論文 - 詳細
| RRC ID | 38147 |
|---|---|
| 著者 | Balakrishnan K, Burger JA, Quiroga MP, Henneberg M, Ayres ML, Wierda WG, Gandhi V. |
| タイトル | Influence of bone marrow stromal microenvironment on forodesine-induced responses in CLL primary cells. |
| ジャーナル | Blood |
| Abstract |
Forodesine, a purine nucleoside phosphorylase inhibitor, displays in vitro activity in chronic lymphocytic leukemia (CLL) cells in presence of dGuo, which is the basis for an ongoing clinical trial in patients with fludarabine-refractory CLL. Initial clinical data indicate forodesine has significant activity on circulating CLL cells, but less activity in clearing CLL cells from tissues such as marrow. In tissue microenvironments, lymphocytes interact with accessory stromal cells that provide survival and drug-resistance signals, which may account for residual disease. Therefore, we investigated the impact of marrow stromal cells (MSCs) on forodesine-induced response in CLL lymphocytes. We demonstrate that spontaneous and forodesine-induced apoptosis of CLL cells was significantly inhibited by human and murine MSCs. Forodesine-promoted dGuo triphosphate (dGTP) accumulation and GTP and ATP depletion in CLL cells was inhibited by MSCs, providing a mechanism for resistance. Also, MSCs rescued CLL cells from forodesine-induced RNA- and protein-synthesis inhibition and stabilized and increased Mcl-1 transcript and protein levels. Conversely, MSC viability was not affected by forodesine and dGuo. Collectively, MSC-induced biochemical changes antagonized forodesine-induced CLL cell apoptosis. This provides a biochemical mechanism for MSC-derived resistance to forodesine and emphasizes the need to move toward combinations with agents that interfere with the microenvironment's protective role for improving current therapeutic efforts. |
| 巻・号 | 116(7) |
| ページ | 1083-91 |
| 公開日 | 2010-8-19 |
| DOI | 10.1182/blood-2009-10-246199 |
| PII | S0006-4971(20)34612-7 |
| PMID | 20442367 |
| PMC | PMC2938131 |
| MeSH | Animals Apoptosis / drug effects Blotting, Western Bone Marrow / physiology* Cell Proliferation / drug effects Cells, Cultured Humans Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy* Leukemia, Lymphocytic, Chronic, B-Cell / pathology* Lymphocytes / drug effects Lymphocytes / metabolism Mesenchymal Stem Cells / drug effects Mesenchymal Stem Cells / metabolism Mice Myeloid Cell Leukemia Sequence 1 Protein Proto-Oncogene Proteins c-bcl-2 / genetics Proto-Oncogene Proteins c-bcl-2 / metabolism Purine Nucleosides / pharmacology* Purine-Nucleoside Phosphorylase / antagonists & inhibitors* Pyrimidinones / pharmacology* RNA, Messenger / genetics Reverse Transcriptase Polymerase Chain Reaction Stromal Cells / physiology* |
| IF | 17.794 |
| 引用数 | 37 |
| WOS 分野 | HEMATOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 3 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | |