Cell Based Assays Completed with the Mantle Cell Lymphoma Cell Lines Z138 and NCEB-1 Indicate That Combinations of Bortezomid and Flavopiridol Interact To Achieve Synergistic Activity.
Notice bibliographique
Résumé
Abstract Mantle cell lymphoma (MCL) has the poorest long-term survival of all the lymphoma subtypes. CHOP-like regimens currently represent the standard of care for individuals with MCL, but traditional chemotherapeutic regimens do not elicit disease free survival times that are comparable to other sub classes of B-cell lymphomas. Median survival rate of a MCL patient still is approximately 3 years. Therefore new, targeted therapeutics are needed to improve the clinical outcome of MCL. The aim of the study was to identify and characterize combination effects achieved when flavopiridol, a Cyclin D1 inhibitor, and bortezomib, a proteosome inhibitor, are used in a combination setting together or with other agents contained in the CHOP regimen. Two MCL cell lines, Z138 and NCEB-1, were tested for cytotoxicity of drugs alone and in combinations, where alamar blue was used to assess cell viability. The resulting data were analyzed by using the median effect principle introduced by Chou and Talalay. In addition, mechanisms governing measured cytotoxic effects and combination effects were studied by DNA staining (propidium iodine), Caspase 3/7 activation and by western analysis of cyclinD1, NfkB, Bcl-xl, Bax and Bcl-2. The combination of bortezomib and flavopiridol was found to be synergistic in both cell lines studied. Synergistic interactions were dependent on drug-to-drug ratio. In NCEB-1, a ratio 1:12000 (bortezomib:flavopiridol) determined based on the IC90 of each of the individual agents showed synergy over a broad range of fa values (representing the fraction of affected cells). At ratios based on the IC10 and IC50 of the agents when used alone produced effects that were estimated to be antagonistic by the median effect principle. In the Z138 cell line, drug to drug ratios based on the individual agent IC50 and IC90 resulted in synergistic interactions. Consistent with the objective of identifying synergistic combinations, a clear dose reduction was observed to achieve a given therapeutic goal (e.g. 90% cell kill). 10-fold less bortezomib and 55-fold less flavopiridol would be required to achieve 90% cell death/cytostasis based on addition of the agents alone. Mechanistic studies showed that bortezomib in the combination and alone activated the caspase-dependent apoptotic pathway. The combination of bortezomib and flavopiridol for treatment of MCL would appear to an appropriate choice for clinical evaluation, however novel strategies must be developed in order to insure that combination effects observed in cell based screening assays are capture in patients. In this regard it is important to consider drug-drug ratio effects as well as combination engendered toxicities, both parameters that can be evaluated through careful pharmacodynamic assessments in well defined animal models of MCL.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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) | 0,000 | 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 tête enseignante, 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 ».