Retrovirus-mediated gene transfer in cancer therapy
ABSTRACT Retroviral vectors are one of the most promising systems for the transfer and the expression of therapeutic genes in human gene therapy protocols. This review will focus both on the advantages and intricacies of retroviral vectors themselves as well as on the application of these vector systems in experimental and clinical cancer therapy protocols. Therefore, the retrovirus life cycle and the general features of retroviral vectors, including possible targeting strategies with retroviral vectors, are overviewed. These topics are followed by the presentation of genes with emphasis on their potential as tools in somatic cell cancer therapy (cytokines, lymphokines, colony-stimulating growth factors, suppressor genes, antisense oncogenes, suicide genes). Finally, a prospect on the application of retroviral vectors will be described.
- SourceAvailable from: Michael Emerman[show abstract] [hide abstract]
ABSTRACT: Previously, we described "promoter suppression" in infectious retrovirus vectors with two genes and an internal promoter. Here, we examined several parameters of promoter suppression and found that the amount of suppression in an integrated retrovirus vector was dependent both on whether the vector was derived from spleen necrosis virus or murine leukemia virus and on which internal promoter was present in the vector. Murine leukemia virus vectors showed less suppression than analogous spleen necrosis virus vectors. Furthermore, the amount of suppression was not dependent on either the relative strengths of the promoters nor the distance between the promoters. Moreover, we found that in vectors in which one promoter was suppressed, there was an inverse correlation between the DNaseI sensitivity of the chromatin surrounding a promoter and the suppression of its expression.Nucleic Acids Research 01/1987; 14(23):9381-96. · 8.28 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: We have devised a sensitive means to assess the anti-tumor effect of cytokines that act via the mobilization of host-mediated defenses. This assay involves transfecting malignant cells to produce a specific cytokine (in this case, IL-4) and measuring the ability of transfectants to form tumors alone and when mixed with a variety of nontransfected tumor cells. In this way, we have identified a potent, non-cell autonomous, anti-tumor effect of IL-4 which is effective against a wide range of tumor cell types in vivo. The effect is reversed by anti-IL-4 antibody, correlates closely with levels of IL-4 production, and is evident in nu/nu mice. The anti-tumor effect seems to be mediated by an inflammatory infiltrate composed of eosinophils and macrophages.Cell 06/1989; 57(3):503-12. · 31.96 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: IL-2 gene was introduced through retroviral vectors into the highly malignant and poorly immunogenic 3LL-D122 clone. Both high and low D122-IL-2 secretors showed elimination of tumorigenicity in syngeneic immune-competent mice; however, in nude mice only the high IL-2 secretor showed reduced tumorigenicity as compared with parental D122 cells. Also, following intravenous inoculation, only the high IL-2 secretor showed reduced generation of metastases, whereas the low IL-2 secretors were as highly metastatic as parental cells. These results seem to indicate that low levels of IL-2 secreted by tumor cells are sufficient to activate T cells, while higher levels are needed in order to activate non-T-cell effectors. D122-IL-2 secretors induced high levels of anti-tumor CTL, while their sensitivity to the lytic activity of these CTL was similar to the sensitivity of D122 cells, thus indicating that the elevation of immunogenicity of IL-2 secretors was essentially due to the secreted IL-2. In accordance with CTL induction, pre-immunization with IL-2 secretors protected mice against subsequent challenge of parental cells. Moreover, immunization in an "immunotherapy protocol" i.e., vaccination of mice carrying an established tumor of parental D122 cells with inactivated D122-IL2 infectants, almost completely eliminated the generation of lung metastases by D122 cells, thus providing a rationale for the use of IL-2 gene transferred tumor cells as a modality for treatment of metastasis.International Journal of Cancer 03/1993; 53(3):471-7. · 6.20 Impact Factor