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Gene transfer of drug resistance genes. Implications for cancer therapy
M M Gottesman1, U A Germann, I Aksentijevich
1Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Abstract:
Two general approaches to the gene therapy of cancer have been proposed: (1) strategies that use exogenous genes to modify cancer cells so that they are less malignant or more susceptible to host defenses or to killing by exogenous agents; and (2) approaches that modify host cells so that they are more effective in eliminating cancer cells or more resistant to agents that are used to treat cancer. In both cases, the development of vectors that encode in vivo selectable phenotypes, such as drug resistance, would be extremely valuable because of the inherent inefficiency of gene transfer and the potential of such vectors to protect normal tissues against toxic agents. To allow the selection of cells in vivo that have been transduced with vectors for gene therapy, we have utilized the human multidrug resistance (MDR1) gene. The product of this gene is a 170,000-dalton glycoprotein known as P-glycoprotein, which acts as an energy-dependent efflux pump for a great many cytotoxic anticancer drugs, including doxorubicin, daunorubicin, etoposide, teniposide, actinomycin D, and taxol. Vectors encoding an MDR1 cDNA are able to transduce many cell types, including bone marrow cells, with high efficiency to allow selection of drug resistance in vitro and in vivo in mouse models. Thus, it should be possible to protect the bone marrow of patients undergoing intensive chemotherapy by transduction of their bone marrow with MDR1 vectors. Furthermore, the ability to select for the presence of the MDR1 cDNA in vivo means that it can be used to introduce otherwise nonselectable genes into the bone marrow for therapy of cancer and other diseases.
Insights
Gene therapy for cancer can be improved using the multidrug resistance (MDR1) gene. This gene confers drug resistance, enabling selection of modified cells for enhanced cancer treatment and protection of healthy tissues.
Area of Science:
- Molecular Biology
- Cancer Genetics
- Gene Therapy
Background:
- Gene therapy for cancer involves modifying either cancer cells or host cells.
- Efficient gene transfer and in vivo selection are critical challenges in gene therapy.
- Drug resistance phenotypes are valuable for selecting transduced cells and protecting normal tissues.
Purpose of the Study:
- To utilize the human multidrug resistance (MDR1) gene for developing selectable gene therapy vectors.
- To demonstrate the efficacy of MDR1 gene transfer for conferring drug resistance in vitro and in vivo.
- To explore the potential of MDR1 vectors for protecting bone marrow during chemotherapy and for introducing other therapeutic genes.
Main Methods:
- Employed vectors encoding the human multidrug resistance (MDR1) gene cDNA.
- Transduced various cell types, including bone marrow cells, with MDR1 vectors.
- Evaluated drug resistance in vitro and in vivo using mouse models.
Main Results:
- MDR1 gene vectors efficiently transduced target cells, including bone marrow.
- Transduced cells exhibited resistance to multiple cytotoxic anticancer drugs (e.g., doxorubicin, taxol).
- Demonstrated successful selection of drug-resistant cells in vivo in mouse models.
Conclusions:
- The MDR1 gene is a valuable tool for creating selectable gene therapy vectors.
- MDR1 gene transfer can protect bone marrow from chemotherapy toxicity.
- MDR1 vectors facilitate the introduction of nonselectable therapeutic genes for various diseases.