Pharmaceutical‐mediated inactivation of p53 sensitizes U87MG glioma cells to BCNU and temozolomide
Bibliographic record
Abstract
Pifithrin-alpha (PFTalpha) is a small molecule inhibitor of p53. By reversibly blocking apoptosis in response to DNA damage, PFTalpha protects normal cells from lethal doses of gamma-radiation (Komarov et al., Science, 1999;285:1733-7). We examined the effect of PFTalpha on the chemosensitivity of a human cancer in which cell cycle arrest, not apoptosis, is the principle cellular consequence of p53 activation. This was of interest because E6 silencing of p53 sensitizes U87MG astrocytic glioma cells to BCNU and temozolomide (TMZ), cytotoxic drugs that are modestly helpful in the treatment of aggressive astrocytic gliomas. We observed that exposure of U87MG cells to PFTalpha before cytotoxic chemotherapy attenuated p53-mediated induction of p21WAF1 protein levels, sensitizing U87MG cells to BCNU and TMZ. Sensitization of U87MG cells was associated with G1 arrest, delayed entry into S-phase and decreased repair of DNA damage by BCNU. Our findings suggest that in addition to protecting normal cells from the toxic effects of radiation and chemotherapy, small molecule inhibitors of p53, like PFTalpha, might play a role in clinical oncology by sensitizing certain resistant cancers to cytotoxic chemotherapies.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".