Abstract A44: Inhibition of EGFR phosphorylation in a panel of human breast cancer cells correlates with synergistic interactions between gefitinib and 5'-DFUR, the bioactive metabolite of Xeloda®
Bibliographic record
Abstract
Abstract The introduction of Xeloda® (capecitabine) in the clinical management of breast cancer has significantly improved survival in patients with mammary carcinoma. It is administered orally and first is metabolized in the liver by carboxylesterases to generate 5'-deoxy- 5-flurocytidine ribose (5'-DFCR), which is subsequently converted to 5'-deoxy-5-fluorouridine ribose (5'-DFUR) by cytidine deaminase. While the latter conversion takes place in tumour and normal tissues, the conversion of 5'-DFUR to the cytotoxic compound 5-FU, occurs principally in the tumour. This reaction is catalyzed by thymidine phosphorylase (TP), which is overexpressed in cancer cells. It has been observed that tumours expressing high levels of TP are the most responsive to capecitabine treatment. Therefore, it was hypothesized that conditions leading to an increase of TP expression could potentiate the action of capecitabine. Our recent studies in a panel of human breast cancer cell lines showed an increase in TP levels upon exposure to gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR). Here, we report on the factors influencing the potency of gefitinib in combination with 5'-DFUR, the bioactive metabolite of capecitabine. The results showed that: 1) 5'-DFUR activity linearly correlated with TP basal level (R2= 0.808), 2) importantly, the strength of the synergistic interaction between gefitinib and 5'-DFUR, as measured by the combination index at IC50 concentrations (CI50) increased with TP fold changes after gefitinib treatment (R2=0.6449), 3) inversely, it decreased with increasing thymidylate synthase (TS) fold changes after gefitinib treatment (R2=0.6229), 4) moreover, the strength of the synergy correlated with an increase in the proportion of cells arrested in the S and G2M phases of cell cycle (R2=0.6355), 5) changes in TP levels correlated with the magnitude of inhibition of EGFR phosphorylation by gefitinib (R2=0.63) but not with its IC50 values for growth inhibition in the cell panel (R2=0.03611), 6) likewise, DNA damage induced by 5'-DFUR alone or in combination with gefitinib did not correlate with IC50 values for growth inhibition. The results in toto suggest that the observed synergistic interactions between gefitinib and 5'-DFUR may be imputed to molecular events associated with inhibition EGFR phosphorylation and modulation of TP/TS expression in the cells. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A44.
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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) | 0.001 | 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) | 0.004 | 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".