Gene therapy of cancer

Gene therapy was initially thought of as a means to correct single gene def ects in hereditary disease. In the meantime, cancer has become by far the m ost important indication for gene therapy in clinical trials. In the forese eable future, the best way to achieve reasonable intratumoral concentration s of a transgene with available vectors is direct intratumoral injection wi th or without the aid of various techniques such as endoscopy or CT-guidanc e. At present, viral and non-viral methods of gene transfer are used either in vivo or ex vivo/in vitro. The most important viral vectors currently in us e in clinical trials comprise retroviruses, adenoviruses, adeno-associated viruses, and herpes viruses. None of the available vectors satisfies all th e criteria of an ideal gene therapeutic system, and vectors with only minim al residues of their parent viruses ("gutless vectors") as well as complete ly "synthetic viral vectors" will gain more and more importance in the futu re. Non-viral gene therapy methods include liposomes, injection of vector-f ree DNA ("naked DNA"), protein-DNA complexes, delivery by "gene gun," calci um-phosphate precipitation, electroporation, and intracellular microinjecti on of DNA. The first clinical trial of gene therapy for cancer was performed in 1991 i n patients with melanoma, and since then more than 5000 patients have been treated worldwide in more than 400 clinical protocols. With the exception o f a case of fatal toxicity in a young man with hereditary liver disease tre ated intrahepatically with high doses of adenovirus, side effects have been rare and usually mild in all these studies and expression of the transgene could be demonstrated in patients in vivo. However, despite anecdotal repo rts of therapeutic responses in some patients, unequivocal proof of clinica l efficacy is still lacking for most of the varied approaches: to gene ther apy in humans. As well as our only fragmentary understanding of the molecul ar pathophysiology of many diseases, the principal reason for the present l ack of clinical success of gene therapy is the very low transduction anti e xpression efficiency in vivo of available vectors. Despite the complexities of gene therapy for cancer, the numerous different approaches can be subdivided into three basic concepts: (1) strengthening of the immune response against a tumour, (2) repair of cell cycle defects c aused by losses of tumour suppressor genes or inappropriate activation of o ncogenes, and (3) suicide gene strategies. In addition, the importance of g ene marker studies and gene therapeutic protection of normal tissue are bri efly covered in this review.