Cellular models of altered base excision repair reveal a differential contribution of reactive oxygen species‐induced 7,8‐dihydro‐8‐oxo‐2′‐deoxyguanosine to the cytotoxic mechanisms of platinum anticancer drugs cisplatin and oxaliplatin
Bibliographic record
Abstract
Cisplatin anticancer therapy is limited by toxicity and onset of tumor resistance. The platinum analog oxaliplatin exhibits increased activity against cisplatin‐resistant cancers, but the mechanisms for this potency remain to be identified. Both drugs form platinum‐DNA crosslinked adducts, and cisplatin causes oxidative DNA damage such as the 7,8‐dihydro‐8‐oxo‐2′‐deoxyguanosine (8‐oxodG) lesion. To assess oxidative DNA damage as a mechanism of platinum compound cytotoxicity, 8‐oxodG‐directed base excision repair (BER) was stably enhanced in human cells by expression of human oxoguanine glycosylase 1 (α ‐ogg1 ) or E. coli formamidopyrimidine glycosylase ( fpg ). Cisplatin and oxaliplatin increased reactive oxygen species (ROS) and 8‐oxodG levels, and cytotoxicity was decreased by antioxidant therapy. Ectopic expression of α ‐ogg1 or fpg induced 8‐oxodG repair and reduced death by ROS initiators (H 2 O 2 , menadione) and both platinum drugs, although protection against cisplatin exceeded that for oxaliplatin. Oxaliplatin also caused an increased proliferative block independent of 8‐oxodG‐mediated effects. We conclude that the 8‐oxodG lesion is cytotoxic, and BER a likely determinant of risk. The greater antitumor efficacy of oxaliplatin appears unrelated to oxidative DNA damage, suggesting a novel strategy for improving the therapeutic index in cancer therapy. (Support: NIEHS grant no. ES013848, CIHR)
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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 | 0.003 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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".