Chemotherapy, but Not Bevacizumab, Increases Tissue Factor Activity Levels In Endothelial Cells, Blood Monocytes, and Non-Small Cell Lung Cancer Cells
Notice bibliographique
Résumé
Abstract Abstract 5117 Introduction: Venous Thromboembolism (VTE) is a complication commonly seen in patients with lung cancer. The risk of VTE is further increased in patients undergoing standard chemotherapy as well as anti-angiogenesis therapies such as bevacizumab. However, the molecular mechanisms between lung cancer, anti-cancer agents, and thrombosis remain poorly understood. In vitro studies suggest that treatment of endothelial cells with particular lung cancer chemotherapy drugs such as cisplatin, gemcitabine and paclitaxel promote coagulation through an increase in tissue factor (TF) activity. However, the effect of these drugs on non-small cell lung cancer cells and monocytes remains largely unknown. It is also unknown if blockage of VEGF function by bevacizumab affects TF activity in endothelial cells and A549 lung cancer cells, both of which express VEGFR-1 and VEGFR-2 receptors. Objective: The purpose of this study was to determine the effects of standard lung cancer chemotherapy agents cisplatin, carboplatin, paclitaxel and gemcitabine on TF activity levels on vascular endothelial cells, blood monocytes, and the non-small cell lung cancer cell line A549. We studied the effects of these chemotherapy agents individually as well as in established combination chemotherapy (cisplatin/gemcitabine and carboplatin/paclitaxel). We also studied the effects of the anti-angiogenesis agent bevacizumab on TF activity levels in endothelial cells and A549 cells. Methods: Human umbilical vein endothelial cells (HUVECs), blood monocytes, and A549 cells were exposed for 24 hours to clinically relevant concentrations of chemotherapy agents or bevacizumab. At the end of treatment time, cell surface TF activity was measured by the generation of factor Xa in the presence of factor VIIa and CaCl2 on drug-treated cells. Cell viability was examined by Trypan Blue exclusion assays. Factor Xa generation was adjusted to exclude non-viable cells (at most, 15% of the cells were non-viable after 24-hour exposure to the anti-cancer agents). Results: Treatment of all cell lines with single chemotherapy agents increased cell surface TF activity. The combinations of cisplatin/gemcitabine and carboplatin/paclitaxel on HUVECs resulted in synergistic and additive effects on TF activity levels, respectively. The increase in TF activity levels were observed in the absence of cell death. In contrast, treatment of HUVECs and A549ccells with bevacizumab did not affect TF activity levels on HUVECs and A549 cells. To confirm that chemotherapy-induced factor Xa generation was TF dependent, we repeated the same assay in the absence of factor VIIa, an essential component of the extrinsic tenase complex. Absence of factor VIIa resulted in no cell surface generation of factor Xa confirming that the generation of factor Xa is due to cell surface TF activity. Conclusions: Our studies are the first to explore the effects of chemotherapy agents on TF activity levels in A549 cells and monocytes, as well as the effects of bevacizumab on TF activity levels in endothelial cells and A549 cells. Our studies suggest that, unlike chemotherapy agents, bevacizumab does not induce a procoagulant phenotype on endothelial cells and A549 cells via the upregulation of TF activity. Disclosures: No relevant conflicts of interest to declare.
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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) | 0,002 | 0,000 |
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 ».