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01.10.2010 | Original Article

The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo

verfasst von: Scott Ackler, Michael J. Mitten, Kelly Foster, Anatol Oleksijew, Marion Refici, Stephen K. Tahir, Yu Xiao, Christin Tse, David J. Frost, Stephen W. Fesik, Saul H. Rosenberg, Steven W. Elmore, Alexander R. Shoemaker

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 5/2010

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Abstract

Purpose

This study was designed to test the ability of the Bcl-2 family inhibitor ABT-263 to potentiate commonly used chemotherapeutic agents and regimens in hematologic tumor models.

Methods

Models of B-cell lymphoma and multiple myeloma were tested in vitro and in vivo with ABT-263 in combination with standard chemotherapeutic regimens, including VAP, CHOP and R-CHOP, as well as single cytotoxic agents including etoposide, rituximab, bortezomib and cyclophosphamide. Alterations in Bcl-2 family member expression patterns were analyzed to define mechanisms of potentiation.

Results

ABT-263 was additive with etoposide, vincristine and VAP in vitro in the diffuse large B-cell lymphoma line (DLBCL) DoHH-2, while rituximab potentiated its activity in SuDHL-4. Bortezomib strongly synergized with ABT-263 in the mantle cell lymphoma line Granta 519. Treatment of DoHH-2 with etoposide was associated with an increase in Puma expression, while bortezomib upregulated Noxa expression in Granta 519. Combination of ABT-263 with cytotoxic agents demonstrated superior tumor growth inhibition and delay in multiple models versus cytotoxic therapy alone, along with significant improvements in tumor response rates.

Conclusions

Inhibition of the Bcl-2 family of proteins by ABT-263 enhances the cytotoxicity of multiple chemotherapeutics in hematologic tumors and represents a promising addition to the therapeutic arsenal for treatment of these diseases.

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Titel: The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo
verfasst von: Scott Ackler
Michael J. Mitten
Kelly Foster
Anatol Oleksijew
Marion Refici
Stephen K. Tahir
Yu Xiao
Christin Tse
David J. Frost
Stephen W. Fesik
Saul H. Rosenberg
Steven W. Elmore
Alexander R. Shoemaker
Publikationsdatum: 01.10.2010
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 5/2010
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-009-1232-1

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The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo