Future applications of cancer genetics chemosensitivity and gene therapy

Aside from the applications of genetic screening in the small number of familial cancers, genetic technologies will have more and more applications in the research and treatment of cancer. By defining the genetic abnormalities and alterations in specific types of cancer, we have massively increased our understanding of how these tumours develop, helping us to understand how to target and fight them, and at the same time discovering new drug targets. The closer that specific tumour cells have been studied, the more genetic abnormalities and differences in their genetic profile have been discovered, even in cells that are supposedly from the same tumour type. Techniques such as DNA microchips are allowing us simultaneously to profile many of the genetic changes from tumour to tumour. The more we understand how certain tumours with certain molecular profiles behave, the more we will be able specifically to tailor treatments for them. Eventually we will be able to tailor specific drug regimens for specific tumours, minimizing drug resistance and side effects.

Ultimately the best way of treating a cancer would be to find a way of genetically modifying the tumour cells, correcting the genetic defect. This technique is known as 'gene therapy', and currently much research is going into potential mechanisms for delivering genes to target cells, inhibiting the expression of specific genes and correcting genetic defects. This technology is a still a long way from becoming a useful clinical treatment, but has such great potential for the future that it has to be discussed here. There have been several potential gene delivery systems discovered to date, and potential vectors currently being studied include attenuated DNA and RNA viruses that integrate part of their genome (containing the target gene) into a target cell. These viruses have had most of their viral genes removed to stop them replicating, but there are still safety and immunological problems with the technique. Non-viral vectors that avoid these problems are also currently in development, including liposome vector systems, but these have a lower efficiency of gene transfer and do not integrate genes into the chromosome, so gene expression is for a shorter duration (Strachan and Read, 1999).

Recessive monogenic disorders are the most amenable diseases to be treated with this technique, because only small amounts of introduced gene product can potentially have an effect. Trials have been carried out on diseases including adenosine deaminase deficiency (ADA), cystic fibrosis and familial hypercholesterolaemia. The use of gene therapy technologies to treat cancers is potentially more complicated, because a cancer cell can have several different genes mutated. Tumour cells are constantly being selected against, and evolve resistance to, various treatments, so similar problems would need to be overcome if this technique was used as a cancer therapy. Different strategies have been tested in cancers including pancreatic cancer (Halloran et al., 2000). Strategies have included the addition of copies of working tumour suppressor genes, and techniques that attempt to enable targeted cell death. This works by the genetic introduction into the tumour of an enzyme that can convert non-toxic drug precursors into toxic forms that will selectively kill the tumour cells without any side effects. More research is needed to improve the targeting of this technology, and increase the efficiency, gene uptake and safety, but despite these problems gene therapy has enormous potential for the future of medicine.

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