Methotrexate, Paclitaxel, and Doxorubicin Radiosensitize <i>HER2</i>-Amplified Human Breast Cancer Cells to the Auger Electron–Emitting Radiotherapeutic Agent <sup>111</sup>In-NLS-Trastuzumab
Bibliographic record
Abstract
UNLABELLED: Our goal in this study was to elucidate the mechanisms by which methotrexate radiosensitizes HER2-positive human breast cancer cells to the Auger electron emitter (111)In-trastuzumab modified with nuclear-localization sequence peptides ((111)In-NLS-trastuzumab) and to compare these mechanisms with the potential sensitizing effects of paclitaxel and doxorubicin when combined with this radiopharmaceutical. METHODS: Experiments were performed in MDA-MB-231 human breast cancer cells, their HER2-transfected subclones (231-H2N), and 2 trastuzumab-resistant variants (trastuzumab-resistant-1 and -2 [TrR1 and TrR2]). Effects of coexposure of these cells to (111)In-NLS-trastuzumab and low-dose, radiosensitizing methotrexate, paclitaxel, or doxorubicin were assessed by clonogenic cell-survival assay. Quantification of residual DNA damage was measured by the gammaH2AX-immunofluorescence assay, and cell cycle distribution was measured by fluorescence-activated cell sorting analysis. The radiation-enhancement ratio was calculated as the ratio of the surviving fraction (SF) of cells treated with (111)In-NLS-trastuzumab alone to that of cells treated concurrently with (111)In-NLS-trastuzumab and methotrexate, paclitaxel, or doxorubicin. RESULTS: A reduction in the SF in HER2-positive 231-H2N (55.7% +/- 1.3%) and TrR1 (62.6% +/- 6.5%) cells was demonstrated after exposure to (111)In-NLS-trastuzumab (approximately 0.2 MBq/microg, 100 nmol/L) but not in MDA-MB-231 or TrR2 cells expressing low levels of HER2 (SF > 90%, P > 0.05). Coadministration of methotrexate, paclitaxel, or doxorubicin enhanced the cytotoxicity of (111)In-NLS-trastuzumab toward 231-H2N and TrR1 cells but not toward MDA-MB-231 or TrR2 cells. The radiation-enhancement ratios for methotrexate, paclitaxel, and doxorubicin for 231-H2N or TrR1 cells were 2.0-2.2, 1.6-1.8, and 2.7-2.8, respectively. Methotrexate or doxorubicin combined with (111)In-NLS-trastuzumab, compared to treatment with (111)In-NLS-trastuzumab alone, significantly increased residual gammaH2AX foci in 231-H2N and TrR1 cells but not in MDA-MB-231 or TrR2 cells or in any cell line treated concurrently with paclitaxel and (111)In-NLS-trastuzumab. Cells exposed to low-dose methotrexate accumulated in the G(1)/S phase of the cell cycle, whereas low-dose paclitaxel or doxorubicin caused cells to arrest in the G(2)/M phase. CONCLUSION: Low-dose methotrexate, paclitaxel, or doxorubicin potently sensitized HER2-overexpressing human breast cancer cells, with and without acquired trastuzumab-resistance, to the Auger electron emissions from (111)In-NLS-trastuzumab through cell cycle distribution changes and in part through the inhibitory effects of these agents on DNA damage repair.
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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) | 0.001 | 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, 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".