Antileukemic Effects of the Novel Agent Elesclomol.
Notice bibliographique
Résumé
Abstract Abstract 2736 Poster Board II-712 Elesclomol (N-malonyl-bis (N′-methyl-N′-thiobenzoyl hydrazide)) is an investigational first-in-class oxidative stress inducer that triggers apoptosis in cancer cells (Kirshner et al., Mol Cancer Ther 2008;7:2319–27). In the clinic, elesclomol is well tolerated in humans and showed activity in combination with paclitaxel in patients with refractory solid tumors (Berkenblit et al., Clin Cancer Res 2007;13:584–90). The aims of the current study are to examine the activity of elesclomol against a range of AML cell lines, including primary patient blast cultures, to investigate the mechanisms of drug action and the potential to combine elesclomol with other agents, and to identify candidate biomarkers for monitoring effects during treatment of leukemia patients with elesclomol. Here we describe the effects of elesclomol treatment in 4 AML cell lines selected based on their varying molecular attributes. Effects on cellular redox state and mitochondrial function were monitored using a flow cytometry incorporating the glutathione (GSH) probe monobromobimane, the reactive oxygen species (ROS) probe carboxy-dichlorofluorescin and the mitochondrial membrane potential stain DiIC(1)5. In addition, outer cell membrane integrity was determined by propidium iodide exclusion. Dual staining of fixed, permeabilized cells with phospho-specific antibodies to p38 and SAPK/JNK was used to determine if elesclomol treatment results in activation of the stress-activated MAP kinase pathways. Elesclomol showed potent anti-leukemic effects in vitro at concentrations as low as 10nM, which is well below the concentrations achieved in cancer patients, and greater toxicity was achieved with prolonged drug exposure. In OCI-AML2, a factor-independent, poorly differentiated AML cell line, toxicity was associated with loss of reduced GSH that coincided with a large increase in ROS generation and depolarization of the mitochondrial inner membrane, and later with loss of surface membrane integrity. A similar pattern was seen in OCI-M2, a p53-deficient erythroblastic leukemia cell line, except that during the early stages of drug effect these cells showed a large increase in reduced GSH, suggesting that initially they are able to compensate for drug-induced oxidative stress through enhanced cellular antioxidant production. In contrast, the factor-dependent line OCI-AML5, which appeared most sensitive to elesclomol, showed loss of outer membrane integrity without obvious prior oxidative stress while the Flt-3 ITD mutant line MV4-11 showed an initial loss of mitochondrial membrane potential without accompanying oxidative stress. Strikingly, we did not observe activation of the stress-responsive p38 or SAPK/JNK pathways in any of these 4 cell lines tested, suggesting that this is not a prominent response to elesclomol activity in AML and that additional mechanisms may be at work for the activity of elesclomol in these cells. Further investigations are ongoing and additional studies, including evaluation of elesclomol activity in primary leukemic cells from AML patients, will be presented. In summary, elesclomol is a potent novel compound that exerts anti-leukemic effects in tissue culture at drug concentrations that are well below those achieved in patients, suggesting that it might be active in leukemia patients. Disclosures: Chow: Synta Pharmaceuticals Inc.: Research Funding. Nagai:Synta Pharmaceuticals Inc.: Employment. He:Synta Pharmaceuticals Inc.: Employment. Blackman:Synta Pharmaceuticals Inc.: Employment, Equity Ownership. Barsoum:Synta Pharmaceuticals Inc.: Employment, Equity Ownership. Vukovic:Synta Pharmaceuticals Inc.: Employment, Equity Ownership. Hedley:Synta Pharmaceuticals Inc.: Research Funding.
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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 ».