ABSTRACT
While efforts have been directed in looking for new antibiotics from soil bacteria, or using genomics/proteomics/synthetic chemistry and high throughput screening for developing new drugs, very litde attention has been given to a potential new source for our drugs. We are refer ring to pathogenic bacteria, some of which live in our body for years to cause chronic infections. These are not the commensal bacteria that live in our guts or other tissues but these are pathogenic bacteria that grow extremely slowly, often in a biofilm mode or forming a protective granule for latency and doing little harm to host normal cells. Bacteria, of course, have evolutionary wisdom because they were the first to appear on earth, preceding other higher forms of life and became organelle such as mitochondria in eukaryotes including mammals.3,4 It is no wonder, therefore, that many pathogenic bacteria take over host functions by direcdy injecting in the host cells some of their own proteins, known as effectors or virulence factors that mimic mammalian signaling or other cellular mechanisms to interfere in host defense.5 Once established in the host cells, some of the extracellular pathogens form biofilms on epithelial cells and can survive for long periods of time without causing significant damage to the host cells. Once settling down for long term residency, however, these pathogenic bacteria appear to also become protective of their turf, try ing to prevent other intruders to get in and either dislodge the bacteria or kill the host, whereby the bacteria lose their sanctuary. Thus the preventive measures the resident pathogens take very much resemble the functions of the host innate or adaptive immune system, mediated through production of immunoglobulins. It now appears that some of the bacterial weapons, for example azurin from the extracellular pathogen Pseudomonas aeruginosa, not only demonstrate promiscuity in attacking different intruders and disarming them at multiple steps6 but also show interesting structural similarity with the variable domains of immunoglobulins.7 It is to be emphasized here that humans have large genomes of more than three billion nucleotides and therefore human im mune systems can produce by a switch-recombination shuffling mechanism individual immuno globulins that can target individual antigens present in invading pathogens. In contrast, bacteria have small genomes of a few million bases and do not possess the capability to design individual deterrents for individual target molecules in the invaders. On the other hand, as mentioned earlier, bacteria have evolutionary wisdom and a knowledge base of the cellular regulatory circuits and metabolic pathways of mammalian and other higher forms of life and can consequently design their weapons in such a way that such weapons are uniquely active against many target cellular components of parasites, viruses or even cancer, that are considered by the pathogenic bacteria as intruders in their habitat.6,7
Pathogenic Bacteria as Anticancer Agents That pathogenic bacteria target cancers and allow their regression has been known for more
than a hundred years and reviewed extensively.815 In general, bacteria belonging to genera such as Samonella, Shigella, Clostridia, L istena, Yersinia and Bifidobactena have been shown to preferen tially target cancer cells and grow in the core hypoxic areas of the tumors that are normally resistant to radiation or chemotherapy. However, introduction of live, pathogenic or even nonpathogenic bacteria activates immune surveillance in animals and humans, leading to toxicity problems. Thus most vector bacteria are attenuated through introduction of various genetic mutations or deletions so that they cause minimal toxicity problems.11,15,16 In addition, to enhance the anticancer effect of the vector bacteria, various genes encoding cytokines, toxins, prodrug-converting enzymes or inhibitors of angiogenesis have been cloned in eukaryotic expression plasmids for allowing cancer regression.8,10,15 For example, Salmonella strains have been used as a delivery vehicle to express cloned E. coli cytosine deaminase gene in three patients where such genes were shown to be expressed without significant adverse effect.17 A combination of C. n o vyi-N T and anti-microtubule agents, that inhibited microtubule synthesis or stabilized microtubules, showed rapid or slow tumor regression.16 More importandy, cloned genes or DNA vaccines with antiangiogenic agents led to significant growth inhibition of tumor cells,18,19 suggesting that bacterial vectors can be usefully
employed to specifically target tumor vasculature and growth. However, preclinical animal studies or phase I studies have shown limited bacterial tumor colonization and tumor regression17,20,21 sug gesting that better tumor targeting and sustained colonization and antitumor activity are needed to apply live bacteria in useful cancer therapy. The only strain of live bacteria that is used today in cancer therapy is Mycobactenum bovis BCG. Although originally believed to allow regression of melanoma, leukaemia or prostate cancer, such effects have not been found to be consistent. The major application ofM . bovis BCG today is against bladder cancer, which can give complete response in 80% of patients8 as an immunotherapeutic agent.
