The combination of the proteasome inhibitor bortezomib and the Bcl-2 antisense molecule oblimersen sensitizes human B-cell lymphomas to cyclophosphamide

Owen A. O'Connor, Emily A. Smith, Lorraine E. Toner, Julie Teruya-Feldstein, Stanley Frankel, Mark Rolfe, Xiaohui Wei, Shujun Liu, Guido Marcucci, Kenneth K. Chan, Asher A Chanan Khan

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Purpose: To determine whether the combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen can sensitize human lymphoma to cyclophosphamide. Experimental Design: Cytotoxicity assays were conducted to determine if there was any additive or synergistic interaction between the combinations of bortezomib, oblimersen, and cyclophosphamide using a standard trypan blue exclusion assay. Based on these experiments, in vivo experiments in severe combined immunodeficiency beige mice were done using human lymphoma xenografts in which different schedules were explored. Bcl-2 and oblimersen levels were determined in treated tumors, some of which were resected at the end of the in vivo experiment and evaluated pathologically. Results: The results suggest that the combination of bortezomib and oblimersen seem to interact in at least an additive fashion, and that the addition of cyclophosphamide to this drug combination can markedly improve tumor cell kill. In addition, it seems that these drug combinations may be schedule-dependent, with a requirement for oblimersen pretreatment. Animals treated with the triplet drug combination in a schedule-dependent manner experienced pathologic complete regression of disease, which was not observed in other treatment cohorts. The addition of bortezomib also seemed to increase the levels of intracellular oblimersen, which resulted in a marked reduction in Bcl-2. Histologic studies confirmed marked necrosis and caspase-3 activation only in the cohort receiving all three drugs. Conclusion: The use of Bcl-2-directed therapy and a proteasome inhibitor sensitizes human lymphoma cells to cytotoxic drugs like cyclophosphamide. This combination may offer new opportunities for integrating novel targeted therapies with conventional chemotherapy.

Original languageEnglish (US)
Pages (from-to)2902-2911
Number of pages10
JournalClinical Cancer Research
Volume12
Issue number9
DOIs
StatePublished - May 1 2006
Externally publishedYes

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Proteasome Inhibitors
B-Cell Lymphoma
Cyclophosphamide
Drug Combinations
Lymphoma
Appointments and Schedules
Severe Combined Immunodeficiency
Trypan Blue
Heterografts
Caspase 3
Pharmaceutical Preparations
Bortezomib
oblimersen
Neoplasms
Research Design
Necrosis
Therapeutics
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The combination of the proteasome inhibitor bortezomib and the Bcl-2 antisense molecule oblimersen sensitizes human B-cell lymphomas to cyclophosphamide. / O'Connor, Owen A.; Smith, Emily A.; Toner, Lorraine E.; Teruya-Feldstein, Julie; Frankel, Stanley; Rolfe, Mark; Wei, Xiaohui; Liu, Shujun; Marcucci, Guido; Chan, Kenneth K.; Chanan Khan, Asher A.

In: Clinical Cancer Research, Vol. 12, No. 9, 01.05.2006, p. 2902-2911.

Research output: Contribution to journalArticle

O'Connor, OA, Smith, EA, Toner, LE, Teruya-Feldstein, J, Frankel, S, Rolfe, M, Wei, X, Liu, S, Marcucci, G, Chan, KK & Chanan Khan, AA 2006, 'The combination of the proteasome inhibitor bortezomib and the Bcl-2 antisense molecule oblimersen sensitizes human B-cell lymphomas to cyclophosphamide', Clinical Cancer Research, vol. 12, no. 9, pp. 2902-2911. https://doi.org/10.1158/1078-0432.CCR-05-0308
O'Connor, Owen A. ; Smith, Emily A. ; Toner, Lorraine E. ; Teruya-Feldstein, Julie ; Frankel, Stanley ; Rolfe, Mark ; Wei, Xiaohui ; Liu, Shujun ; Marcucci, Guido ; Chan, Kenneth K. ; Chanan Khan, Asher A. / The combination of the proteasome inhibitor bortezomib and the Bcl-2 antisense molecule oblimersen sensitizes human B-cell lymphomas to cyclophosphamide. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 9. pp. 2902-2911.
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abstract = "Purpose: To determine whether the combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen can sensitize human lymphoma to cyclophosphamide. Experimental Design: Cytotoxicity assays were conducted to determine if there was any additive or synergistic interaction between the combinations of bortezomib, oblimersen, and cyclophosphamide using a standard trypan blue exclusion assay. Based on these experiments, in vivo experiments in severe combined immunodeficiency beige mice were done using human lymphoma xenografts in which different schedules were explored. Bcl-2 and oblimersen levels were determined in treated tumors, some of which were resected at the end of the in vivo experiment and evaluated pathologically. Results: The results suggest that the combination of bortezomib and oblimersen seem to interact in at least an additive fashion, and that the addition of cyclophosphamide to this drug combination can markedly improve tumor cell kill. In addition, it seems that these drug combinations may be schedule-dependent, with a requirement for oblimersen pretreatment. Animals treated with the triplet drug combination in a schedule-dependent manner experienced pathologic complete regression of disease, which was not observed in other treatment cohorts. The addition of bortezomib also seemed to increase the levels of intracellular oblimersen, which resulted in a marked reduction in Bcl-2. Histologic studies confirmed marked necrosis and caspase-3 activation only in the cohort receiving all three drugs. Conclusion: The use of Bcl-2-directed therapy and a proteasome inhibitor sensitizes human lymphoma cells to cytotoxic drugs like cyclophosphamide. This combination may offer new opportunities for integrating novel targeted therapies with conventional chemotherapy.",
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AU - Smith, Emily A.

AU - Toner, Lorraine E.

AU - Teruya-Feldstein, Julie

AU - Frankel, Stanley

AU - Rolfe, Mark

AU - Wei, Xiaohui

AU - Liu, Shujun

AU - Marcucci, Guido

AU - Chan, Kenneth K.

AU - Chanan Khan, Asher A

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