Abstract A51: Chemotherapy rescues hypoxic tumor cells and induces reoxygenation and repopulation - an effect that is inhibited by the hypoxia-activated pro-drug TH-302
Notice bibliographique
Résumé
Abstract Introduction: Hypoxia is associated with tumor treatment failure. Tumor cells closest to blood vessels are well nourished and rapidly proliferating but hypoxic cells located farther away are slowly-proliferating. Chemotherapy targets rapidly proliferating cells and therefore may spare hypoxic cells because of poor drug distribution to them. Intervals between administrations of chemotherapy allow normal tissues to recover but might also allow re-oxygenation and resumed proliferation of formerly hypoxic cells due to a better supply of nutrients to them. Tumor cell repopulation following radiation therapy is well-documented; but repopulation following chemotherapy and its effect on hypoxia has not been studied. Hypoxia activated pro-drugs (i.e. TH-302) may inhibit tumor repopulation by killing hypoxic cells. Here we evaluate repopulation following chemotherapy and the effect of TH-302 on changes in hypoxia over time in human tumor xenografts. Methods: Human breast (MCF7) tumor bearing mice were administered two specific markers of hypoxia (pimonidazole [pimo] and EF5). Hypoxia-labeled tumor cells were recognized in tumor sections (in relation to DioC7+ve functional tumor blood vessels) using immunohistochemistry. Proliferating cells were identified by an antibody to Ki67. Mice were treated with pimo and: saline, doxorubicin, TH-302 or TH-302 + doxorubicin; EF5 was given after a variable interval of 24, 48, 72, 96 or 120 hours and tumors collected. Changes in the hypoxia, proliferation and oxygen status of formerly hypoxic (pimo+ve) cells were quantified by their Ki67 status and uptake of EF5 as a function of time. Results: Following doxorubicin treatment, the proportion of hypoxic cells in the entire tumor decreased from 1.5% (pimo+ve) prior to injection to 0.7% (EF5+ve) at 24 hours. The percentage of pimo+ve formerly hypoxic cells that are no longer hypoxic (i.e. EF5 – ve) at 24 hours was 90% after doxorubicin compared to 27% in controls, indicating rescue of previous hypoxic cells that would have died in the absence of treatment. Proliferation of these pimo+ve cells that were cycling (Ki67+ve) increased from 7% to 15.0% at 24 hours and then slowly decreased. TH-302 + doxorubicin combination inhibited repopulation by reducing Ki-67 to 1%. Conclusions: Chemotherapy (doxorubicin) treatment paradoxically contributes to tumor treatment failure (tumor cell repopulation) at all time points investigated by causing formerly hypoxic cells to become oxygenated and proliferate above those levels found in the untreated control tumors. TH-302 treatment led to increased DNA damage and inhibited hypoxic cell proliferation and tumor repopulation, thereby increasing chemotherapeutic outcome. Supported by a research grant from the Canadian Institutes for Health Research. Citation Format: Jasdeep K. Saggar, Ian F. Tannock. Chemotherapy rescues hypoxic tumor cells and induces reoxygenation and repopulation - an effect that is inhibited by the hypoxia-activated pro-drug TH-302. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A51. doi:10.1158/1538-7445.CHTME14-A51
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».