Thalidomide and its derivatives: emerging from the wilderness

Gordon, JN; Goggin, Patrick

doi:10.1136/pmj.79.929.127

Cited by 72 publications

(31 citation statements)

References 71 publications

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“…In the present study, we investigated whether thalidomide or lenalidomide were capable of reducing the viability of MCL cells in vitro and whether this effect could be augmented by combining either drug with rituximab. We were unable to demonstrate a direct effect of thalidomide or lenalidomide on MCL cell viability despite using concentrations (50 µg/ml) far exceeding physiological ones (thalidomide 1–4 µg/ml [18]), suggesting that these agents alone are not capable of inducing significant levels of MCL cell death. However, we did find that both drugs indirectly affect viability by enhancing PBMC-mediated toxicity and that lenalidomide induced significantly higher levels of toxicity than thalidomide.…”

Section: Discussionmentioning

confidence: 99%

Activity of Thalidomide and Lenalidomide in Mantle Cell Lymphoma

Richardson

Eve²,

Copplestone³

et al. 2009

Acta Haematol

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Thalidomide and lenalidomide are immunomodulatory drugs that show promise in mantle cell lymphoma (MCL). In this study, their potential mechanisms of action against MCL cells were investigated, both alone and in combination with rituximab. Thalidomide, lenalidomide and rituximab have no direct effect on MCL cell viability. However, both immunomodulatory drugs indirectly affect viability by enhancing peripheral blood mononuclear cell-mediated cytotoxicity, with lenalidomide inducing significantly higher levels of toxicity than thalidomide. Rituximab induces both complement-dependent and antibody-dependent cellular cytotoxicity (ADCC) against MCL cells. Rituximab-induced ADCC is enhanced by lenalidomide and, to a lesser extent, thalidomide. Preliminary in vivo findings in MCL patients treated with thalidomide support a role for natural killer cells in the efficacy of these drugs. In conclusion, our data support a role for immunomodulatory drugs in the treatment of MCL.

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Section: Discussionmentioning

confidence: 99%

Activity of Thalidomide and Lenalidomide in Mantle Cell Lymphoma

Richardson

Eve²,

Copplestone³

et al. 2009

Acta Haematol

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“…Thalidomide (a-N-phthalimidoglutaramide) has complex immune-modulatory and anti-inflammatory properties. It has been shown to down-regulate the production of TNF-α and other pro-inflammatory cytokines in monocytes, to inhibit the transcription factor nuclear factor kappa B (NFkB), down-regulate cyclooxygenase 2, and to inhibit angiogenesis [124,125] . One randomized placebo-controlled trial in patients with cancer cachexia showed that the drug was well-tolerated and effective at attenuating loss of weight and lean body mass in patients with advanced pancreatic cancer [126] .…”

Section: Thalidomide and Etanerceptmentioning

confidence: 99%

Cancer cachexia, mechanism and treatment

Aoyagi¹,

Terracina²,

Ali³

et al. 2015

WJGO

370

282

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It is estimated that half of all patients with cancer eventually develop a syndrome of cachexia, with anorexia and a progressive loss of adipose tissue and skeletal muscle mass. Cancer cachexia is characterized by systemic inflammation, negative protein and energy balance, and an involuntary loss of lean body mass. It is an insidious syndrome that not only has a dramatic impact on patient quality of life, but also is associated with poor responses to chemotherapy and decreased survival. Cachexia is still largely an underestimated and untreated condition, despite the fact that multiple mechanisms are reported to be involved in its development, with a number of cytokines postulated to play a role in the etiology of the persistent catabolic state. Existing therapies for cachexia, including orexigenic appetite stimulants, focus on palliation of symptoms and reduction of the distress of patients and families rather than prolongation of life. Recent therapies for the cachectic syndrome involve a multidisciplinary approach. Combination therapy with diet modification and/or exercise has been added to novel pharmaceutical agents, such as Megestrol acetate, medroxyprogesterone, ghrelin, omega-3-fatty acid among others. These agents are reported to have improved survival rates as well as quality of life. In this review, we will discuss the emerging understanding of the mechanisms of cancer cachexia, the current treatment options including multidisciplinary combination therapies, as well an update on new and ongoing clinical trials.

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“…Both cytokines are regulated by thalidomide and CAM. The inhibition of TNF-α is one of the most significant properties of thalidomide by human-activated monocytes [25], and IL-6 is also inhibited by thalidomide treatment [26]. The addition of CAM reduces the levels of TNF-α and IL-6 in several cell types, such as synovial fibroblast-like cells and alveolar macrophages [27,28].…”

Section: Discussionmentioning

confidence: 99%

Clarithromycin Synergistically Enhances Thalidomide Cytotoxicity in Myeloma Cells

Qiu¹,

Shao²,

Mei³

et al. 2015

Acta Haematol

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Clarithromycin (CAM) is a macrolide antibiotic that is widely used in the treatment of respiratory tract infections, sexually transmitted diseases and infections caused by the Helicobacter pylori and Mycobacterium avium complex. Recent studies showed that CAM was highly effective against multiple myeloma (MM) when used in combination with immunomodulatory drugs and dexamethasone. However, the related mechanism is still unknown. As 3 immunomodulatory agents are all effective in the respective regimen, we postulated that CAM might enhance the effect of immunomodulatory drugs. We evaluated the interaction effects of CAM and thalidomide on myeloma cells. Taking into consideration that thalidomide did not affect the proliferation of myeloma cells in vitro, we cocultured myeloma cells with peripheral blood monocytes and evaluated the effects of CAM and thalidomide on the cocultured cell model. Data showed that thalidomide and CAM synergistically inhibited the proliferation of the cells. On this same model, we also found that thalidomide and CAM synergistically decreased the secretion of tumor necrosis factor-α and interleukin-6. This might be caused by the effect of the 2 drugs on inhibiting the activation of ERK1/2 and AKT. These data suggest that the efficacy of CAM against MM was partly due to its synergistic action with the immunomodulatory agents.

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Thalidomide and its derivatives: emerging from the wilderness

Cited by 72 publications

References 71 publications

Activity of Thalidomide and Lenalidomide in Mantle Cell Lymphoma

Activity of Thalidomide and Lenalidomide in Mantle Cell Lymphoma

Cancer cachexia, mechanism and treatment

Clarithromycin Synergistically Enhances Thalidomide Cytotoxicity in Myeloma Cells

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