Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity.

J Clin Oncol 2005 May 11;23(15):3404-11. Epub 2005 Apr 11.

Division of Hematology-Oncology, The Comprehensive Cancer Center, The Ohio State University, 433A Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA.

Purposes: Pharmacologic downregulation of Bcl-2, an antiapoptotic protein overexpressed in cancer, might increase chemosensitivity in acute myeloid leukemia (AML). Herein, we investigated the feasibility of this approach in untreated elderly AML patients by administering oblimersen sodium (G3139), an 18-mer phosphorothioate antisense to Bcl-2, during induction and consolidation treatments.

Patients And Methods: Untreated patients with primary or secondary AML (stratified to cohort 1 or 2, respectively) who were > or = 60 years received induction with G3139, cytarabine, and daunorubicin at one of two different dose levels (45 and 60 mg/m2) and, on achievement of complete remission (CR), consolidation with G3139 and high-dose cytarabine. An enzyme-linked immunosorbent assay (ELISA)-based assay was used to measure plasma and intracellular concentrations (IC) of G3139. Bcl-2 mRNA and protein levels were quantified by real-time reverse transcriptase polymerase chain reaction and ELISA, respectively, in bone marrow samples collected before induction treatment and after 72 hours of G3139 infusion, prior to initiation of chemotherapy.

Results: Of the 29 treated patients, 14 achieved CR. With a median follow-up of 12.6 months, seven patients had relapsed. Side effects of this combination were similar to those expected with chemotherapy alone and were not dose limiting at both dose levels. After 72-hour G3139 infusion, Bcl-2/ABL mRNA copies were decreased compared with baseline (P = .03) in CR patients and increased in nonresponders (NRs; P = .05). Changes in Bcl-2 protein showed a similar trend. Although plasma pharmacokinetics did not correlate with disease response, the median IC of the antisense was higher in the CR patients compared with NRs (17.0 v 4.4 pmol/mg protein, respectively; P = .05).

Conclusion: G3139 can be administered safely in combination with intensive chemotherapy, and the degree of Bcl-2 downmodulation may correlate with response to therapy.

Download full-text PDF

Source Listing
May 2005
Get 20% Off Journals at

Similar Publications

Drugs and Clinical Approaches Targeting the Antiapoptotic Protein: A Review.

Biomed Res Int 2019 29;2019:1212369. Epub 2019 Sep 29.

Department of Laboratory Medicine, Central Hospital of Panyu District, Guangzhou, Guangdong 511400, China.

B-cell lymphoma 2 (Bcl-2) is a regulator protein involved in apoptosis. In the past few decades, this protein has been demonstrated to have high efficacy in cancer therapy, and several approaches targeting Bcl-2 have been tested clinically (e.g. Read More

View Article and Full-Text PDF

Structural optimization and additional targets identification of antisense oligonucleotide G3139 encapsulated in a neutral cytidinyl-lipid combined with a cationic lipid in vitro and in vivo.

Biomaterials 2019 03 3;197:182-193. Epub 2019 Jan 3.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, No.38 Xueyuan Road, Haidian District, Beijing 100191, China. Electronic address:

Antisense oligonucleotides (ASOs) usually contain a fully phosphorothioate (PS) backbone, which possibly interact with many genes and proteins under intracellular conditions. G3139 is an ASO that targets Bcl-2 mRNA and induces cell apoptosis. Here, we report a kind of cytidinyl-lipid combined with a cationic lipid (DNCA/CLD, molar ration, 28:3, named mix), which may interact with oligonucleotides via H-bond formation, pi-stacking and electrostatic interaction, accompanied by low zeta potentials. Read More

View Article and Full-Text PDF

The Development and Current Use of BCL-2 Inhibitors for the Treatment of Chronic Lymphocytic Leukemia.

Curr Hematol Malig Rep 2017 02;12(1):11-19

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.

The BCL-2 family of proteins integrates pro- and anti-apoptotic signals within the cell and is responsible for initiation of caspase-dependent apoptosis. Chronic lymphocytic leukemia (CLL) cells are particularly dependent on the anti-apoptotic protein BCL-2 for their survival, making this an attractive therapeutic target in CLL. Several early efforts to create inhibitors of the anti-apoptotic family members faced significant challenges, but eventually, the BCL-2 specific inhibitor venetoclax moved forward in CLL. Read More

View Article and Full-Text PDF
February 2017

Lipid Nanoparticles Loaded with an Antisense Oligonucleotide Gapmer Against Bcl-2 for Treatment of Lung Cancer.

Pharm Res 2017 02 28;34(2):310-320. Epub 2016 Nov 28.

Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, 43210, USA.

Purpose: Bcl-2 is an anti-apoptotic gene that is frequently overexpressed in human cancers. G3139 is an antisense oligonucleotide against bcl-2 that has shown limited efficacy in clinical trials. Here, we report the synthesis of a new antisense oligonucleotide containing additional chemical modifications and its delivery using nanoparticles. Read More

View Article and Full-Text PDF
February 2017

Combined effect of G3139 and TSPO ligands on Ca(2+)-induced permeability transition in rat brain mitochondria.

Arch Biochem Biophys 2015 Dec 20;587:70-7. Epub 2015 Oct 20.

Institut für Neurobiochemie, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Leipziger Str. 44, 39120, Magdeburg, Germany. Electronic address:

Permeability of the mitochondrial outer membrane is determined by the activity of voltage-dependent anion channels (VDAC) which are regulated by many factors and proteins. One of the main partner-regulator of VDAC is the 18 kDa translocator protein (TSPO), whose role in the regulation of membrane permeability is not completely understood. We show that TSPO ligands, 1 μM PPIX and PK11195 at concentrations of 50 μM, accelerate opening of permeability transition pores (mPTP) in Ca(2+)-overloaded rat brain mitochondria (RBM). Read More

View Article and Full-Text PDF
December 2015