Chemoradiation Cancer Therapy: Molecular Mechanisms of Cisplatin Radiosensitization
Bibliographic record
Abstract
Sensitization of malignant cells to ionizing radiation plays a key role in cancer treatments that combine chemotherapy and radiation therapy. Enhancement by chemotherapeutic agents of DNA base damages and clustered damage, which are among the most detrimental cellular modifications, is expected to contribute significantly to the radiosensitization process; however, with the exception of double-strand breaks (DSBs), no measurements exist on the enhancement of such damages induced by the abundant secondary low-energy electrons (LEEs) created by ionizing radiation. This lack of information restricts our global understanding of the molecular mechanisms involved in chemoradiation therapy. Here we measure the enhancements of LEE-induced damages resulting from the binding of cisplatin to plasmid DNA (pGEM-3Zf(−), 3197 bp). The enhancement factors (EFs) are reported for base damages (BDs) on one strand and clustered damages consisting of BDs and single-strand break (SSBs) with adjacent BDs on the opposite strand. Five-monolayer films of cisplatin–plasmid-DNA complexes in a molar ratio of 5:1 are prepared by lyophilization and irradiated in vacuum with monoenergetic electrons at the resonance energies of 4.6 and 9.6 eV. Cross-links, SSBs, DSBs and the loss of the supercoiled configuration are analyzed by the agarose gel electrophoresis. Irradiated samples are treated with E. coli base excision repair endonuclease (Nth and Fpg) enzymes to reveal by electrophoresis base modifications occurring within two helical turns of the DNA helix. From the dose–response curves, the total DNA damages induced at each energy are 244 ± 42 and 359 ± 44 × 10 –15 electron –1 molecule –1, while the percentages of base modifications in these totals are 55 and 54%, respectively. Binding of cisplatin to DNA increases base modifications by EFs of 2.4 and 1.9, respectively; these are the largest finite EFs observed. Enhancement of all lesions can be explained by invoking two general mechanisms of electron transfer coupled to transient anions formation in cisplatin–DNA complexes. The present results provide more complete information on the radiosensitization of LEE-induced damages to DNA by cisplatin.
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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 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 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".