The combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen sensitizes human B-cell lymphomas to cyclophosphamide
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.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2006 |
|---|---|
| Erschienen: |
2006 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
|---|---|
| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 12(2006), 9 vom: 01. Mai, Seite 2902-11 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
O'Connor, Owen A [VerfasserIn] |
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| Anmerkungen: |
Date Completed 21.08.2006 Date Revised 19.11.2015 published: Print Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM162583362 |
|---|
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| 041 | |a eng | ||
| 100 | 1 | |a O'Connor, Owen A |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen sensitizes human B-cell lymphomas to cyclophosphamide |
| 264 | 1 | |c 2006 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
| 338 | |a Band |b nc |2 rdacarrier | ||
| 500 | |a Date Completed 21.08.2006 | ||
| 500 | |a Date Revised 19.11.2015 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a PURPOSE: To determine whether the combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen can sensitize human lymphoma to cyclophosphamide | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Boronic Acids |2 NLM | |
| 650 | 7 | |a Oligonucleotides, Antisense |2 NLM | |
| 650 | 7 | |a Protease Inhibitors |2 NLM | |
| 650 | 7 | |a Proteasome Inhibitors |2 NLM | |
| 650 | 7 | |a Pyrazines |2 NLM | |
| 650 | 7 | |a Thionucleotides |2 NLM | |
| 650 | 7 | |a Bortezomib |2 NLM | |
| 650 | 7 | |a 69G8BD63PP |2 NLM | |
| 650 | 7 | |a oblimersen |2 NLM | |
| 650 | 7 | |a 85J5ZP6YSL |2 NLM | |
| 650 | 7 | |a Cyclophosphamide |2 NLM | |
| 650 | 7 | |a 8N3DW7272P |2 NLM | |
| 700 | 1 | |a Smith, Emily A |e verfasserin |4 aut | |
| 700 | 1 | |a Toner, Lorraine E |e verfasserin |4 aut | |
| 700 | 1 | |a Teruya-Feldstein, Julie |e verfasserin |4 aut | |
| 700 | 1 | |a Frankel, Stanley |e verfasserin |4 aut | |
| 700 | 1 | |a Rolfe, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Xiaohui |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Shujun |e verfasserin |4 aut | |
| 700 | 1 | |a Marcucci, Guido |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Kenneth K |e verfasserin |4 aut | |
| 700 | 1 | |a Chanan-Khan, Asher |e verfasserin |4 aut | |
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