Bcl-2 expression in rituximab refractory cutaneous B-cell lymphoma

Wobser, Marion; Voigt, Heike; Eggert, Andreas O.; Houben, Roland; Kauczok, Claudia S.; Bröcker, Eva B.; Becker, Jürgen C.

doi:10.1038/sj.bjc.6603762

Cited by 24 publications

(21 citation statements)

References 14 publications

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“…Furthermore, ABT-263 dramatically enhanced the efficacy of several approved oncology agents in B-cell malignant xenograft models. Recent reports have described the role of both Bcl-2 and Bcl-xL in conferring resistance to rituximab (35)(36)(37). In the DoHH2 diffuse large B-cell xenograft, ABT-263 dramatically enhanced rituximab treatment above what was observed with each agent alone and induced complete regression of the majority of treated tumors.…”

Section: Discussionmentioning

confidence: 97%

ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor

et al. 2008

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Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1) is commonly associated with tumor maintenance, progression, and chemoresistance. We previously reported the discovery of ABT-737, a potent, smallmolecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable, which would limit chronic single agent therapy and flexibility to dose in combination regimens. Here we report the biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (K i 's of <1 nmol/L for Bcl-2, Bcl-xL, and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% to 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim), leading to the initiation of apoptosis within 2 hours posttreatment. In human tumor cells, ABT-263 induces Bax translocation, cytochrome c release, and subsequent apoptosis. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small-cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in small-cell lung cancer and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility both as a single agent and in combination regimens. [Cancer Res 2008;68(9):3421-8]

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Section: Discussionmentioning

confidence: 97%

ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor

et al. 2008

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“…4). Research on patients suffering from relapsed or refractory cutaneous B-cell lymphoma disclosed a strong upregulation of the antiapoptotic molecule Bcl-2 compared with pretherapeutic levels, which suggests that upregulation of Bcl-2 plays a major role in therapy resistance [134]. Furthermore, Jazirehi et al [135] generated rituximab-resistant B-cell NHL cell lines by increasing the concentration of rituximab in the culture medium, and then found lower expression of CD20 in these resistant clones.…”

Section: Enhancing Apoptosis In Rituximab Therapymentioning

confidence: 99%

The Role of Complement in the Mechanism of Action of Rituximab for B-Cell Lymphoma: Implications for Therapy

2008

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Rituximab, a genetically engineered chimeric monoclonal antibody specifically binding to CD20, was the first antibody approved by the U.S. Food and Drug Administration for the treatment of cancer. Rituximab significantly improves treatment outcome in relapsed or refractory, low-grade or follicular B-cell nonHodgkin's lymphoma (NHL). However, there are also some challenges for us to overcome: why ϳ50% of patients are unresponsive to rituximab in spite of the expression of CD20, and why some responsive patients develop resistance to further treatment. Although the antitumor mechanisms of rituximab are not completely understood, several distinct antitumor activities of rituximab have been suspected, including complementdependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), apoptosis, and direct growth arrest. To counteract resistance to rituximab therapy, several strategies have been developed to: (a) augment the CDC effect by increasing CD20 expression, heteroconjugating rituximab to cobra venom factor and C3b, and inhibiting membrane complement regulatory protein, especially CD59, function; (b) enhance the ADCC effect through some immunomodulatory cytokines and CR3-binding ␤-glucan; and (c) reduce the apoptotic threshold or induce apoptotic signaling on the tumor. Extensive studies indicate that rituximab combined with these approaches is more effective than a single rituximab approach. Herein, the mechanism of action of and resistance to rituximab therapy in B-cell NHL, in particular, the involvement of the complement system, are extensively reviewed. The Oncologist 2008;13: 954 -966

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“…Redistribution of CD20 to membrane lipid rafts by anti-CD20 results in the clustering of antibody molecules and enhancing C1q binding, the first step in the CDC induction mechanism (4). In addition to these above cytotoxic mechanisms, homotypic cell aggregation has been reported to be involved in antibody-induced cytotoxicity as well as the induction of apoptosis (5)(6)(7). CD20 antibodies have been classified as type I or type II depending on their functional characteristics.…”

Section: Introductionmentioning

confidence: 99%

BM-ca is a newly defined type I/II anti-CD20 monoclonal antibody with unique biological properties

Nishida

Uematsu²,

Kobayashi³

et al. 2011

Int J Oncol

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Abstract. Rituximab (chimeric anti-CD20 mAb) is currently used in the treatment of B-NHL and B cell malignancies, alone or in combination with chemotherapy. However, subsets of patients do not initially respond and/or develop resistance to additional treatments. Hence, there is a need to develop more effective anti-CD20 mAbs that may improve clinical response. BM-ca is a novel humanized anti-CD20 mAb that was tested against several B-NHL cell lines and was compared to several anti-CD20 mAbs (Rituximab, ofatumumab, 2H7, B1 and B-Ly1). BM-ca was shown to strongly induce both homotypic cell aggregation and redistribution of CD20 to membrane lipid rafts. BM-ca was also able to induce programmed cell death (apoptosis) without the need for cross-linking and demonstrated potent complement-dependent cytotoxicity (CDC). BM-ca was more cytotoxic than rituximab even in malignant B cells expressing low amounts of membrane CD20. Type I anti-CD20 mAbs typically induce minimal levels of homotypic cell aggregation and apoptosis but strong localization of CD20 to lipid rafts and potent CDC. Type II anti-CD20 mAbs typically exert the reverse activities. Noteworthy, BM-ca exhibits properties that are shared by both type I and type II anti-CD20 mAbs, which may reflect the recognition of a new CD20 epitope and/or exhibit different molecular signaling. Overall, the present data show that BM-ca is a novel anti-CD20 mAb that may be classified as a type I/II. The therapeutics efficacy of BM-ca awaits its use in clinical trials. IntroductionThe use of rituximab as a single agent or in combination with cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP), is now a standard therapy for nonHodgkin's lymphoma (NHL) (1,2). NHL patients do not always completely respond to rituximab therapy, however, and a subset of patients who initially responded become resistant or less responsive to further treatment (3). Despite a great number of reports, the in vivo mechanisms responsible to predict the clinical outcome in NHL after anti-CD20 treatment remain elusive. Complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and apoptosis are all potential cytotoxic mechanisms, although it is unclear which mechanism is important in vivo. Redistribution of CD20 to membrane lipid rafts by anti-CD20 results in the clustering of antibody molecules and enhancing C1q binding, the first step in the CDC induction mechanism (4). In addition to these above cytotoxic mechanisms, homotypic cell aggregation has been reported to be involved in antibody-induced cytotoxicity as well as the induction of apoptosis (5-7).CD20 antibodies have been classified as type I or type II depending on their functional characteristics. Type I exhibits strong CDC activity but weak apoptosis whereas type II shows the opposite, i.e., weak CDC and strong apoptosis. Type I antibodies have the ability to redistribute CD20 to membrane lipid rafts whereas type II do not. Further, type I induce little homotypic cell aggregation whereas homotypic ce...

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Bcl-2 expression in rituximab refractory cutaneous B-cell lymphoma

Cited by 24 publications

References 14 publications

ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor

ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor

The Role of Complement in the Mechanism of Action of Rituximab for B-Cell Lymphoma: Implications for Therapy

BM-ca is a newly defined type I/II anti-CD20 monoclonal antibody with unique biological properties

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