Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro

Dredge, Keith; Horsfall, Rebecca; Robinson, Simon P.; Zhang, Linghua; Lu, Ling; Tang, Yang; Shirley, Michael A.; Muller, George W.; Schäfer, Peter; Stirling, David I.; Dalgleish, Angus; Bartlett, J. Blake

doi:10.1016/j.mvr.2005.01.002

Cited by 259 publications

(170 citation statements)

References 21 publications

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“…There is a deficit of information in this area, and although there are limited reports detailing reduced migratory characteristics in endothelial cells, there are very little data reporting these effects in tumour cells (Dredge et al, 2005;Komorowski et al, 2006). In accordance with the findings of the soft agar study, migration and invasion capacity was significantly hampered by IMiD treatment.…”

Section: Discussionmentioning

confidence: 88%

“…This proprietary class of therapeutic analogues, as exemplified by lenalidomide (Revlimid, Celgene, Summit, NJ, USA, CC-5013) was developed on the basis of structural activity relationship studies focussing on molecular alterations to the central ring framework of the thalidomide molecule as an approach to enhancing the immunomodulatory characteristics of the agents (Stirling, 2001;Bartlett et al, 2004). Allied to this enhancement, IMiDs, such as thalidomide, display potent anti-proliferative, apoptotic and antiangiogenic properties both in vivo and in a wide spectrum of tumour cell lines (Dredge et al, 2002(Dredge et al, , 2005Shalapour et al, 2006;Verhelle et al, 2007). At present, lenalidomide is approved by the US Food and Drug Administration for use in patients with myelodysplastic syndromes (associated with no or 5q-deletions), and in combination with dexamethasone in patients with multiple myeloma who have received one previous therapy (Dimopoulos et al, 2007;Weber et al, 2007).…”

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confidence: 99%

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Inhibition of metastatic potential in colorectal carcinoma in vivo and in vitro using immunomodulatory drugs (IMiDs)

et al. 2009

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BACKGROUND: Thalidomide and lenalidomide are FDA approved for the treatment of multiple myeloma and, along with pomalidomide, are being investigated in various other cancers. Although these agents display immunomodulatory, anti-angiogenic and anti-apoptotic effects, little is known about their primary mode of therapeutic action in patients with cancer. METHODS: As part of a continuing research effort, we have investigated the effects of these agents on the metastatic capacity of murine colorectal cancer cell lines both in vivo and in vitro. Allied to these, we have studied their effects on the molecular pathways associated with metastasis. RESULTS: Results indicate that thalidomide, lenalidomide and pomalidomide significantly inhibit the metastatic capability of colorectal carcinoma cells. Anchorage-independent growth, used as a coarse indicator of transformation, was significantly reduced, as were migratory capacity and invasive competence. In addition, an in vivo experimental metastasis model also showed that treatment with the drugs resulted in a significantly lower number of metastatic pulmonary nodules relative to control mice. Allied to these cellular and phenotypic changes were alterations in molecular markers of metastasis and in intracellular signalling competency. CONCLUSIONS: These results provide evidence that in addition to their immunomodulatory effects, thalidomide, lenalidomide and pomalidomide can impair the metastatic capacity of tumours, and that this mechanism may involve alterations to cell signalling functionality.

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Section: Discussionmentioning

confidence: 88%

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confidence: 99%

Inhibition of metastatic potential in colorectal carcinoma in vivo and in vitro using immunomodulatory drugs (IMiDs)

et al. 2009

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“…9,31 In the last decade, a significant influence of other cellular and mesenchymal marrow components not involved in the neoplastic clone, but influencing marrow insufficiency and prognosis of MDS was detected. This has resulted in various anti-inflammatory, immunomodulatory or anti-angiogenic approaches, [32][33][34][35] which, indeed, appear to improve the quality of life and prognosis of patients by inducing a hematologic and even a cytogenetic remission in a significant proportion of patients, [32][33][34][35] indicating that the leading symptoms of MDS, the marrow insufficiency and its life-threatening complications, depend considerably on extra-hematopoietic factors. MF is worth considering in this context since it is a fundamental alteration of marrow architecture, which may lead by itself to cytopenias and thus, may aggravate the symptoms of marrow insufficiency.…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of these observations, it is recommended to consider MF as a significant unfavorable prognostic factor in diagnosing and prognosticating disease, and to reassess its prognostic significance in newer anti-inflammatory, immunomodulatory or antiangiogenic therapy concepts. [32][33][34][35] …”

Section: Mds With Mfmentioning

confidence: 99%

Marrow fibrosis predicts early fatal marrow failure in patients with myelodysplastic syndromes

et al. 2007

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“…Among the pro-angiogenic genes VEGFA and IL8 were induced by hypoxia (Ref. 102 ) than endothelial cell proliferation through the interference of PIk3/AKT signaling [128,129]. Finally, in pre-clinical in vivo mouse MM models both thalidomide and lenalidomide induced a significant reduction of tumor-associated MVD [130,131].…”

Section: Anti Angiogenic Effect Of the Novel Anti-mm Agents And Futurmentioning

confidence: 99%

Angiogenesis and Multiple Myeloma

Giuliani

Storti

Bolzoni

et al. 2011

Cancer Microenvironment

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The bone marrow microenvironment in multiple myeloma is characterized by an increased microvessel density. The production of pro-angiogenic molecules is increased and the production of angiogenic inhibitors is suppressed, leading to an "angiogenic switch". Here we present an overview of the role of angiogenesis in multiple myeloma, the pro-angiogenic factors produced by myeloma cells and the microenvironment, and the mechanisms involved in the myeloma-induced angiogenic switch. Current data suggest that the increased bone marrow angiogenesis in multiple myeloma is due to the aberrant expression of angiogenic factors by myeloma cells, the subsequent increase in pro-angiogenic activity of normal plasma cells as a result of myeloma cell angiogenic activity, and the increased number of plasma cells overall. Hypoxia also contributes to the angiogenic properties of the myeloma marrow microenvironment. The transcription factor hypoxia-inducible factor-1α is overexpressed by myeloma cells and affects their transcriptional and angiogenic profiles. In addition, potential roles of the tumor suppressor gene inhibitor of growth family member 4 and homeobox B7 have also been recently highlighted as repressors of angiogenesis and pro-angiogenic related genes, respectively. This complex pathogenetic model of myeloma-induced angiogenesis suggests that several proangiogenic molecules and related genes in myeloma cells and the microenvironment are potential therapeutic targets.

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Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro

Cited by 259 publications

References 21 publications

Inhibition of metastatic potential in colorectal carcinoma in vivo and in vitro using immunomodulatory drugs (IMiDs)

Inhibition of metastatic potential in colorectal carcinoma in vivo and in vitro using immunomodulatory drugs (IMiDs)

Marrow fibrosis predicts early fatal marrow failure in patients with myelodysplastic syndromes

Angiogenesis and Multiple Myeloma

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