Immunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and angiogenesis in vivo

Lentzsch, Suzanne; LeBlanc, Richard; Podar, Klaus; Davies, Faith E.; Lin, Boris K.; Hideshima, Teru; Catley, Laurence; Stirling, David I.; Anderson, Kenneth C.

doi:10.1038/sj.leu.2402745

Cited by 154 publications

(78 citation statements)

References 18 publications

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“…Preclinical studies in murine myeloma models confirm such a hypothesis. 39,40 These results assume greater importance with the targeted development of thalidomide analogs, and ongoing studies with other antiangiogenic agents in myeloma such as 2-methoxyestradiol and Bevacizumab. The significance of persistent blood vessels in the marrow is not clear.…”

Section: Resultsmentioning

confidence: 99%

Effect of thalidomide therapy on bone marrow angiogenesis in multiple myeloma

et al. 2004

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Bone marrow (BM) angiogenesis is increased in multiple myeloma and is an important prognostic factor for survival. Previous studies have shown that BM angiogenesis does not change following chemotherapy or stem cell transplant. Given its potential antiangiogenic effect, we evaluated if thalidomide therapy would affect the BM microvessel density (MVD). We studied BM angiogenesis in 81 patients with various disease stages treated with thalidomide with or without dexamethasone. MVD was determined as previously described. MVD was compared between pretreatment marrows and those obtained 4-6 months following therapy. The median (range) MVD pretherapy was 28 (2-116) and post-therapy was 15 (3-97). A partial or complete response was seen in 58% of patients, stable disease in 41% and progressive disease in one patient. MVD decreased significantly in responders (median decrease of 12, Po0.001). In contrast, no significant change in MVD was seen in those failing to respond to thalidomide. Unlike the lack of resolution of angiogenesis reported with other therapies, we demonstrate for the first time a significant decrease in microvessels with thalidomide therapy. Although not conclusive, this result lends further support to the hypothesis that angiogenesis is a relevant therapeutic target in myeloma.

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Section: Resultsmentioning

confidence: 99%

Effect of thalidomide therapy on bone marrow angiogenesis in multiple myeloma

et al. 2004

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“…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]. Although this evidence suggests that thalidomide and IMiDs have an anti-angiogenic activity, a reduction of MVD as well as VEGF levels is not always seen with thalidomide response in MM patients [100,125,127,132], suggesting that both the in vivo anti angiogenic effect of these drugs and the contribution of their antiangiogenic activity to the overall anti-tumor effect is uncertain.…”

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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“…This is consistent with previous preclinical and clinical data, showing that thalidomide is less potent than IMiDs. [22][23][24][25][26][27] Pharmacokinetic studies from healthy volunteers and phase 1 trials of CC-4047 have shown that systemic levels between 1 M and 5 M are achievable (Dr David Stirling, Celgene, Warren, NJ; oral communication, October 5, 2005). In our study, significant inhibition of osteoclast formation was observed at concentrations of 1 M CC-4047.…”

Section: Discussionmentioning

confidence: 99%

“…on May 10, 2018. by guest www.bloodjournal.org From the in vitro and in vivo growth of MM cells. 22,23 In initial clinical phase 1 and 2 trials, single agent CC-4047 and CC-5013 in combination with dexamethasone achieved response rates of over 50% in relapsed and refractory MM. [24][25][26] We have shown that CC-4047 induces a shift in lineage commitment, resulting in increased myeloid cell development at the expense of erythroid cell commitment from human hematopoietic progenitors.…”

mentioning

confidence: 99%

Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1

Anderson

Gries

Kurihara

et al. 2006

Blood

144

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IntroductionThe major source of morbidity and possible mortality associated with multiple myeloma (MM) is osteolytic bone destruction throughout the axial skeleton. Lytic bone lesions occur in 70% to 80% of these patients, and are frequently associated with severe bone pain and pathologic fractures. 1 Besides MM, osteolytic lesions also occur in connection with bone metastases from solid tumors. Although the exact incidence of bone metastases is unknown, it is estimated that 350 000 people die with bone metastases each year in the United States. 1 Osteolytic lesions represent an extreme of a continuum of dysregulation of the normal bone remodeling process with excessive bone resorption mediated by osteoclasts (OCLs). OCLs are multinucleated cells that derive from monocyte/macrophage lineage cells. [2][3][4][5][6] How commitment to a given lineage occurs among macrophages, OCLs, and dendritic cells has not been fully elucidated, but complex signaling mechanisms are known to control OCL differentiation. 7 These signals include cytokines such as macrophage colony-stimulating factor (CSF-M), granulocytemacrophage colony-stimulating factor (CSF-GM), and interleukin-3, 8 which are macrophage-inducing cytokines, and the receptor activator of NF-B ligand (RANKL), which is a critical factor for late stages of OCL development. 9 In addition to cytokines, several transcription factors are vital for OCL formation; the most important are PU.1 10 and c-fos. 11,12 PU.1 (Spi-1) is essential for the development of myeloid and B-lymphoid cells. [13][14][15] In myeloid cells, PU.1 is known to regulate transcription of both c-fms and CD11b/CD18 (Mac1), both of which are central to the OCL phenotype. 16-18 PU.1-deficient mice show a failure in macrophage differentiation, and osteoclastogenesis is inhibited at a very early stage of differentiation. 10,19 Mice deficient in c-fos exhibit osteopetrosis due to an OCL differentiation defect, while the number of macrophages increases, indicating that c-fos acts on a later stage of OCL development. 10,11 It is clear that any disruption of hematopoiesis can profoundly affect OCL numbers.Thalidomide was originally developed in the 1950s to treat pregnancy-induced morning sickness. Following the discovery of its teratogenic effects, it was subsequently withdrawn from the market in 1961. 20 Since the discovery of thalidomide's antimyeloma activity in the late 1990s, 21 new and more potent immunomodulatory derivatives (IMiDs) of thalidomide such as CC-4047 (Actimid) and CC-5013 (Revlimid) with fewer side effects have been developed. In previous studies, we showed that IMiDs inhibit For personal use only. on May 10, 2018. by guest www.bloodjournal.org From the in vitro and in vivo growth of MM cells. 22,23 In initial clinical phase 1 and 2 trials, single agent CC-4047 and CC-5013 in combination with dexamethasone achieved response rates of over 50% in relapsed and refractory MM. [24][25][26] We have shown that CC-4047 induces a shift in lineage commitment, resulting in increased myeloid cell deve...

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Immunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and angiogenesis in vivo

Cited by 154 publications

References 18 publications

Effect of thalidomide therapy on bone marrow angiogenesis in multiple myeloma

Effect of thalidomide therapy on bone marrow angiogenesis in multiple myeloma

Angiogenesis and Multiple Myeloma

Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1

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