Bendamustine-based therapy as first-line treatment for non-Hodgkin lymphoma

Gil, Lidia; Kaźmierczak, Maciej; Kroll-Balcerzak, R.; Komarnicki, Mieczysław

doi:10.1007/s12032-014-0944-1

Cited by 13 publications

(7 citation statements)

References 33 publications

(21 reference statements)

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“…However, the management of relapsed/refractory disease represents a challenge, and a series of novel agents have entered clinical trials. Among these new strategies, bendamustine (Ben), a bifunctional alkylating agent, in combination with rituximab could be recommended as a first-line therapy for MCL (34). In our study, we first observed the cytotoxic effect and apoptosis induced by R and/or Ben in Maver and Z138 cells, and the results confirmed that silencing of B7-H3 increases chemosensitivity in both the single drug and two drug combination groups.…”

Section: Discussionsupporting

confidence: 70%

B7-H3 silencing inhibits tumor progression of mantle cell lymphoma and enhances chemosensitivity

Zhang

Wang

et al. 2015

International Journal of Oncology

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Abstract. B7-H3 (CD276), known as a member of B7 immunoregulatory family, is a type I transmembrane glycoprotein aberrantly expressed in numerous types of cancer and associated with poor prognosis. However, the role of B7-H3 in oncogenesis and chemosensitivity of mantle cell lymphoma (MCL) remains unknown. We determined the effects of downregulating B7-H3 expression on tumor progression and the sensitivity of chemotherapeutic drug in mantle cell lymphoma. B7-H3 knockdown was performed using lentivirus transduction in the Maver and Z138 mantle cell lymphoma cell lines, respectively. The effects of B7-H3 on cell proliferation, cycle, migration and invasion were investigated by CCK-8 assay, methyl cellulose colony forming assay, PI staining, and Transwell assays in vitro. By establishing Maver and Z138 xenograft models, the effects of B7-H3 on tumorigenicity were observed, and Ki-67 and PCNA was detected by immunohistochemistry. The downregulation of B7-H3 significantly decreased tumor proliferation in MCL in vitro and in vivo. In the B7-H3 knockdown groups of Maver and Z138 xenograft models, the mean inhibition rate of tumor growth was 59.1 and 65.0% (p=0.010 and 0.003), and the expression of both Ki-67 and PCNA were significantly lower, respectively. After B7-H3 silencing, the cell cycles of Maver and Z138 were both arrested at G0/G1 phase, and the cell migration rates and invasion capacity were decreased as well. Moreover, the impacts of B7-H3 RNAi on the antitumor effect of chemotherapy drugs were determined with CCK-8 and Annexin V-FITC/PI assays in vitro and with xenograft models in vivo. The silencing of B7-H3 increased the sensitivity of Maver and Z138 cells to rituximab and bendamustine and enhanced the drug-induced apoptosis, respectively. Our study demonstrates for the first time that B7-H3 promotes mantle cell lymphoma progression and B7-H3 knockdown significantly enhances the chemosensitivity. This may provide a new therapeutic approach to mantle cell lymphoma. IntroductionMantle cell lymphoma (MCL), a heterogeneous subtype of B-cell non-Hodgkin lymphoma (NHL), accounts for ~7% of NHL cases in the USA and Europe and has one of the worst outcomes of all the lymphomas (1,2). It is characterized by the t(11;14) (q13;q32) translocation, which results in overexpression of cyclin D1 and deregulation of the cell cycle (2). At initial diagnosis, most patients with the median age ~68-70 years have advanced stage disease, and the median overall survival is 3-5 years (3). Although several novel agents have proven to be effective, MCL remains a largely incurable disease and the following relapse is still challenging. Therefore, understanding the molecular mechanisms of MCL pathogenesis and drug resistance will aid in the development of highly active targeted therapies for the disease.B7-H3, a new member of B7 immunoregulatory family with immunoglobulin-like structure (4), is induced in activated dendritic cells, monocytes and T cells (5). Aberrant expression of B7-H3 has been reported and associated with poor prog...

