Tumour-Selective Salmonella-Based Cancer Therapy

Abstract

Cancer therapies fail for several primary reasons; lack ofdrug effect on the cancerous tissue~ lack of selectivity for the cancerous tissue, andlor inadequate delivery to the target tissue. Drug effect and selectivity can be improved by increased understanding of molecular and cellular differences between cancer and normal tissues, thus enabling the design of drugs that potently affect cancer-specific molecular targets associated with malignant behaviour. Another approach is to improve the selective delivery ofanti-cancer agents to tumours. One approach is to use carriers that bind to cancer...specific targets, such as antibodies (Hall, 1995). However, most targeting approaches, even if selective, tend not to deliver sufficiently high concentrations of the agent to the tumour to induce significant therapeutic effects. Recent findings suggest that the pathogenic bacterium Sallnonella, when genetically modified, can be used to selectively deliver therapeutic agents to solid tumours at high concentrations (Pawelek et ai., 1997; Low et ai., 1999a). These attenuated bacteria are administered either systemically or locally, whereupon they typically replicate 1000 times greater in the tumour than in other tissue. The basis for preferential colonization and accumulation of Salmonella in tumours appears to include some of the same characteristics of tumours that provide resistance to drug and immune-based therapies (Bermudes et aI., 2000a,b). Why tumours are susceptible to Sabnonella is not well understood and probably includes a variety of factors. Poor penetration of components of the immune system, including antibodies, complement, CD8+ T-cells, granulocytes and macrophages