Antisense inhibition of methylenetetrahydrofolate reductase (MTHFR) reduces survival of cancer cells in vitro and in vivo
Bibliographic record
Abstract
3103 Background: Methylenetetrahydrofolate reductase (MTHFR) is an enzyme of folate metabolism that is required for methionine biosynthesis. Various cancer cell lines are methionine dependent, i.e. they have an increased requirement for methionine and cannot, in contrast to untransformed cells, generate methionine from homocysteine. Our study was undertaken to determine whether inhibition of MTHFR gene expression might decrease cancer cell survival. Methods: Phosphorothioate oligonucleotides directed against the MTHFR gene were utilized in vitro and in vivo, to assess their anti-tumor properties. As a specific target, we selected a sequence in exon 5 (EX5) of the MTHFR mRNA and, as a control (CT), we used its scrambled sequence. The anti-tumor activity was determined with oligonucleotides alone or in combination with standard chemotherapeutic agents. Results: : Colon, lung, breast, prostate carcinoma and neuroblastoma cell lines were transfected with 200–400nM of EX5 on 2–3 consecutive days. Cell numbers were decreased by 60%–80% compared to treatment with CT. The combination of EX5 with cytostatics (5-fluorouracil, cisplatin, paclitaxel) showed an additive effect: cell numbers (colon carcinoma, lung carcinoma, prostate carcinoma, respectively) were decreased by 40%–50% compared to therapy with either agent alone. In vivo, phosphorothioate oligonucleotides were administered to athymic CD1 nude mice bearing colon (SW-620) and lung (A-549) carcinoma tumors. Tumor growth in the group treated with EX5 was decreased by ∼ 40% in comparison with the group injected with CT. MTHFR protein levels in tumors were analyzed by Western blotting; the density of the MTHFR band was quantified, relative to the density of the internal control (actin). MTHFR protein levels in tumors treated with EX5 were 60% - 70% lower than those treated with CT. Preliminary results of combined therapy in vivo on A-549 tumors have demonstrated additive effects. Conclusions: Inhibition of MTHFR expression affects cancer cell survival. Oligonucleotides or small molecule inhibitors of the enzyme should be considered in cancer chemotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Strida Pharma Inc.
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How this classification was reachedexpand
Direct model labels (unvalidated)
Per-model category and study-design labels from the labeling rounds. They are machine output, unvalidated, and the disagreement between models ships as data. No study design here is MEDLINE-validated yet.
| Model arm | Categories | Study design | Confidence |
|---|---|---|---|
| gemma | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Bench or experimental | low |
| gpt | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Bench or experimental | high |
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 | 0.000 | 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 itClassification
machine, unvalidatedLabeled directly by 2 models reading the full record.
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".