A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia

Lévy, Vincent; Zohar, Sarah; Bardin, Christophe; Vekhoff, Anne; Chaoui, Driss; Rio, Bernard; Legrand, Olivier; Sentenac, S; Rousselot, Philippe; Raffoux, Emmanuel; Chast, François; Chevret, Sylvie; Marie, Jean‐Pierre

doi:10.1038/sj.bjc.6603265

Cited by 55 publications

(31 citation statements)

References 28 publications

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“…Although this drug has activity as a single agent in hematologic malignancies (40,41), it did not reduce the size of established solid tumors in clinical studies (42,43). Our report might provide an explanation for the lack of benefit of homoharringtonine in solid tumors.…”

Section: Discussionmentioning

confidence: 72%

A Chemical Screen Identifies Anisomycin as an Anoikis Sensitizer That Functions by Decreasing FLIP Protein Synthesis

et al. 2007

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Malignant epithelial cells with metastatic potential resist apoptosis that normally occurs upon loss of anchorage from the extracellular matrix, a process termed ''anoikis.'' Resistance to anoikis enables malignant cells to survive in an anchorage-independent manner, which leads to the formation of distant metastases. To understand the regulation of anoikis, we designed, automated, and conducted a high-throughput chemical screen for anoikis sensitizers. PPC-1 anoikisresistant prostate cancer cells were seeded in hydrogel-coated ultralow binding plates for suspension conditions and standard tissue culture plates to promote adhesion. After seeding, cells were treated with aliquots from a library of previously characterized small molecules, and viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt, assay. From this chemical screen, we identified anisomycin that induced apoptosis in suspension conditions, but was not toxic to these cells grown under adherent conditions. Anisomycin sensitized cells to anoikis by decreasing levels of the caspase-8 inhibitor FLIP and subsequently activating the death receptor pathway of caspase activation. Although anisomycin activated c-Jun-NH 2 -kinase and p38, these kinases were not functionally important for the effect of anisomycin on anoikis and FLIP. Rather, anisomycin decreased FLIP and sensitized cells to anoikis by inhibiting its protein synthesis. Finally, we showed that anisomycin decreased distal tumor formation in a mouse model of prostate cancer metastases. Thus, a novel chemical screen identified anisomycin as an anoikis sensitizer that acts by decreasing FLIP protein synthesis. Our results suggest that FLIP is a suppressor of anoikis and inhibiting FLIP protein synthesis may be a useful antimetastatic strategy. [Cancer Res 2007;67(17):8307-15]

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Section: Discussionmentioning

confidence: 72%

A Chemical Screen Identifies Anisomycin as an Anoikis Sensitizer That Functions by Decreasing FLIP Protein Synthesis

et al. 2007

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“…19 In a clinical trial in hematologic malignancies the maximal tolerated dose of HHT administered subcutaneously in AML was 5 mg/m 2 /day for 9 days, which generated mean peak plasma concentration of 96.1 Ϯ 20.3 ng/mL (176 Ϯ 37nM). 40 In CML clinical trials, the total dose of HHT used was 2.5 mg/m 2 /day, administered by subcutaneous injection twice daily for 7-14 days. This was well tolerated in each study and was subsequently shown to be active in patients with the T315I mutation of Bcr-Abl.…”

