Gene therapy and gastrointestinal cancer: concepts and clinical facts

Background: Principles of the treatment of gastrointestinal cancer with gen e therapy evolved from the advent of techniques in molecular biology, from increasing insights into the molecular basis of tumorigenesis and from the need to develop more efficient treatment modalities. Any gene therapy appro ach has to take two major tasks into consideration: the therapeutic gene ha s to be delivered into the target cell population with high efficiency, spe cificity and safety, and has to act in a way that provides a benefit to the patient. Discussion: Data on 22 clinical trials on malignancies of the gas trointestinal tract are available. They utilize a variety of gene-delivery methods and target cell populations, and there is considerable variety amon g their strategies. Gene transfer is performed by injection of naked plasmi d DNA and by use of DNA-liposome complexes and viral vectors. In some cases , the gene transfer is carried out ex vivo and the patients receive genetic ally modified cells, whereas other approaches deliver the vector to the tar get cell population in vivo. The theoretical concepts of gene therapy can b e divided into three groups. One approach makes use of suicide genes compri sing bacterial or viral genes that convert a nontoxic prodrug into a highly cytotoxic chemotherapeutic agent at the tumor site. This approach aims at higher therapeutic specificity and fewer side effects than with the systemi c delivery of cytotoxic agents. The second strategy makes an attempt to inv oke the immune system to destroy malignant cells. Different strategies, suc h as immunization with genetically modified tumor cells or transfer of new genes to T cells, are considered to have clinical benefits. The major advan tage of these immunotherapeutic approaches is the systemic effect both on t he primary tumor and on metastases. The third strategy evolved from the ins ight that cancer is a genetic disease caused by activation of oncogenes or inactivation of tumor-suppressor genes. Compensation of genetic defects by the downregulation of activated oncogenes or the restoration of tumor-suppr essor-gene functions may be able to revert the malignant phenotype of cance r cells. Of the 22 gene-therapy trials, 17 trials focus on immunotherapy. O nly two trials make use of suicide genes and, in three trials, a functional copy of the p53 tumor-suppressor gene was reintroduced into malignant cell s. Modalities for gene transfer and the strategies underlying gene therapy will be discussed in the context of gastrointestinal malignancies and the p otential benefits for patients.