Oncolytic bacteria in cancer therapy

The most significant problem for cancer gene therapy is how to selectively deliver a therapeutic gene to the tumour. To overcome this problem several vectors (replication-defective viruses, cationic liposomes as well as physical methods such as electroporation or gene gun) were tried, but their selectivity has been low.
Compared with normal tissue vasculature, blood vessels in tumours are often irregular, tortuous and leaky. With increasing distance from blood vessels, chronically and acutely hypoxic as well as necrotic regions within tumour become more prevalent. Hypoxia is a typical feature found in most solid tumours. The poorly vascularized regions of tumours represent a major obstacle to effective treatment.
It has been known for some time that certain facultative and obligatory anaerobic bacteria can selectively accumulate and replicate within hypoxic tumour regions. These bacteria can kill tumour cells (the oncolytic mechanism is not well known) or, alternatively, unarmed bacteria can be used as a vector suitable for delivering therapeutic genes to tumours. One of the better known oncolytic bacteria is an obligatory anaerobic genus Clostridium that has the ability to proliferate selectively in the hypoxic and necrotic regions as well as efficiently inhibit growth of solid tumours. The spores of Clostridium novyi with deleted gene encoding a lethal toxin can germinate within avascular regions of murine tumours and can kill viable tumour cells in a yet unknown way. Numerous data show that the facultative anaerobe attenuated Salmonella typhimurium, exhibits high specific accumulation in tumours (103 times greater than in other tissues). Several experiments have shown that Salmonella typhimurium can inhibit growth of primary tumours and metastases. The investigated strain of Salmonella typhimurium, called VNP20009, carries deletions in the msbB and purI loci that result in loss of virulence. These bacteria, with additional gene encoding cytosine deaminase, can metabolise a non-toxic prodrug (5-fluorocytosine) to a highly toxic drug (5-fluorouracil).
Besides preclinical investigations that show potential application of oncolytic bacteria in experimental cancer therapy, one genetically modified strain of Salmonella typhimurium is currently in Phase I trials in cancer patients.
This article summarises the results of investigations using oncolytic bacteria for the therapy of tumours. Successful combination of bacteriolytic therapy with chemotherapy or radiotherapy may provide in the future a new strategy for treatment of solid tumours as well as metastases.