Related Experiment Videos
Antisense therapy of hematologic malignancies
1Department of Experimental Hematology, St. Bartholomew Royal London School of Medicine, UK.
Abstract:
Many tumor cells are inherently resistant to curative treatment due to an altered pattern of gene expression. It is an attractive and logical proposition to use this difference within the lymphoma cell to eradicate the malignant process. One such new therapeutic approach based on the "silencing" of genes involved in the prevention of apoptosis is Bcl-2 antisense oligonucleotide (AO) therapy. In the field of lymphoma, obvious targets included follicular lymphoma with the t(15;18) translocation, which results in deregulated expression of the Bcl-2 gene, chemoresistance, and subsequent protection against lymphoma cell death. Targeting the initiating codon of the Bcl-2 gene decreases both cell viability and Bcl-2 protein expression in lymphoma and leukemia cell lines that overexpress Bcl-2. Preclinical toxicity studies using a Bcl-2 AO G3139 (Genta, San Diego, CA) show good tolerance at a dose of 10 mg/kg, which is considerably higher than the dose required for good antilymphoma efficacy. In a phase I clinical study, G3139 was well tolerated with minimal toxicity in a dose escalation up to 147.2 mg/m2/d. Evidence of efficacy includes a responder with stage IVB follicular lymphoma who achieved complete clinical and radiologic response that has lasted more than 2 years. The main dose-limiting toxicity has been reversible thrombocytopenia related to the thioate backbone. Other antisense reagents are also in development to combat non-Hodgkin's lymphoma (NHL). These include oligonucleotides that target the messages of the Bcl-X(L) and protein kinase-Calpha (PKCalpha) genes. AOs may also have an application in tumors expressing mutant p53. AOs against MDM2 genes have shown the ability to restore wild-type p53 expression, suggesting that as oncogenic pathways are unraveled, normal cell growth and death patterns may be restored by molecular manipulation. Downregulation of antiapoptosis by AOs in the human setting has low toxicity and antilymphoma activity in cases in which conventional chemotherapy has failed. In the future, antisense therapy followed by chemotherapy may overcome chemoresistance to provide effective therapy for a range of malignancies.
Insights
Bcl-2 antisense oligonucleotide (AO) therapy targets gene expression in lymphoma cells, showing efficacy and low toxicity. This approach offers a promising new treatment for refractory lymphomas and other malignancies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tumor cells often exhibit inherent resistance to treatment due to altered gene expression.
- Targeting specific genes like Bcl-2 offers a strategy to eradicate malignant cells by exploiting these differences.
Purpose of the Study:
- To evaluate the efficacy and safety of Bcl-2 antisense oligonucleotide (AO) therapy in lymphoma.
- To explore the potential of AO therapy in overcoming chemoresistance and treating refractory malignancies.
Main Methods:
- Utilized Bcl-2 antisense oligonucleotide (AO) therapy, specifically G3139, to target the Bcl-2 gene.
- Conducted preclinical toxicity studies and a Phase I clinical trial with dose escalation.
- Investigated AOs targeting Bcl-X(L), protein kinase-Calpha (PKCalpha), and MDM2 genes.
Main Results:
- G3139 demonstrated good tolerance in preclinical studies and was well-tolerated with minimal toxicity in a Phase I clinical trial.
- A complete clinical and radiologic response lasting over 2 years was observed in a patient with stage IVB follicular lymphoma.
- Reversible thrombocytopenia was identified as the main dose-limiting toxicity.
Conclusions:
- Downregulation of antiapoptotic genes using AOs shows low toxicity and significant antilymphoma activity, particularly in cases resistant to conventional chemotherapy.
- AO therapy holds promise for overcoming chemoresistance and may be combined with chemotherapy for effective treatment of various malignancies.
- Further development of antisense reagents targeting other genes (Bcl-X(L), PKCalpha, MDM2) is ongoing for non-Hodgkin's lymphoma and other cancers.