111In-labeled EGF is selectively radiotoxic to human breast cancer cells overexpressing EGFR.
Why this work is in the frame
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Bibliographic record
Abstract
UNLABELLED: Our objective was to determine whether the internalization and nuclear translocation of human epidermal growth factor (hEGF) after binding to its cell surface receptor (EGFR) could be exploited to deliver the Auger electron emitter 111In into EGFR-positive breast cancer cells for targeted radiotherapy. METHODS: hEGF was derivatized with diethylenetriamine pentaacetic acid (DTPA) and radiolabeled with 111In-acetate. The internalization of 111In-DTPA-hEGF by MDA-MB-468 breast cancer cells (1.3x10(6) EGFRs/cell) was determined by displacement of surface-bound radioactivity by an acid wash. The radioactivity in the cell nucleus and chromatin, isolated by differential centrifugation, was measured. The effect on the growth rate of MDA-MB-468 or MCF-7 (1.5x10(4) EGFRs/cell) cells was determined after treatment in vitro with 111In-DTPA-hEGF, unlabeled DTPA-hEGF, or 111In-DTPA. The surviving fraction of MDA-MB-468 or MCF-7 cells treated in vitro with 111In-DTPA-hEGF was determined in a clonogenic assay. The radiotoxicity in vivo against normal hepatocytes or renal tubular cells was evaluated by measuring alanine aminotransferase (ALT) or creatinine levels in mice administered high amounts of 111In-DTPA-hEGF (equivalent to human doses up to 14,208 MBq) and by light and electron microscopy of the tissues. RESULTS: Approximately 70% of 111In-DTPA-hEGF was internalized by MDA-MB-468 cells within 15 min at 37 degrees C and up to 15% was translocated to the nucleus within 24 h. Chromatin contained 10% of internalized radioactivity. The growth rate of MDA-MB-468 cells was decreased 3-fold by treatment with 111In-DTPA-hEGF (45-60 mBq/cell). Treatment with unlabeled DTPA-hEGF caused a 1.5-fold decrease in growth rate, whereas treatment with 111In-DTPA had no effect. Targeting of MDA-MB-468 cells with up to 130 mBq/cell of 111In-DTPA-hEGF resulted in a 2-logarithm decrease in their surviving fraction. No decrease in the growth rate or surviving fraction of MCF-7 cells was evident. There was no evidence of hepatotoxicity or renal toxicity in mice administered high amounts of 111In-DTPA-hEGF. Radiation dosimetry estimates suggest that the radiation dose to an MDA-MB-468 cell targeted with 111In-DTPA-hEGF could be as high as 25 Gy with up to 19 Gy delivered to the cell nucleus. CONCLUSION: 111In-DTPA-hEGF is a promising novel radiopharmaceutical for targeted Auger electron radiotherapy of advanced, hormone-resistant breast cancer.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.003 | 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 it