Differentiation of Human B-Cell Tumors: A Preclinical Model for Differentiation Therapy

Al‐Katib, Ayad; Mohammad, Ramzi M.

doi:10.1007/978-1-4613-1253-6_12

Cited by 2 publications

(2 citation statements)

References 37 publications

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“…There are different ways of classifying malignant lymphoid disorders based on morphology, clinical behavior, cell lineage, immunophenotypes, genetic abnormalities or a combination of these features [ 2 - 4 ]. We have chosen to catalogue malignant B-lymphoid disorders according to the state of differentiation they represent and established a number of cell lines representing them [ 5 ]. According to this schema, B-cell tumors are believed to represent discrete stages of B-cell differentiation from the most immature (like ALL) to the most mature (like MM and Waldenstrom's Macroglobulinemia [WM]) stages.…”

Section: Introductionmentioning

confidence: 99%

SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status

et al. 2009

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The Bcl-2 family of proteins is critical to the life and death of malignant B-lymphocytes. Interfering with their activity using small-molecule inhibitors (SMI) is being explored as a new therapeutic strategy for treating B-cell tumors. We evaluated the efficacy of TW-37, a non-peptidic SMI of Bcl-2 against a range spectrum of human B-cell lines, fresh patient samples and animal xenograft models. Multiple cytochemical and molecular approaches such as acridine orange/ethidium bromide assay for apoptosis, co-immunoprecipitation of complexes and western blot analysis, caspase luminescent activity assay and apoptotic DNA fragmentation assay were used to demonstrate the effect of TW-37 on different B-cell lines, patient derived samples, as well as in animal xenograft models. Nanomolar concentrations of TW-37 were able to induce apoptosis in both fresh samples and established cell lines with IC 50 in most cases of 165-320 nM. Apoptosis was independent of proliferative status or pathological classification of B-cell tumor. TW-37 was able to block Bim-Bcl-X L and Bim-Mcl-1 heterodimerization and induced apoptosis via activation of caspases -9, -3, PARP and DNA fragmentation. TW-37 administered to tumor-bearing SCID mice led to significant tumor growth inhibition (T/C), tumor growth delay (T-C) and Log 10 kill, when used at its maximum tolerated dose (40 mg/kg × 3 days) via tail vein. TW-37 failed to induce changes in the Bcl-2 proteins levels suggesting that assessment of baseline Bcl-2 family proteins can be used to predict response to the drug. These findings indicate activity of TW-37 across the spectrum of human Bcell tumors and support the concept of targeting the Bcl-2 system as a therapeutic strategy regardless of the stage of B-cell differentiation.

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Section: Introductionmentioning

confidence: 99%

SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status

et al. 2009

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“…The immunoglobulin idiotype, CD 19,20,38,54 138,MUC1 and HM1.24 are some of them (Treon et al, 2000). CD20 is a specific pan B-cell antigen that can be expressed on mature plasma cell of MM or WM (Anderson et al, 1984;Al-Katib and Mohammad, 1996). Up to 50% plasma cell leukemia and from 75 to 100% in WM patients (Anderson et al, 1984).…”

Section: Discussionmentioning

confidence: 98%

Rituximab, Cyclophosphamide, Dexamethasone (RCD) Regimen Induces Cure in WSU-WM Xenograft Model and a Partial Remission in Previously Treated Waldenstrom's Macroglobulinemia Patient

Mohammad

Aboukameel

Nabha

et al. 2002

Journal of Drug Targeting

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Waldenstrom's macroglobulinemia (WM) is an uncommon lymphoproliferative disease which remains incurable with current treatment protocols. We have previously established a permanent WM cell line, WSU-WM, which grows as a xenograft in severe combined immune deficient (SCID) mice. In this study, we investigated the antitumor effects of Rituximab (RTX), Cyclophosphamide (CTX), Dexamethasone (DEX) [RCD]-Regimen in vivo WSU-WM SCID xenograft and in a patient with WM. For the pre-clinical efficacy study, WSU-WM-bearing SCID mice were randomly assigned to receive RTX (150 mg/kg/inj, i.v., QDX5), CTX (90 mg/kg/inj, s.c. QDX5) as single agents or diluent. The combination group received RTX at 150 mg/kg/inj, QDX5; CTX at 150 mg/kg/inj, QODX3 and DEX at 1.0 mg/kg/inj, i.v., QDX5. Tumor growth inhibition (T/C), tumor growth delay (T - C), and log10 kill (net) for RTX and CTX were 24.5%, 37 days, 5.52 and 88%, 0.0 days, 0.0log10 kill, respectively. No cures were observed with either agent; however, all mice (6/6, with bilateral tumors) were cured when treated with RCD-regimen. A 57-year-old patient with relapsed WM was treated with the RCD-regimen and showed an excellent partial remission for seven months. The patient tolerated the treatment very well, the hemoglobin improved dramatically, platelets remained stable, the IgM level normalized and there was only minimal involvement of bone marrow. Based on these results, the RCD regimen is effective against WM and its activity should be further evaluated in clinical trials.

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Differentiation of Human B-Cell Tumors: A Preclinical Model for Differentiation Therapy

Cited by 2 publications

References 37 publications

SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status

SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status

Rituximab, Cyclophosphamide, Dexamethasone (RCD) Regimen Induces Cure in WSU-WM Xenograft Model and a Partial Remission in Previously Treated Waldenstrom's Macroglobulinemia Patient

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