Biomedical subjects
Publications and source records attributed to R Vile.
Two recent studies that involve perturbing tumour blood supply provide new hope for anti-cancer therapies. The first uses elegant molecular engineering to achieve tumour-specific blood clots and the second reports the identification of a natural inhibitor, endostatin, which is produced from tumour extracellular matrix.
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Angiostatin, a recently discovered anti-angiogenic factor, offers the hope of long-term control of metastatic cancers following surgery.
Successful gene therapy requires not only the identification of an appropriate therapeutic gene for treatment of the disease, but also a delivery system by which that gene can be delivered to the desired cell type both efficiently and accurately. Reductions in accuracy will inevitably also reduce efficiency since fewer particles will be available for delivery to the correct cells if many are sequestered into nontarget cells. In addition, the therapy will have net benefit to the patient only if gene delivery is sufficiently restricted such that normal cells are left unaffected by any detrimental affects of bystander cell transduction. Here we review how currently available delivery systems, both plasmid and viral, can be manipulated to improve their targeting to specific cell types. Currently, targeting is achieved by engineering of the surface components of viruses and liposomes to achieve discrimination at the level of target cell recognition and/or by incorporating transcriptional elements into plasmid or viral genomes such that the therapeutic gene is expressed only in certain target cell types. In addition, we discuss emerging vectors and suggest how gene therapy delivery systems of the future will be composites of the best features of diverse vectors already in use.
Gene therapy for cancer relies upon the delivery of a therapeutic gene to a target cell population which may comprise either the tumour cells themselves or specific host effector cells with anti-tumour activity. In addition, gene delivery may be targeted directly to the tumour cells in vivo or towards cells explanted from the patient. The precise requirements of the delivery system depend upon the specific therapeutic strategy being used. In each case, however, delivery must be accurate, efficient and must result in correctly regulated expression of the gene in only the desired cell type. Equally important, the delivery system must be safe for both the patient and the community as a whole. Here, we summarize the types of gene therapy which have been proposed for the treatment of cancer and review how currently available delivery systems are suited to each of these individual strategies.
To target therapeutic genes specifically to melanoma cells, we have constructed recombinant retroviruses where transcriptional control of the murine interleukin-2 (mIL-2) or herpes simplex virus thymidine kinase (HSVtk) genes is provided by the 5' promoter region of the murine tyrosinase gene. Tissue-specific expression of these genes is observed both at the mRNA and protein levels in the B16 melanoma line compared with NIH3T3 fibroblasts. Thus, B16 cells infected with one such retrovirus containing the HSVtk gene exhibited a > 90% reduction in colony-forming efficiency after exposure to 1 microgram/ml ganciclovir, relative to controls, whereas similarly infected NIH3T3 cells showed < 10% reduction in colony-forming efficiency under comparable conditions. The degree of preservation of tissue-specific expression from the internal tyrosinase promoter depended upon the exact molecular design of the vector, possibly as a consequence of the interference between closely juxtaposed promoters within the provirus. Our results show that retroviral vectors can be prepared with the capacity to regulate expression of inserted genes specifically in a particular cell type and may be useful for developing efficient, targeted vectors for the in vivo delivery of genetic therapies for malignant melanoma.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.