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 stil l a significant fraction of patients that will not benefit from the therapy available today. The identification of new techniques, such as gene therap y, may therefore be of great importance for future therapeutic applications . Suicide gene therapy is one of several gene therapeutic approaches to tre at cancer. A suicide gene is a gene encoding a protein, frequently an enzym e, that in itself is nontoxic to the genetically modified cell. However, wh en a cell is exposed to a specific nontoxic prodrug, this is selectively co nverted by the gene product into toxic metabolites that kill the cell, The suicide gene most commonly employed, both in experimental and a clinical se ttings, is herpes simplex thymidine kinase (HSVtk). Some suicide gene produ cts also induce a so-called 'bystander effect', i.e. a toxic effect on adja cent nongene modified tumour cells and sometimes also on more distant tumou r cells, The bystander effect is most evident in tumour cells that have a h igh 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 use d for the ex vivo purging of tumour cells in bone marrow or peripheral bloo d stem cell autografts or for inactivation of effector cells, such as antit umour T donor lymphocytes in allogeneic transplantation to prevent severe g raft versus host reactions. New constructs, e.g. combining suicide genes an d immunresponse enhancing genes or suicide genes and connexin inducing gene s may further improve the value of suicide gene therapy.