Abstract 1680: Effect of folate and γ-glutamyl hydrolase modulation on in vitro chemosensitivity of colon and breast cancer cells to antifolates and 5-fluorouracil
Bibliographic record
Abstract
Abstract Background: γ-Glutamyl hydrolase (GGH) removes terminal glutamates of polyglutamylated folates and antifolates, thereby facilitating hydrolysis and efflux of folates and antifolates from the cell. Therefore, GGH plays an important role in regulating intracellular folates and antifolates for optimal folate-dependent one-carbon transfer reactions and antifolate-induced cytotoxic effects, respectively. We have previously reported that GGH modulation significantly affects chemosensitivity of colon and breast cancer cells to 5-fluorouracil (5FU) and methotrexate (MTX) by changing intracellular retention of a folate cofactor (5,10-methylenetetrahydrofolate) necessary for the cytotoxic effects of 5FU and by changing intracellular retention of MTX, respectively. In the present study, we investigated whether exogenous folate concentrations further influence the effects of GGH modulation on the chemosensitivity to antifolates and 5FU. Methods: Human HCT116 colon and MDA-MB-435 breast cancer cells were stably transfected with the sense GGH cDNA or GGH-targeted siRNA, respectively, to generate an in vitro model of GGH overexpression and inhibition. In vitro chemosensitivity to pemetrexed (MTA, positive control), trimetrexate (TMTX, negative control), MTX and 5FU under 2.3 μM folic acid (FA) and 100 nM and 50 nM of 5-methyltetrahydrofolate (5MTHF) was determined. Results: In HCT116 cells, GGH overexpression increased chemosensitivity to MTA and 5FU alone at all concentrations (p<0.05). At 2.3 uM FA, GGH overexpression decreased chemosensitivity to MTX and 5FU+leucovorin (LV) and enhanced TMTX chemosensitivity while it increased chemosensitivity to MTX and 5FU+LV and decreased TMTX chemosensitivity at 50 nM 5MTHF (p<0.05). At all concentrations, GGH inhibition decreased chemosensitivity to MTX and 5FU alone whereas it enhanced 5FU+LV chemosensitivity (p<0.05). GGH inhibition decreased chemosensitivity to MTA at 2.3 uM FA and 100 nM 5MTHF while MTA chemosensitivity increased at 50 nM 5MTHF (p<0.05). In MDA-MB-435 cells, GGH overexpression decreased chemosensitivity to all drugs at all concentration, and to 5FU alone at 50nM 5MTHF (p<0.05). GGH inhibition decreased chemosensitivity to MTX and TMTX at all concentrations while it increased chemosensitivity to MTA at 100 nM and 50 nM 5MTHF, and to 5FU+LV at 2.3 uM FA and 100 nM 5MTHF, respectively (p<0.05). Conclusions: As proof of principle, we provide functional evidence that GGH modulation affects the chemosensitivity of colon and breast cancer cells to antifolates and 5FU. These GGH modulation-induced changes in chemosensitivity are highly complex and further influenced by different folate forms and concentrations. Our data suggest that both GGH modulation and folate status affect chemosensitivity of colon and breast cancer cells to antifolates and 5FU. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1680. doi:10.1158/1538-7445.AM2011-1680
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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) | 0.000 | 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) | 0.002 | 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 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".