MICROBIAL MOLECULAR BIOLOGY & GENETICS
Resistance to conventional anticancer therapies in patients with advanced solid tumors has prompted the need of alternative cancer therapies. Moreover, the success of novel cancer therapies depends on their selectivity for cancer cells with limited toxicity to normal tissues. Several decades after Coley's work a variety of natural and genetically modified non-pathogenic bacterial species are being explored as potential antitumor agents, either to provide direct tumoricidal effects or to deliver tumoricidal molecules. Live, attenuated or genetically modified non-pathogenic bacterial species are capable of multiplying selectively in tumors and inhibiting their growth. Due to their selectivity for tumor tissues, these bacteria and their spores also serve as ideal vectors for delivering therapeutic proteins to tumors. Bacterial toxins too have emerged as promising cancer treatment strategy. The most potential and promising strategy is bacteria based gene-directed enzyme prodrug therapy. Although it has shown successful results in vivo yet further investigation about the targeting mechanisms of the bacteria are required to make it a complete therapeutic approach in cancer treatment.
Cancer is characterized by uncontrolled and invasive growth of cells. These cells may spread to other parts of the body, and this is called metastasis. Although conventional anticancer therapies, consisting of surgical resection, radiotherapy and chemotherapy, are effective in the management of many patients but for about half of cancer sufferers these are ineffective, so alternative techniques are being developed to target their tumours. Experimental cancer treatments are medical therapies intended or claimed to treat cancer by improving, supplementing or replacing conventional methods. These include photodynamic therapy, HAMLET (human alpha-lactalbumin made lethal to tumor cells), gene therapy, telomerase therapy, hyperthermia therapy, dichloroacetate (DCA), non-invasive RF cancer treatment, complementary and alternative therapy, diet therapy, insulin potentiating therapy and bacterial treatment . But many of these therapies are controversial due to lack of evidence, efficacy, feasibility, availability, specificity and selectivity. It has been reported that some microorganisms display selective replication in tumor cells or preferential accumulation in the tumor micro-environment thus offering a great potential for cancer therapy. Many viruses, like vaccinia virus, Newcastle disease virus, reovirus and adenovirus with an E1a deletion, which are intended to achieve selective replication and killing of tumor cells have been investigated. Viruses have shown the most potential to carry altered genes to cancer cells, to find target cells in body and ability to latch onto these cells. Oncolytic viruses cause lysis (rupture) of cancer cells, which can then be processed by the adaptive immune system, which can then target similar cells in other parts of the body. But the effective use of such viruses is sometimes hindered by the production of potentially neutralizing antibodies generated against them . It has been reported that some bacterial species also preferentially replicate and accumulate within tumors. Moreover, they possess certain advantageous features such as motility, capacity to simultaneously carry and express multiple therapeutic proteins, and elimination by antibiotics, thus making bacterial treatment a promising new strategy in cancer treatment . This review highlights the use of bacteria in cancer therapy as a novel experimental strategy.
The role of bacteria as anticancer agent was recognized almost hundred years back. The German physicians W. Busch and F. Fehleisen separately observed that certain types of cancers regressed following accidental erysipelas (Streptococcus pyogenes) infections that occurred whilst patients were hospitalized . Independently, the American physician William Coley noticed that one of his patients suffering from neck cancer began to recover following an infection with erysipelas. He began the first well-documented use of bacteria and their toxins to treat end stage cancers. He developed a safer vaccine in the late 1800's composed of two killed bacterial species, S. pyogenesand Serratia marcescens to simulate an infection with the accompanying fever without the risk of an actual infection [5,6]. And the vaccine was widely used to successfully treat sarcomas, carcinomas, lymphomas, melanomas and myelomas. Complete, prolonged regression of advanced malignancy was documented in many cases . Toxic bacterial derivatives 'Coley's toxins' were also studied for potential anticancer activity . The early success of Coley's toxins provided the grounds for current advances in this field.
After Coley's initial observations, scientists discovered that certain species of anaerobic bacteria, such as those belonging to the genus Clostridium, thrive and consume oxygen-poor cancerous tissue whereas die when they come in contact with the tumor's oxygenated sides, meaning they would be harmless to the rest of the body . These findings provided the rationale for using the bacteria as oncolytic agents. However, bacteria don't consume all parts of the malignant tissue thus underlying the need of combining the therapy with chemotherapeutic treatments. Thus bacteria can be implied as sensitising agents for chemotherapy. Bacterial products like endotoxins (Lipopolysaccharides) have to some extent already been tested for cancer treatment. Bacterial toxins can be used for tumor destruction and cancer vaccines can be based on immunotoxins of bacterial origin . Bacteria can be exploited as delivery agents for anticancer drugs, and as vectors for gene therapy. Spores of anaerobic bacteria can be used for the aforementioned strategies because only spores that reach an oxygen starved area of a tumour will germinate, multiply and become active. The use of genetically modified bacteria for selective destruction of tumors, and bacterial gene-directed enzyme prodrug therapy have shown promising potential. The detailed overview of these bacteria based approaches is given below.