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Section: Discussionsupporting

confidence: 70%

B7-H3 silencing inhibits tumor progression of mantle cell lymphoma and enhances chemosensitivity

Zhang

Wang

et al. 2015

International Journal of Oncology

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“… 80 BR regimen has gained popularity in the US for excellent tolerance and superior outcomes in other indolent B-cell lymphomas. 105 ORR of 93% has been achieved in patients with R/R EMZL (CR 71%) with the BR regimen with durable remissions at a cost of 29% incidence of Grade III–IV hematological toxicity. 106 The proteasome inhibitor bortezomib also has significant single-agent activity in R/R EMZL with an ORR of 48% (CR 31%).…”

Section: Management Of Mzlmentioning

confidence: 99%

Management of relapsed/refractory marginal zone lymphoma: focus on ibrutinib

Denlinger¹,

Epperla²,

William³

2018

CMAR

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Marginal zone lymphomas (MZLs) consist of a diverse family of malignancies, which are derived from B-cells. The disease subtypes are recognized extranodal, nodal, and splenic MZLs. The disease characteristics, clinical course, and treatment vary considerably based on the site of involvement. In 2017, the US Food and Drug Administration approved ibrutinib, a first in class Bruton’s tyrosine kinase inhibitor that revolutionized the care of chronic lymphocytic leukemia patients; for, the treatment of relapsed/refractory MZL based on pivotal open-label Phase II trial demonstrated an overall response rate of 48%, with a complete response rate of 3%, median progression-free survival of 14.2 months, and median overall survival not yet reached at a median follow-up of 19.4 months. In this review, we aim to summarize the current conundrums in the management of MZL and the evolving role of ibrutinib in the treatment of MZL.

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“…In the 1990s bendamustine got into the focus of research again [ 6 ]. It is approved for the treatment of chronic lymphocytic leukemia (CLL) [ 7 , 8 ], indolent non-Hodgkin lymphoma (NHL) [ 9 ] and multiple myeloma (MM) [ 10 , 11 ] or as second line therapy of refractory diseases [ 12 – 14 ] in various countries. Current clinical trials suggest beneficial effects in the treatment of solid cancer types such as breast cancer [ 15 ] or small-cell lung cancer [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Esters of Bendamustine Are by Far More Potent Cytotoxic Agents than the Parent Compound against Human Sarcoma and Carcinoma Cells

et al. 2015

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The alkylating agent bendamustine is approved for the treatment of hematopoietic malignancies such as non-Hodgkin lymphoma, chronic lymphocytic leukemia and multiple myeloma. As preliminary data on recently disclosed bendamustine esters suggested increased cytotoxicity, we investigated representative derivatives in more detail. Especially basic esters, which are positively charged under physiological conditions, were in the crystal violet and the MTT assay up to approximately 100 times more effective than bendamustine, paralleled by a higher fraction of early apoptotic cancer cells and increased expression of p53. Analytical studies performed with bendamustine and representative esters revealed pronounced cellular accumulation of the derivatives compared to the parent compound. In particular, the pyrrolidinoethyl ester showed a high enrichment in tumor cells and inhibition of OCT1- and OCT3-mediated transport processes, suggesting organic cation transporters to be involved. However, this hypothesis was not supported by the differential expression of OCT1 (SLC22A1) and OCT3 (SLC22A3), comparing a panel of human cancer cells. Bendamustine esters proved to be considerably more potent cytotoxic agents than the parent compound against a broad panel of human cancer cell types, including hematologic and solid malignancies (e.g. malignant melanoma, colorectal carcinoma and lung cancer), which are resistant to bendamustine. Interestingly, spontaneously immortalized human keratinocytes, as a model of “normal” cells, were by far less sensitive than tumor cells against the most potent bendamustine esters.

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Bendamustine-based therapy as first-line treatment for non-Hodgkin lymphoma

Cited by 13 publications

References 33 publications

B7-H3 silencing inhibits tumor progression of mantle cell lymphoma and enhances chemosensitivity

B7-H3 silencing inhibits tumor progression of mantle cell lymphoma and enhances chemosensitivity

Management of relapsed/refractory marginal zone lymphoma: focus on ibrutinib

Esters of Bendamustine Are by Far More Potent Cytotoxic Agents than the Parent Compound against Human Sarcoma and Carcinoma Cells

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