The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions

Lu, Ling; Payvandi, Faribourz; Wu, Lang; Zhang, Linghua; Hariri, Robert; Man, Hon‐Wah; Chen, Roger S.; Muller, George W.; Hughes, Christopher C.W.; Stirling, David I.; Schäfer, Peter; Bartlett, J. Blake

doi:10.1016/j.mvr.2008.08.003

Cited by 208 publications

(154 citation statements)

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“…11 In addition, it has been also reported that the inhibitory effect of the proteasome inhibitor Bortezomib on tumor angiogenesis involves the repression of HIF-1a transcriptional activity 12 and that lenalidomide inhibits HIF-1a protein expression in endothelial cells. 13 In conclusion, we demonstrate that MM-BM environment is hypoxic, HIF-1a protein is highly expressed by MM cells and it modulates the transcriptional and proangiogenic profiles of MM cells and their proangiogenic properties, suggesting that HIF-1a is involved in MM-induced angiogenesis and it could be a potential therapeutic target in MM patients.…”

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confidence: 62%

Low bone marrow oxygen tension and hypoxia-inducible factor-1α overexpression characterize patients with multiple myeloma: role on the transcriptional and proangiogenic profiles of CD138+ cells

et al. 2010

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confidence: 62%

Low bone marrow oxygen tension and hypoxia-inducible factor-1α overexpression characterize patients with multiple myeloma: role on the transcriptional and proangiogenic profiles of CD138+ cells

et al. 2010

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“…For instance, daratumumab is known to induce its effects against multiple myeloma predominantly via complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity, while lenalidomide induces multiple myeloma cell apoptosis via a mechanism involving increase in p21 WAF-1 expression and cell arrest in the G0-G1 phase. [28][29][30] Obviously, targeting multiple myeloma cells via various mechanisms is a primary goal of combination strategies to diminish the chance of developing resistance. A combination therapy becomes, however, more powerful if the agents work synergistically to improve each others' actions.…”

Section: Discussionmentioning

confidence: 99%

Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab

et al. 2010

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The online version of this article has a supplementary Appendix. BackgroundIn our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. Design and MethodsTo explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. ResultsDaratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cellmediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. ConclusionsOur results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma. daratumumab. Haematologica 2011;96(2):284-290. doi:10.3324/haematol.2010 This is an open-access paper.

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“…[14][15][16] There are three plausible approaches of introducing lenalidomide to upfront therapy: (i) lenalidomide maintenance following initial chemoimmunotherapy, (ii) addition of concomitant lenalidomide treatment to chemoimmunotherapy or (iii) both. Based on the in vitro synergy of lenalidomide with rituximab and cytotoxic therapy, 18,19 as well as the potential impact on microenvironment mediated drug resistance, 20,21 we elected to first test the combination approach. The addition of concurrent lenalidomide to R-CHOP is challenging because of the potential for overlapping hematological toxicity that may result in a negative impact on the dose intensity of R-CHOP, a potentially curative regimen in this setting.…”

Section: Discussionmentioning

confidence: 99%

Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study

et al. 2011

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Lenalidomide was shown to have significant single-agent activity in relapsed aggressive non-Hodgkin's lymphoma (NHL). We conducted a phase I trial to establish the maximum tolerated dose of lenalidomide that could be combined with R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone). Eligible patients were adults with newly diagnosed, untreated CD20 positive diffuse large cell or follicular grade III NHL. Patients received oral lenalidomide on days 1-10 with standard dose R-CHOP every 21 days. All patients received pegfilgrastim on day 2 of the cycle and aspirin prophylaxis. The lenalidomide dose levels tested were 15, 20 and 25 mg. A total of 24 patients were enrolled. The median age was 65 (35-82) years and 54% were over 60 years. Three patients received 15 mg, 3 received 20 mg and 18 received 25 mg of lenalidomide. No dose limiting toxicity was found, and 25 mg on days 1-10 is the recommended dose for phase II. The incidence of grade IV neutropenia and thrombocytopenia was 67% and 21%, respectively. Febrile neutropenia was rare (4%) and there were no toxic deaths. The overall response rate was 100% with a complete response rate of 77%. Lenalidomide at the dose of 25 mg/day administered on days 1 to 10 of 21-day cycle can be safely combined with R-CHOP in the initial chemotherapy of aggressive B-cell lymphoma.

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The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions

Cited by 208 publications

References 24 publications

Low bone marrow oxygen tension and hypoxia-inducible factor-1α overexpression characterize patients with multiple myeloma: role on the transcriptional and proangiogenic profiles of CD138+ cells

Low bone marrow oxygen tension and hypoxia-inducible factor-1α overexpression characterize patients with multiple myeloma: role on the transcriptional and proangiogenic profiles of CD138+ cells

Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab

Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study

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