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[Gene therapy using anticancer drug-resistance genes]
1Division of Experimental Chemotherapy, Japanese Foundation for Cancer Research, Tokyo, Japan.
Abstract:
Myelosuppression is a major dose-limiting factor in cancer chemotherapy. Introduction of drug-resistance genes into bone marrow cells of cancer patients has been proposed to overcome this limitation. In theory, any gene whose expression protects cells against the toxic effects of chemotherapy should be useful in vivo for this purpose. Among such genes, human multidrug-resistance gene (MDR1) has been studied most extensively for this purpose, and clinical trials of drug-resistance gene therapy have been started in the US for cancer patients who undergo high-dose chemotherapy with autologous hematopoietic stem cell transplantation. In Japan, our clinical protocol of MDR1 gene therapy "A clinical study of drug-resistance gene therapy to improve the efficacy and safety of chemotherapy against breast cancer" has been submitted to the government. To improve the efficacy and safety of this drug-resistance gene therapy, we have constructed a series of MDR1-bicistronic retrovirus vectors using a retrovirus backbone of Harvey murine sarcoma virus and internal ribosome entry site (IRES) from picornavirus to co-express a second gene with the MDR1 gene. MDR1-MGMT bicistronic vectors can be used to protect bone marrow cells of cancer patients from combination chemotherapy with MDR1-related anticancer agents and nitrosoureas. In addition, MDR1-bicistronic retrovirus vectors can be designed to use the MDR1 gene as an in vivo selectable marker to enrich the transduced cells which express therapeutic genes, if disease is curable by the expression of a single-peptide gene in any types of bone marrow cells or peripheral blood cells.
Insights
Drug resistance gene therapy using MDR1-bicistronic retrovirus vectors can protect bone marrow cells from chemotherapy. This approach aims to improve cancer treatment efficacy and safety by enhancing drug resistance.
Area of Science:
- Biotechnology
- Molecular Biology
- Cancer Research
Context:
- Myelosuppression is a significant limitation in cancer chemotherapy, impacting treatment efficacy and patient safety.
- Drug resistance gene therapy offers a potential strategy to mitigate chemotherapy-induced toxicity.
- The human multidrug-resistance gene (MDR1) is a key candidate for conferring drug resistance in hematopoietic stem cells.
Purpose:
- To develop novel MDR1-bicistronic retrovirus vectors for enhanced drug resistance gene therapy.
- To co-express the MDR1 gene with therapeutic genes using an internal ribosome entry site (IRES).
- To improve the safety and efficacy of chemotherapy for cancer patients.
Summary:
- Constructed MDR1-bicistronic retrovirus vectors using Harvey murine sarcoma virus and picornavirus IRES.
- These vectors enable co-expression of MDR1 and a second gene, such as MGMT, for protection against specific chemotherapies.
- MDR1-bicistronic vectors can also serve as an in vivo selectable marker for enriching gene-modified cells.
Impact:
- Potential to protect bone marrow cells from combination chemotherapy, including MDR1-related agents and nitrosoureas.
- Facilitates the development of more effective and safer cancer treatment regimens.
- Enables enrichment of gene-transduced cells for therapeutic gene expression, potentially applicable to various cancers.