Suicide gene therapy: possible applications in haematopoietic disorders

Although the treatment results for some forms of haematologic malignancies are excellent, especially for the childhood acute leukaemias, there is still a significant fraction of patients that will not benefit from the therapy available today. The identification of new techniques, such as gene therapy, may therefore be of great importance for future therapeutic applications. Suicide gene therapy is one of several gene therapeutic approaches to treat cancer. A suicide gene is a gene encoding a protein, frequently an enzyme, that in itself is nontoxic to the genetically modified cell. However, when a cell is exposed to a specific nontoxic prodrug, this is selectively converted by the gene product into toxic metabolites that kill the cell. The suicide gene most commonly employed, both in experimental and a clinical settings, is herpes simplex thymidine kinase (HSVtk). Some suicide gene products also induce a so-called 'bystander effect', i.e. a toxic effect on adjacent nongene modified tumour cells and sometimes also on more distant tumour cells. The bystander effect is most evident in tumour cells that have a high number of gap junctions, cellular channels build up by proteins called connexins. Many tumours, amongst them many haematological ones, have a low number of gap junctions. Therefore, it is important to develop gap junction independent drug delivery systems. Suicide gene technology may also be used for the ex vivo purging of tumour cells in bone marrow or peripheral blood stem cell autografts or for inactivation of effector cells, such as antitumour T donor lymphocytes in allogeneic transplantation to prevent severe graft versus host reactions. New constructs, e.g. combining suicide genes and immune response enhancing genes or suicide genes and connexin inducing genes may further improve the value of suicide gene therapy.