The role of the bystander effect in suicide gene therapy

In recent years, a combination of cytogenetic and molecular techniques has allowed the identification of the precise genetic alterations that underlie the stepwise progression to malignancy. This is particularly true of colorectal carcinoma, and the genetic events associated with key stages in the clonal progression, from normal colonic mucosa through early and late adenomatous changes to localised malignancy, have been clearly identified. Attempts have been made to exploit this knowledge to develop new therapeutic strategies for the treatment of patients with cancer, and a number of experimental approaches to 'cancer gene therapy' have been described. These include strategies designed to suppress the expression of an oncogene or to restore the function of a defective tumour suppressor gene. Alternative approaches involve either strategies designed to enhance an antitumour immune response or the insertion of genes conferring drug resistance or drug sensitivity. The identification and precise sequencing of oncogenes has led to the development of antisense strategies for cancer gene therapy. These therapies aim to suppress the expression of a specific oncogene. Antisense oligonucleotides are short sequences of RNA that are complementary to cellular mRNA oncogene transcripts. Antisense transcripts bind to oncogene mRNA and thereby inhibit mRNA translation. In several in vitro models, this has resulted in the inhibition of proliferation and reversal of the malignant phenotype. Mutations of tumour suppressor genes also contribute to the development of malignancy. Indeed, mutation of the tumour suppressor gene TP53 is the most common genetic alteration in human malignancy. One of the prime functions of wild-type TP53 is thought to be the prevention of DNA damage accumulation and chromosomal instability that may predispose tumour formation. A further approach to cancer gene therapy, therefore, involves the restoration of a defective tumour suppressor gene. In vitro, the transduction of wild-type TP53 has been shown to arrest the growth of a colorectal carcinoma cell line and in vivo, wild-type TP53 has prevented tumour growth and led to the regression of established tumours. However, there are a number of problems associated with these therapies. Perhaps the most obvious is that it may be necessary to genetically modify each individual malignant cell within a tumour in order to achieve a therapeutic effect. This is an unrealistic prospect given the efficiency of