Synergistic Activity of the Novel Src/Abl Inhibitor Bosutinib in Combination with Imatinib.
Notice bibliographique
Résumé
Abstract The oncogenic fusion protein Bcr-Abl is the underlying cause of Chronic Myeloid Leukemia (CML), and it is present in up to 35% of Acute Lymphoblastic Leukemia (ALL). The discovery of a selective Abl inhibitor, Imatinib mesylate, has revolutionized the treatment of CML. Recently, several new inhibitors have been developed with the aim of increasing both potency and selectivity against Abl. Bosutinib (SKI-606, Wyeth) is a dual Src/Abl inhibitor that showed an in vitro activity in the low nanomolar range on several BCR-ABL positive cells and it is, at present, in phase II clinical trials. Bosutinib is devoid of activity against some known “off-target” kinases blocked by imatinib, such as PDGFR and c-Kit. In addition structural and modelling data attribute to Bosutinib the ability to bind Bcr-Abl in the intermediate/active conformation, while Imatinib is able to bind only the inactive conformation of Bcr-Abl. In this study we analyzed in vitro the combination of Imatinib and Bosutinib in Bcr-Abl expressing cell lines to evaluate the possibility to decrease dosage of both drugs, increasing or maintaining the same efficacy but avoiding toxic effects. Combination effects were evaluated according to the method of Chou and Talalay, in which the combination index (CI) value is calculated for a combination of two drugs and allows the quantification of synergism: CI <1, =1 or >1 indicate synergistic, additive or antagonistic interactions, respectively. Proliferation assays on a panel of Imatinib-sensitive and Imatinib-resistant BCR-ABL positive cell lines were performed. Cells were treated with Imatinib and Bosutinib as single agents or in three ratio combinations (1:3, 1:10, 1:33 in favour to Imatinib) across a wide range of concentrations. Combination indexes (CI) calculated at IC50, IC75 and IC90 for K562 cells (Imatinib-sensitive), suggest a synergistic to very strong synergistic effect (CI= 0.01-0.53). Similarly, in KCl22, KU812 and Lama84 cells (Imatinib-sensitive) moderate to strong synergistic effects were observed. A slight to moderate synergism was also obtained in three Imatinib-resistant cell lines tested: Lama84R (CI=0.63-0.88), K562R (CI=0.63-0.82) and KCL22R (CI=0.62-0.92). Western blot analysis of the tyrosine phosphorylation status of K562S cells treated with a mixture of 100nM Imatinib and 10nM Bosutinib revealed a substantially more pronounced inhibition compared with either 100nM Imatinib or 10nM Bosutinib alone. The effect of the combination was also assessed in murine Ba/F3 cells transfected with either wild type (WT) or mutated forms of BCR-ABL. Parental Ba/F3 cells were not affected by the presence of both drugs, while in Ba/F3 BCR-ABL WT the CI ranged from 0.49 to 0.85, indicating moderate synergism. The combination of Imatinib and Bosutinib inhibited the growth of Ba/F3 BCR-ABL Y253F with a slight synergism (CI 0.77-0.87). No synergistic effect was observed on Ba/F3 BCR-ABL E255K and on the highly resistant T315I mutant. Fresh leukemic cells obtained from three CML patients were also studied. In these samples synergistic effects between Bosutinib and Imatinib were confirmed (CI=0.52, 0.73, 0.62). The different binding modes of Imatinib and Bosutinib may justify the synergistic effect observed in the CML lines. This results support a possible therapeutic advantage for the combination of Bosutinib and Imatinib against Philadelphia positive leukemias.
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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) | 0,001 | 0,000 |
| Bibliométrie | 0,001 | 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) | 0,001 | 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 ».