogenous overproduction of TNF-a in patients suffering from various different diseases [1, 25-27, 32, 47].…”

Section: Discussionmentioning

confidence: 99%

Thalidomide affects the skeletal system of ovariectomized rats

Kaczmarczyk-Sedlak

Folwarczna

Trzeciak

2009

Pharmacological Reports

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Abstract:Apart from having written an inglorious chapter in the history of medicine, thalidomide is currently being intensely studied because of its multidimensional activity. The aim of this study was to examine the effects of thalidomide on the skeletal system in ovariectomized and non-ovariectomized rats. The experiments were carried out with female Wistar rats, divided into eight groups: sham-operated control rats; sham-operated rats receiving thalidomide at doses of 15, 30 or 60 mg/kg, po; ovariectomized control rats; ovariectomized rats receiving thalidomide at doses of 15, 30 or 60 mg/kg, po. The drug was administered for 4 weeks. Body mass gain and the mass of the uterus, liver, spleen and thymus were studied. Macrometric parameters and content of mineral substances, calcium and phosphorus in the femur, tibia and L-4 vertebra and histomorphometric parameters of the femur and tibia were examined. In the femur, the mechanical properties of the whole bone and of the femoral neck were examined. Thalidomide did not affect the skeletal system of the non-ovariectomized rats. Bilateral ovariectomy induced osteoporotic skeletal changes in mature female rats. The effects of thalidomide on the skeletal system of ovariectomized rats depended on the dose used. With a dose of 15 mg/kg, po, thalidomide counteracted some osteoporotic changes induced by estrogen deficiency. With a dose of 60 mg/kg, po, thalidomide intensified the destructive effects of estrogen deficiency on the rat skeletal system.

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“…However, in vitro experiments demonstrated that even in the absence of metabolism, thalidomide also inhibited angiogenesis and affects cytokine expression in various cell types, [15][16][17] although high concentrations are required. It was, therefore, suggested that some metabolite catalyzed by CYP2C19 may have a greater antimyeloma activity than thalidomide itself or could enhance other intermediate Responses after thalidomide-based therapy Number of patients (n) © F e r r a t a S t o r t i F o u n d a t i o n products to exert their pharmacologic effect.…”

confidence: 99%

Polymorphisms of CYP2C19 gene are associated with the efficacy of thalidomide-based regimens in multiple myeloma

Hou²,

Jiang

et al. 2007

Haematologica

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In this study, CYP2C19 genotypes were tested by the polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) method in 92 patients with multiple myeloma (MM). Sixty-two patients were treated with thalidomide plus dexamethasone (Thal+Dex) and 30 with thalidomide combined with chemotherapy (Thal+CC). The overall response rate of extensive metabolizers (EMs) was statistically higher than that of poor metabolizers (PMs) (62.6% vs. 33.3%, p<0.05). Similar results were also observed in the Thal+Dex cohort. For the first time, our primary data suggested that the polymorphisms of CYP2C19 gene are associated with the efficacy of thalidomide based regimens in MM.

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Differential regulation by thalidomide and dexamethasone of cytokine expression in human peripheral blood mononuclear cells

Cited by 116 publications

References 27 publications

Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma

Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma

Thalidomide affects the skeletal system of ovariectomized rats

Polymorphisms of CYP2C19 gene are associated with the efficacy of thalidomide-based regimens in multiple myeloma

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