Elsevier

The Lancet Oncology

Volume 4, Issue 9, September 2003, Pages 548-556
The Lancet Oncology

Review
Bacteria as tumour-targeting vectors

https://doi.org/10.1016/S1470-2045(03)01194-XGet rights and content

Summary

Live bacteria were first actively used in the treatment of cancer nearly 150 years ago, work that ultimately led to the study of immunomodulation. Today, with the discovery of bacterial strains that specifically target tumours, and aided by genomic sequencing and genetic engineering, there is new interest in the use of bacteria as tumour vectors. Bifodobacterium, Clostridium, and Salmonella have all been shown to preferentially replicate within solid tumours when injected from a distal site, and all three types of bacteria have been used to transport and amplify genes encoding factors such as prodrug-converting enzymes, toxins, angiogenesis inhibitors, and cytokines. In this review we provide a historical discussion of this area, and describe the development of the bacteria, which are currently being prepared for use in clinical trials in patients with cancer.

Section snippets

Clostridium

The idea of fusing bacteria as vectors to carry inherent or engineered anticancer agents to tumours was not thought of in these earl studies. It was several decades after the work of Fehleisen and Coley before the use of bacteria as tumour vectors was attempted, initially with spores from the Clostridium family. Clostridia are a group of anaerobes that can successfully colonise necrotic tissue, resulting in gas gangrene. As early as 1813, Vautier reported patients with cancer who seemed to be

Bifidobacterium

Bifidobacterium are also gram-positive anaerobic bacteria that have been found to colonise large tumours, probably because of the anaerobic environments present in parts of large tumours. In contrast to Clostridia, Bifidobacteria are non-pathogenic, non-spore-forming, and found naturally in the digestive tract of humans and some other mammals, and therefore may be safer live bacterial agents to use in the treatment of tumours. Cell-wall extracts have been used as immunomodulators—a similar

Salmonella

Salmonella are gram-negative, facultative anaerobes that are a common cause of intestinal infections. Salmonella are also known to colonise human tumours.34, 35, 36, 37 Owing to substantial immunostimulation produced by Salmonella lipopolysaccharide and other components, systemic infection with Salmonella induces septic shock and high mortality in humans if not treated soon enough. However, early studies by Bacon and co-workers showed that Salmonella virulence in mice is attenuated in some

Tumour amplified protein expression therapy

The potential for bacteria to serve as protein expression systems is enormous. Salmonella and other bacteria that target tumours extend this potential to include the delivery and expression of anticancer therapeutic proteins within cancerous tissue. Although bacteria cannot carry out mammalian glycosylation and other protein modifications, there are many effector proteins for which such modifications are unnecessary. The herpes simplex thymidine kinase (HSVTK) is an example of a

Diagnostic imaging of tumours

The diagnostic imaging of tumours is another potentially powerful application of tumour targeting, and the HSVTK system was shown to be a useful model for this approach. Tumour localisation of 2′-fluoro-2′deoxy-5-iodouracil-β-D-arabinofuranoside (FIAU), labelled with carbon-14, was shown in mice with tumours pretreated with Salmonella expressing HSVTK.72 FIAU radioactivity and bacterial count data showed a Salmonella-dependent FIAU accumulation at least 30 times higher in tumour tissue than in

Intratumoural induction of reporter genes by external stimuli

Externally sustained or pulsed regulation of anticancer genes within tumours could improve the antitumour capabilities of these genes. For studies on intratumoural gene induction in Salmonella, we explored two promoter/reporter systems: the luciferase gene controlled by the tetracycline-sensitive promoter (Clairmont C, Pike J, Troy K, and Bermudes D, Vion Pharmaceuticals, CT, USA, personal communication), and the colicin E3 gene controlled by an SOS-sensitive promoter.50 Salmonella carrying the

Future directions

Anecdotal case reports from more than 200 years ago describe tumour regression in patients with severe bacterial infections. Application of bacteria in cancer therapy was pioneered independently by Friedrich Fehleisen and William B Coley in the late 1800s and early 1900s, leading eventually to immunomodulation for the treatment of cancer.1, 2, 3, 4, 5, 6 Several more recent studies have now shown the potential of genetically engineered live bacteria as tumour-targeting vectors in human cancer

Search strategy and selection criteria

Published and unpublished data for this review were identified by searches of MEDLINE and PubMed with the search terms “bacteria and cancer”, “Clostridium and cancer”, “Bifidobacterium and cancer”, “Salmonella and cancer”, “tumour vector”, “tumour targeting”, and “gene therapy and cancer”. References from relevant articles and abstracts from recent international conferences were also included.

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