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Updated: Jul 8, 2026
Examining BCL-2 Family Function with Large Unilamellar Vesicles
Published on: October 5, 2012
Chemosensitisation of malignant melanoma by BCL2 antisense therapy
B Jansen1, V Wacheck, E Heere-Ress
1Department of Dermatology, University of Vienna, Vienna General Hospital, Austria. burkhard.jansen@univie.ac.at
Background:
Chemoresistance of malignant melanoma has been linked to expression of the proto-oncogene BCL2. Antisense oligonucleotides (ASO) targeted against BCL2 mRNA decreased BCL2 protein concentrations, increased tumour-cell apoptosis, and led to tumour responses in a mouse xenotransplantation model when combined with systemic dacarbazine. This phase I-II clinical study investigated the combination of BCL2 ASO (augmerosen, Genasense, G3139) and dacarbazine in patients with advanced malignant melanoma expressing BCL2.
Methods:
In a within-patient dose-escalation protocol, 14 patients with advanced malignant melanoma were given augmerosen intravenously or subcutaneously in daily doses of 0.6-6.5 mg/kg plus standard dacarbazine treatment (total doses up to 1000 mg/m2 per cycle). Toxicity was scored by common toxicity criteria. Plasma augmerosen concentrations were assayed by high-performance liquid chromatography. In serial tumour biopsy samples, BCL2 protein concentrations were measured by western blotting and tumour-cell apoptosis was assessed.
Findings:
The combination regimen was well tolerated, with no dose-limiting toxicity. Haematological abnormalities were mild to moderate. Lymphopenia was common, but no febrile neutropenia occurred. Higher doses of augmerosen were associated with transient fever. Four patients had liver-function abnormalities that resolved within 1 week. Steady-state plasma concentrations of augmerosen were attained within 24 h, and increased with administered dose. By day 5, daily doses of 1.7 mg/kg and higher led to a median 40% decrease in BCL2 protein in melanoma samples compared with baseline, concomitantly with increased tumour-cell apoptosis, which was greatly increased after dacarbazine treatment. Six patients have shown antitumour responses (one complete, two partial, three minor). The estimated median survival of all patients now exceeds 12 months.
Interpretation:
Systemic administration of augmerosen downregulated the target BCL2 protein in metastatic cancer. Such downregulation of BCL2, combined with standard anticancer therapy, offers a new approach to the treatment of patients with resistant neoplasms.
Insights
This study shows that combining augmerosen (BCL2 antisense oligonucleotide) with dacarbazine effectively reduces BCL2 protein in advanced melanoma patients, leading to tumor responses and improved survival.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Malignant melanoma chemoresistance is linked to BCL2 proto-oncogene expression.
- Antisense oligonucleotides (ASO) targeting BCL2 mRNA reduce BCL2 protein and enhance apoptosis.
- Preclinical models showed BCL2 ASO combined with dacarbazine induced tumor responses.
Purpose of the Study:
- Investigate the safety and efficacy of combining BCL2 ASO (augmerosen) with dacarbazine.
- Evaluate BCL2 protein downregulation and tumor cell apoptosis in patients with advanced melanoma.
Main Methods:
- Phase I-II clinical study with 14 advanced melanoma patients.
- Dose-escalation of augmerosen (0.6-6.5 mg/kg) combined with dacarbazine.
- Assessed toxicity, plasma augmerosen levels, BCL2 protein expression, and tumor apoptosis.
Main Results:
- The combination was well-tolerated with no dose-limiting toxicity.
- Augmerosen doses of 1.7 mg/kg and higher decreased BCL2 protein by 40% and increased apoptosis.
- Six patients showed anti-tumor responses, and median survival exceeded 12 months.
Conclusions:
- Systemic augmerosen effectively downregulates BCL2 protein in metastatic melanoma.
- Combining BCL2 ASO with standard chemotherapy offers a novel treatment strategy for resistant neoplasms.
