Increasing specificity of anti-tumor therapy: Cytotoxic protein delivery by non-pathogenic clostridia under regulation of radio-induced promoters

Background: pathogenic clostridia, genetically engineered to express therapeutic genes, will specifically target hypoxic regions in tumors. This specificity can be further improved if expression of these genes is controlled by a radioinduced promoter, leading to spatial and temporal control of gene expression. Materials and Methods: Following administration of Clostridium spores to tumor bearing mts, normal tissue and tumoral specimens were compared for colonization. Clostridium was genetically modified to express tumor necrosis factor ct or cytosine deaminase. Expression of these proteins was assayed. Northern blot hybridizations were used to detect genes which are radio-induced. Results: Clostridium gave a selective colonization of tumors. The recombinant clostridia expressed in vitro and in vivo TNF alpha and cytosine deaminase. Clostridial SOS-repair genes were induced at a nose of 2 Gy. Conclusions: pathogenic Clostridium can be used for tumor specific delivery of therapeutic genes. The specificity can be improved via radio-induced promoters. Overall, this new gene delivery system can lead to an increase of the therapeutic ratio in cancer treatment.