Mammalian Target of Rapamycin Inhibition Synergistically Increases Cytotoxicity of Vinorelbine in Breast Cancer Cells.
Bibliographic record
Abstract
5080 Inhibition of the serine-threonine kinase mammalian target of rapamycin (mTOR) has been reported to enhance the efficacy of several cytotoxic agents. Recent findings suggest that mTOR may be involved in a signaling pathway activated by microtubule-damaging drugs. The PI3K and AKT kinase pathway is a direct upstream regulator of mTOR. Using cells containing constitutively active myristoylated AKT it has been shown that AKT markedly increases resistance to microtubule-directed agents and a significant component of this AKT-mediated protection is mTOR-dependent. Other downstream targets of mTOR include the insulin receptor substrate-1 (IRS-1), a key adapter transmitting signals from activated insulin/insulin-like growth factor-1 receptors (IGF-1R). When IRS-1 is phosphorylated on a serine by mTOR, it dissociates from IGF-1R resulting in its proteasomal degradation. Also, recent data has shown that a recombinant humanized anti-IGF-1R antibody enhances the antitumor activity of vinorelbine in a non small cell lung cancer cell line. The aim of this study was to determine the nature of the interactions between mTOR inhibitors and microtubule-directed agents. Experimental Design: MCF-7 breast cancer cells were exposed for 72 hours either to the mTOR inhibitor rapamycin, at concentrations ranging from 0.1 to 100 (nM), the microtubule-directed agent Vinorelbine, at concentrations ranging from 0.01 to 10 (μg/ml) or simultaneous combination of both agents at a fixed ratio . Growth inhibition was measured using the MTT assay and synergistic interactions between the drugs were measured using the median-effect plot analysis and calculations of the combination index (CI) by the method of Chou and Talalay. Expression of AKT, PTEN and IGF-1R was assessed using western blot analysis. Results: Treatment with rapamycin or vinorelbine, as single agents, induced dose dependent growth inhibition. Synergistic interaction was obtained with the combination of rapamycin and vinorelbine, as evaluated by median-effect plot analysis and a combination index isobologram method (CI
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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) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".