The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo
| Autor: | Michael J. Mitten, Anatol Oleksijew, Steven W. Elmore, Scott L. Ackler, Marion Refici, David Frost, Christin Tse, Stephen K. Tahir, Kelly Foster, Saul H. Rosenberg, Stephen W. Fesik, Yu Xiao, Alexander R. Shoemaker |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Vincristine Lymphoma B-Cell medicine.medical_treatment Mice SCID CHOP Biology Toxicology Mice immune system diseases Cell Line Tumor Proto-Oncogene Proteins hemic and lymphatic diseases Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Pharmacology (medical) Etoposide Multiple myeloma Pharmacology Sulfonamides Chemotherapy Aniline Compounds Bortezomib Drug Synergism medicine.disease Xenograft Model Antitumor Assays Lymphoma Gene Expression Regulation Neoplastic Proto-Oncogene Proteins c-bcl-2 Oncology Cancer research Mantle cell lymphoma Apoptosis Regulatory Proteins Multiple Myeloma medicine.drug |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 66:869-880 |
| ISSN: | 1432-0843 0344-5704 |
| Popis: | 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. 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. 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. 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. |
| Databáze: | OpenAIRE |
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