f one considers the purpose of a drug to be to restore normal function of some particular process in the body, then DNA would be considered to be the ultimate drugโฆ' The foundations of molecular medicine rest squarely on Watson and Crick's discovery of the structure and function of DNA. This and the subsequent discovery of mRNA has led to the formulation of the 'central dogma' that dictates the flow of genetic information from DNA to RNA to protein. Aberrations along this pathway can manifest as clinical disorders. Morbidity and mortality rates for a variety of malignant cancers, autoimmune and metabolic disorders have only marginally improved over the past 15 or so years and care for patients is frequently palliative rather than curative. This has prompted the development of several alternative, so called 'biological' strategies (reviewed in Refs 1-5), one of which is somatic gene therapy. This discipline combines molecular biology, classical genetics and pharmacotherapeutics to manipulate the genomic composition of a target cell with the aim of correcting an inherited or acquired defect. The potential range of disorders that is amenable to this form of therapy is vast, resulting in the development of different strategies. Therapeutic efficacy is dependent on judicious consideration of several factors that are common to all of these strategies. These include: (1) choice of target cell type(s); (2) a suitable tissuespecific delivery system; (3) high transfection rate; (4) a suitable promoter/enhancer sequence for sustained and optimal gene expression; and (5) a means for controlling the level of gene expression. Suicide gene therapy is one such strategy that uses the principle of inserting a socalled 'suicide gene' into the target genome. This gene encodes for an enzyme that converts an inactive prodrug into its cytotoxic metabolite(s) so that, upon introduction of the prodrug, the target cell effectively is compelled to commit suicide.
Evolving methods of gene delivery
Several techniques have been developed for transferring genes across the cell membrane (Table 1), many of which are applicable to suicide gene therapy (reviewed in Refs 6, 7). These can be categorized as: (1) physical methods for disrupting the target cell membrane by mechanical or electrical means; (2) chemical methods that employ a variety of non-liposome and liposome-based facilitators;
(3) recombinant viral vectors developed from early systems that are based on manipulation of the papilloma simian virus SV40; and (4) packaging cell lines that have been engineered to create a chimeric genome by incorporating genes that encode for viral envelope proteins. Transfection with a vector construct that contains the appropriate long terminal repeats (LTRs), packaging sequence and suicide gene (Fig. 1) results in the formation of virions that are then used to infect target cells.
53 Burlingham, W.