Dasatinib sensitizes chronic lymphocytic leukemia lymphocytes to chemotherapeutic agents
Bibliographic record
Abstract
AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4753 B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. CLL is characterized by the accumulation in the blood of affected patients of mature quiescent B-lymphocytes. At an early stage of the disease, B-lymphocyte accumulation occurs likely as a consequence of an undefined defect in the apoptotic machinery rather than an increased proliferation of leukemic cells. While the patients often initially respond to conventional treatment with chlorambucil or fludarabine they eventually become resistant to the drugs. De novo and acquired resistance to chemotherapy in CLL have been associated with alterations in apoptosis mediated by the presence of p53 mutations, alterations in the expression of anti-apoptotic factors and/or pro-apoptotic factors and altered DNA repair (alterations in the Rad51-related homologous recombinational pathway and the non homologous endjoining DNA repair pathway). Recently we have shown that inhibition of DNA repair sensitize CLL lymphocytes from treated and untreated patients to chlorambucil and fludarabine, using these drugs in combination with the c-abl inhibitor, Gleevec (Imatinib). Here we report that in vitro the c-abl/src kinase inhibitor Dasatinib: (1) is toxic to CLL lymphocytes and (2) when used at sublethal concentrations sensitizes CLL lymphocytes to chlorambucil and fludarabine. We assess the effect of the drugs alone or in combination using the MTT assay 72 hours after treatment in purified lymphocytes from 30 treated and untreated CLL patients. Dasatinib IC50 ranged from 0.03 to 80 μM. In all cases, when used at sublethal concentrations, Dasatinib sensitized CLL-lymphocytes to chlorambucil and fludarabine irrespectively of the clinical status of the patients. Our results using western blot and flow cytometry analysis with specific antibodies against phospho-Lyn and phospho-c-abl suggest that the effect of Dasatinib on CLL-lymphocytes survival, when used alone or in combination with chlorambucil or fludarabine, is mediated through the inhibition of those kinases. Moreover, Dasatinib specifically inhibits the repair of chlorambucil-induced DNA damage through the inhibition of c-abl kinase.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".