Methotrexate-induced apoptosis is enhanced by altered expression of methylenetetrahydrofolate reductase
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Bibliographic record
Abstract
Folates are essential for DNA synthesis and methylation reactions. The antifolate methotrexate (MTX) is a widely used chemotherapeutic drug which inhibits DNA synthesis and induces apoptosis. Changes in activity of a critical folate-metabolizing enzyme, methylenetetrahydrofolate reductase (MTHFR), might alter the chemosensitivity to MTX, as the MTHFR substrate is required for nucleotide synthesis and its product is used in homocysteine remethylation to methionine. Mild MTHFR deficiency is common in many populations due to a polymorphism at bp 677. We previously showed that altered expression of MTHFR enhanced MTX-induced myelosuppression in mice. To determine the cause of the impaired hematopoietic profile in mice with decreased or increased MTHFR expression, we evaluated MTX-induced apoptosis in the major hemolytic organ, spleen, using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining and caspase-3/7 activity assays, in MTHFR-deficient mice and in MTHFR-overexpressing mice after MTX administration. Decreased or increased expression of MTHFR in mice significantly increased TUNEL-positive cells and caspase-3/7 activities in MTX-treated spleen, compared with that of wild-type littermates. Plasma homocysteine levels correlated with apoptotic index in MTX-treated MTHFR-deficient mice and dUTP/dTTP ratios correlated with apoptotic index in MTX-treated MTHFR-overexpressing mice. The increased apoptosis may therefore relate to hyperhomocysteinemia and deoxyribonucleotide pool imbalances, respectively. Our results suggest that MTHFR underexpression and overexpression enhances MTX-induced apoptosis and myelosuppression, and that genotyping for the MTHFR polymorphism may have therapeutic implications.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.001 | 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 it