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

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.

• Authors: 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
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 66 Issue 5 Pg. 869-80 (Oct 2010) ISSN: 1432-0843 [Electronic] Germany
• PMID: 20099064 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Aniline Compounds
• Apoptosis Regulatory Proteins
• BBC3 protein, human
• PMAIP1 protein, human
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• navitoclax

Topics

• Aniline Compounds (administration & dosage)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis Regulatory Proteins (genetics)
• Cell Line, Tumor
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lymphoma, B-Cell (drug therapy, pathology)
• Mice
• Mice, SCID
• Multiple Myeloma (drug therapy, pathology)
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics)
• Sulfonamides (administration & dosage)
• Xenograft Model Antitumor Assays