Abstract 4692: ABT-888 synergizes treatment of colon cancer cell lines with irinotecan
Bibliographic record
Abstract
Abstract Numerous studies have associated poly [ADP-ribosolose] polymerase 1 (PARP1) with DNA-damage repair. PARP1 rapidly localizes to DNA damage sites where it alters target proteins, (e. g. histones, topoisomerase I and DNA dependent protein kinase (DNA-PK)), through the addition of poly-ADP ribose side chains. By this mechanism, PARP1 plays a role in diverse repair pathways including homologous recombination/non-homologous end joining (HRR/NHEJ). Presently, third generation PARP inhibitors are in use clinically. These drugs have resulted in meaningful clinical responses and an increase in survival in metastatic breast and ovarian cancer patients bearing BRCA-deficient or triple negative tumors. The Abbott lead compound, ABT-888, is a potent PARP1 inhibitor that sensitizes many cancer cells in-vitro and in-vivo to temozolomide. In the present work, we hypothesized that colon cancers would be sensitized to the DNA damaging chemotherapeutic agent, irinotecan by ABT-888. Since PARP1 is involved in DNA repair, we propose that its inhibition would increase irinotecan-induced DNA damage and cell death in colon cancer cells lines. Using the sulforhodamine B assay (SRB), significant synergy (I<1 indicates synergy) was observed between ABT-888 and irinotecan at concentrations as low as 0.06 μM (Table 1). Levels of synergy observed in the SRB assay correlated with levels of PARP1 inhibition measured biochemically in cell lysates. Furthermore, 24h post treatment combinations of ABT-888/SN38 resulted in increased G2/M cell cycle arrest and increased levels of DNA damage as determined by γH2AX staining and comet assay. Additionally, 48h post treatment increased levels of apoptosis were associated with this drug combination. In conclusion this study suggests that ABT-888 may be a clinically effective adjuvant to current colon cancer therapies that include the use of irinotecan. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4692. doi:1538-7445.AM2012-4692
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 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) | 0.003 | 0.001 |
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".