Inhibition of DNA repair in chronic lymphocytic leukemia: Therapeutic implications
Bibliographic record
Abstract
16513 Background: Chronic lymphocytic leukemia (CLL) is an indolent leukemia in which there is an accumulation of immature malignant B-lymphocytes. While treatment with chlorambucil, a nitrogen mustard analogue or fludarabine can control the disease, eventually all patients become resistant to chlorambucil/fludarabine. Chlorambucil’s cytotoxicity is mediated by the interstrand crosslinks (ICLs) introduced into DNA. In mammalian cells, two main pathways are known to be involved in double strand break(DSB) repair: homologous recombinational repair (HRR) and nonhomologous endjoining (NHEJ). Methods: Our laboratory has demonstrated that resistance to chlorambucil involved accelerated repair of the ICLs associated with enhanced DNA repair, specifically enhanced nonhomologous endjoining (NHEJ) and homologous recombinational repair (HRR). We also recently demonstrated that gleevec inhibition of c-abl with resulting inhibition of Rad51-related HRR sensitizes CLL lymphocytes in vitro to chlorambucil. This exciting result has stimulated the development of a clinical protocol to test this combination in CLL. Furthermore, our laboratory has demonstrated that wortmannin, a nonspecific inhibitor of DNA-PK (a key component of NHEJ) sensitizes CLL lymphocytes to chlorambucil. Results: We are actually evaluating the effect of NU7026, a relatively specific DNA-PK inhibitor, in the sensitivity of CLL cells to chlorambucil. Our results indicate that in a CLL cell line (I83) and primary CLL-lymphocytes chlorambucil plus NU7026 have a synergistic cytotoxic effect. Noteworthy, the NU7026 doses used in combination with chlorambucil were not toxic to the cells when used alone. Moreover, chlorambucil treatment induced DNA-PK nuclear foci which were inhibited by NU7026 suggesting that the synergy of both drugs is mediated by Nu7026-inhibition of DNA-PK. Conclusion: NU7026 plus chlorambucil should be a useful combination to treat CLL. No significant financial relationships to disclose.
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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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".