The tumour-Clostridium phenomenon: 50 years of developmental research (Review)

The tumour-Clostridium phenomenon describes the specific affinity of spore forming anaerobes to tumour growth. The discovery of strictly intratumoral tetanus toxic infections in tumour-bearing mice after intravenous spore administration gave the impulse to search for non-toxic clostridial isolates with tumour-selective properties for clostridial biotherapy, i.e. oncolysis, as well as serologic tumour diagnostics without any toxic side-effects. Systematic studies of the oncolytic process and its variables on diverse experimental tumours and laboratory animals revealed that tumour liquefaction, converting necrotic tumour parts to putrid abscesses filled with masses of clostridial forms, stops sharply at the viable rim of the blood-supplied tumour tissue. Similar results were observed in clinical trials, particular of gliomas. Before oncolysis is initiated, the first stage of clostridial multi-plication in the vascularized tissue is inducing a humoral immune response, preceded by phagocytic activity. The majority of tumour-bearing laboratory and domestic animals, so far tested serologically, clinical cancer patients as well, responded with anti-rod antibodies and, independently, anti-spore antibodies. Oncolytic and non-oncolytic Clostridia were equally immunogenic. During the early, immunizing period of clostridial proliferation, analytical tumour-tetanus experiments were focused on potential relations between tumour growth kinetics and rod proliferation. Based on realistic growth models and target principles, computer simulations could reproduce the results, i.e. cumulative curves of tetanus lethality in groups of mice. Thus, crucial assumptions of the mathematical model were ex post confirmed by further experiments. Our working hypothesis concentrates on temporally hypoxic micro-niches close to a pre-mitotic cell with enhanced oxygen demand which can be utilized by anaerobes (randomly) located there. As early immune reactions to clostridial antigens via phagocytosis and humoral immune response will do without invasion in necrobiotic avascular tumour areas, the pacemaker model of tumour-Clostridium interplay extends the scope of genetically engineered Clostridia to early treatment of metastases. Thus, novel concepts, such as 'Clostridia-directed enzyme prodrug-therapy' and 'Combined bacteriolytic therapy', together with immune activation, can come into play.