Phase I study of obatoclax mesylate (GX15-070), a small molecule pan–Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia

O’Brien, Susan; Claxton, David F.; Crump, Michael; Faderl, Stefan; Kipps, Thomas J.; Keating, Michael J.; Viallet, Jean; Cheson, Bruce D.

doi:10.1182/blood-2008-02-137943

Cited by 245 publications

(198 citation statements)

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“…Gossypol induces the generation of reactive oxygen species, which may be responsible for the induction of cell death. 44 In vivo gossypol is known to cause male infertility, whereas obatoclax had been reported to induce both neurological symptoms in early clinical trials of patients with CLL as well as neuronal toxicity in mice, 25,45 which might be because of targets outside the BCL2 family. In this regard a recent study showed that obatoclax exerted growth inhibitory effects at lower concentrations than induction of apoptosis and suggested that obatoclax targeted other proteins in addition to BCL2 family members.…”

Section: Discussionmentioning

confidence: 99%

“…20 ABT-263, obatoclax and AT-101, the (À) enantiomer of gossypol, are in early clinical trials for lymphoid malignancies or solid tumors. [23][24][25] However, despite the use of these inhibitors in preclinical mechanistic studies, proof for their specificity for BCL2 proteins is limited. Specific inhibitors of BCL2 proteins should induce apoptosis in a BAX/BAK-dependent manner with subsequent release of cytochrome c and activation of caspase-9.…”

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confidence: 99%

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Different forms of cell death induced by putative BCL2 inhibitors

et al. 2009

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Several inhibitors of BCL2 proteins have been identified that induce apoptosis in a variety of tumor cells, indicating their potential in cancer therapy. We investigated the specificity of six putative BCL2 inhibitors (obatoclax, gossypol, apogossypol, EM20-25, chelerythrine and ABT-737). Using cells deficient either for Bax/Bak or caspase-9, we found that only ABT-737 specifically targeted BCL2 proteins and induced apoptosis by activation of caspase-9, as only ABT-737 induced apoptosis was completely inhibited in cells deficient for Bax/Bak or caspase-9. Our data show that only ABT-737 is a specific BCL2 inhibitor and all other compounds investigated were not specific for BCL2 proteins. Furthermore, investigations of the effects of these compounds in primary chronic lymphocytic leukemic cells showed that all compounds induced certain biochemical hallmarks of apoptosis, such as release of cytochrome c and caspase cleavage. However, they all caused strikingly different ultrastructural changes. ABT-737 induced all the characteristic ultrastructural changes of apoptosis together with early rupture of the outer mitochondrial membrane, whereas obatoclax, chlelerythrine and gossypol induced pronounced mitochondrial swelling with formation of phospholipid inclusions. Therefore, we conclude that biochemical measurements used earlier to define apoptosis like mitochondrial release of cytochrome c and caspase cleavage, are insufficient to distinguish between classic apoptosis and other forms of cell death.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Different forms of cell death induced by putative BCL2 inhibitors

et al. 2009

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“…Obatoclax (a BH-3 mimetic) has been investigated in a phase I clinical trial for advanced CLL, but its effect was limited. 30 Studies on AT-101 with rituximab showed some efficacy, resulting in partial remissions. 31,32 Therefore, there is a need to develop alternative Mcl-1 inhibitors perhaps in combination with Bcl-2/Bcl-xL inhibitors.…”

Section: Introductionmentioning

confidence: 99%

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

et al. 2015

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The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA), is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose-and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression.However, normal B and T cells were less sensitive than CLL cells (p=0.006 and p<0.001, respectively).

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“…Hemoglobin levels were increased in three patients which made them independent of blood transfusions. Also their www.impactjournals.com/oncotarget thrombocytopenia had slightly improved [44].…”

Section: Obatoclaxmentioning

confidence: 99%

Refractory chronic lymphocytic leukemia - new therapeutic strategies

Schnaiter

Stilgenbauer

2010

Oncotarget

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AbstrAct:Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy. Nevertheless, refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis. Important risk factors are 17p deletion and/or mutation of TP53. For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved. Meanwhile we have to face also refractoriness to alemtuzumab. Importantly, the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL. The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor. Further B-cell antigens are targeted by lumiliximab (CD23), TRU-016 (CD37) and blinatumomab (CD19). Apart from monoclonal antibody therapies, a great number of small molecules are examined for the treatment of refractory and relapsed CLL. Most of these agents aim to overcome apoptosis resistance in CLL cells or influence the microenvironment. Typical targets are regulators of the cell cycle and antiapoptotic molecules like the members of the Bcl-2 family. Up to now the most promising agents appear to be flavopiridol and lenalidomide among others.

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Phase I study of obatoclax mesylate (GX15-070), a small molecule pan–Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia

Cited by 245 publications

References 14 publications

Different forms of cell death induced by putative BCL2 inhibitors

Different forms of cell death induced by putative BCL2 inhibitors

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

Refractory chronic lymphocytic leukemia - new therapeutic strategies

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