Immune Response to Suicide Gene Therapy

Many types of cancer become resistant to current chemotherapeutic and radiotherapeutic interventions. To overcome this situation, applications of gene therapy may be promising. Whereas many types of transgene, such as tumor suppressor genes and cytokine genes, have potential tumoricidal effects (1 ), genes encoding for prodrug-activating enzymes, the so-called suicide genes, are very promising and have been intensively investigated (2 ,3 ). The basic principle underlying suicide gene systems is intracellular conversion of a relatively nontoxic prodrug to a highly toxic drug by an enzyme that is not normally present in the cell. Viruses, bacteria, and fungi often use unique metabolic pathways not used by mammalian cells and contain genes for enzymes that perform metabolic conversions that mammalian cells do not perform. Such distinctive enzymes have often been the targets of drugs developed for the treatment of infections. Such agents are lethal for the infecting microbes but do not harm the host cell because it lacks the enzyme system necessary to activate the drug (4 ,5 ). After genetically modifying tumor cells to express such enzymes, systemic prodrug treatment leads to the selective killing of tumor cells. The effectiveness of suicide gene-prodrug strategies against cancer has been shown in animal models carrying various types of cancer, and the transfer of a suicide gene into tumor cells followed by administration of the appropriate prodrug is currently being used in various clinical gene therapy trials for the treatment of cancer (6 –10 ).