Section: Discussionmentioning

confidence: 99%

Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia

Chen

Guo²,

Chen³

et al. 2011

Blood

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IntroductionChronic lymphocytic leukemia (CLL) is characterized by the gradual accumulation of abnormal neoplastic B cells in the bone marrow and blood. Although the early asymptomatic stage of CLL does not require treatment, the more aggressive forms of the disease cannot be cured by current treatment options. Current first-line treatment for many patients with CLL incorporates a fludarabine-based combination therapy. 1 However, disease relapse invariably occurs after treatment has been discontinued, and almost all patients with CLL will ultimately develop refractory disease. Therefore, new agents targeting the molecular mechanisms of CLL disease progression are highly desired.Antiapoptotic proteins of the B-cell lymphoma-2 (Bcl-2) family are overexpressed in most cases of CLL, and this overexpression is correlated with resistance to therapy and a poor prognosis. 2 Among the Bcl-2 family proteins, myeloid cell leukemia-1 (Mcl-1) has emerged as a significant antiapoptotic protein that promotes the survival of CLL cells both in vitro and in vivo. 3 Mcl-1 acts by preventing the proapoptotic proteins Bak and Bax from disrupting the mitochondrial membrane and initiating apoptosis. 4 Approaches that reduce Mcl-1 levels in CLL cells by direct methods such as small interfering RNA (siRNA) 5 or through indirect approaches to inhibit Mcl-1 transcription resulted in cell death. 6,7 Because the inhibition of apoptosis by Bcl-2 family proteins has been recognized as a distinct oncogenic function, 8,9 agents that antagonize the actions or diminish the expression of antiapoptotic proteins have been developed to induce apoptosis in CLL cells. These compounds, including oblimersen, an antisense oligonucleotide targeting Bcl-2 mRNA, 10 or the BH3 mimetics that interfere with the interaction of the proapoptotic and antiapoptotic proteins of the Bcl-2 family 11,12 are currently in clinical trials for treating CLL. A third strategy takes advantage of the fact that the key antiapoptotic protein in CLL, Mcl-1, is intrinsically unstable. 13 Transient exposure to flavopiridol, roscovitine, or SNS-032, small molecules that block transcription by inhibiting Cdk9, diminishes Mcl-1 transcripts and protein, with the subsequent induction of apoptosis. 6,7,14 These compounds are currently in clinical trials for treating CLL and other B-cell malignancies, and transient exposure schedules have generated responses in fludarabine-resistant disease. 15,16 Because Mcl-1 is thought to function as an oncogene on which CLL cells depend for survival, the striking activities generated by transient exposure to these transcription inhibitors may be attributed to the diminished Mcl-1 levels. This encouraged us to explore inhibition of translation, the subsequent step in protein expression, as an additional approach to activate cell death processes. 17 Earlier studies of inhibitors of translation showed that cycloheximide (CHX) was cytotoxic to CLL cells in vitro 18 and that puromycin enhanced the cytotoxic activity of fludarabine in CLL cells. 19 Recently,...

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“…[25] Dans cet essai, cinq niveaux de dose étaient prévus au départ, et la dose maximale tolérée (5 mg.m −2 /jour soit le quatrième niveau de dose) a été définie après l'inclusion de 18 patients évaluables par cohortes de trois.…”

Section: Essais De Phase 1 De Recherche De Doseunclassified

Les méthodes adaptatives : quand et comment les utiliser dans les essais cliniques ?

2011

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Texte reçu le 8 avril 2011 ; accepté le 16 mai 2011Mots clés : analyse intermédiaire ; essais adaptatifs ; modification du plan d'expérience ; sélection de traitement Résumé -On définit les schémas adaptatifs pour les essais cliniques comme les schémas qui utilisent les données accumulées dans l'essai pour en modifier éventuellement certains aspects, sans compromettre la validité et l'intégrité de l'essai. Par rapport aux essais plus traditionnels, les schémas adaptatifs permettent en théorie de produire la même information, mais de manière plus efficiente. Les avantages et les limites de ce type de schémas ainsi que le poids des contraintes, notamment logistiques, liés à leur utilisation, diffèrent selon que l'essai est un essai exploratoire ou un essai confirmatoire, en vue d'un enregistrement. L'un des éléments importants pour garantir l'intégrité de l'essai est le recours à un comité indépendant pour déterminer les adaptations du plan d'expérience en cours d'essai. Les méthodes adaptatives pour les essais cliniques sont attrayantes et peuvent être acceptées par les autorités compétentes. Elles nécessitent cependant de bien mesurer à l'avance les contraintes qu'elles imposent.

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A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia

Cited by 55 publications

References 28 publications

A Chemical Screen Identifies Anisomycin as an Anoikis Sensitizer That Functions by Decreasing FLIP Protein Synthesis

A Chemical Screen Identifies Anisomycin as an Anoikis Sensitizer That Functions by Decreasing FLIP Protein Synthesis

Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia

Les méthodes adaptatives : quand et comment les utiliser dans les essais cliniques ?

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