Protides of 5-Fluorotroxacitabine Display Potent Anti-Proliferative Properties and Circumvent Deoxycytidine Kinase-Mediated Resistance Associated with Cytotoxic Cytidine Analogues; A Novel Approach for Acute Myeloid Leukemia
Notice bibliographique
Résumé
Abstract The cytotoxic nucleoside cytarabine forms the backbone of AML induction and consolidation therapies, but is associated with severe toxicities that preclude its use in patients unable to tolerate aggressive chemotherapy. Options for patients that do not respond to cytarabine, or relapse post-treatment, are limited. Elderly patients and those with relapsed/refractory AML would particularly benefit from the availability of new agents to develop treatment regimens that provide increased efficacy and tolerability compared to cytarabine, and that have a decreased susceptibility to mechanisms of cytarabine resistance, such as decreased deoxycytidine kinase (dCK) and/or upregulation of cytidine deaminase (CDA). Our preclinical evaluation of potential new anti-proliferative chemotherapeutics identified 5-fluorotroxacitabine (5FTRX), a chain-terminating cytidine-based L-nucleoside, as having promising anti-proliferative activity against AML cell lines, and resistance to degradation by CDA. To understand potential mechanisms of resistance to 5FTRX, we selected a population of THP1 (THP1-R) cells resistant to 5FTRX. THP1-R cells were 66-fold resistant to 5FTRX and cross resistant to cytarabine (35-fold) with CC50 values for both nucleosides >50 μM. We discovered that THP1-R cells had decreased levels of dCK (>95% by Western blot), the kinase responsible for the phosphorylation of cytidine and cytidine analogues such as troxacitabine and cytarabine to their corresponding monophosphates. Confirming the importance of dCK in the activation of 5FTRX and cytarabine, chemical inhibition of dCK also rendered THP1 cells >90-fold resistant to 5FTRX and cytarabine. To develop molecules that overcome resistance to both high CDA and low dCK, we used protide technology to construct nucleotide monophosphate prodrugs of 5FTRX, including one potent example, MV806. MV806 was not dependent upon dCK as it maintained similar efficacy in THP1-R cells with low dCK and against THP1 cells treated with the selective dCK inhibitor. We tested MV806 and 5FTRX in a panel of AML cell lines (n=7). MV806 was more potent than 5FTRX with CC50 values ranging from 0.0020-0.19 μM, compared to 0.057-1.2 μM for 5FTRX. MV806 also demonstrated CC50s <0.1 μM against selected T- and B-cell lymphoma cell lines (e.g. MOLT4 and RAJI). Increased in vitro potency of this prodrug compared to 5FTRX correlated with elevated intracellular triphosphate levels in AML cells; MV806 generated 5-fold more triphosphate than 5FTRX in MV4-11 cells. We also tested MV806 in combination with doxorubicin or azacytidine in two AML cell lines (MV4-11 and THP-1). In both tested cell lines, strong synergy was observed (Bliss independence analysis synergy volumes >100), demonstrating future opportunities for clinical combinations. Finally, we showed that MV806 had DMPK profiles suitable for preclinical and clinical development. Leading protides were highly soluble, had a predicted half-life of >6h in human blood and demonstrated IC50 values >1 μM against major CYP isoforms (2A6, 2C9, 2D6, 3A4) with no evidence of time-dependent inhibition at 1 μM. To conclude, we used protide technology to directly deliver the active monophosphate species of 5FTRX intracellularly and thereby overcome resistance to cytarabine due to down-regulation of dCK and increased CDA expression. Taken together, our findings support the further development of protides of 5FTRX for the treatment of AML, including AML patients with reduced sensitivity to cytarabine through high CDA expression and/or low dCK expression. Disclosures Pinho: Medivir AB: Employment, Equity Ownership. Kylefjord:Medivir AB: Employment, Equity Ownership. Rraklli:Medivir AB: Employment. Rydergård:Medivir AB: Employment, Equity Ownership. Rizoska:Medivir AB: Employment, Equity Ownership. Eneroth:Medivir AB: Employment, Equity Ownership. Bylund:Medivir AB: Employment, Equity Ownership. Moses:Medivir AB: Employment, Equity Ownership. Norin:Medivir AB: Employment, Equity Ownership. Bethell:Medivir AB: Employment, Equity Ownership. Schimmer:Otsuka Pharmaceuticals: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy; Medivir AB: Research Funding. Albertella:Medivir AB: Employment, Equity Ownership. Targett-Adams:Medivir AB: Employment, Equity Ownership.
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) | 0,001 | 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 ».