Previously, we reported extensive diversity among survivors of Salmonella enterica ssp. enterica serovar Typhimurium that were stored for four decades in sealed agar stabs. Thus raising the question: was there selection for greater fitness among eventual survivors? To address this, we cocultured archived LT2 survivors with nonarchived (parental) LT2 strains in competition experiments. Selected archived strains outgrew a nonarchived LT2 sequenced strain. Although we initially assumed this was the result of mutations empowering greater nutritional utilization, we found phage selection was also involved. Phage fels-1 and fels-2 in supernatants were identified by primer/PCR as a putative selective force following single plaque isolations on a prophage-free strain and testing on appropriate hosts. In confirmatory experiments, instead of coculture in Luria-Bertani requiring antibiotic marker insertions, competing strains without markers were inoculated at opposite edges of motility plates. Not only did the archived LT2 population overgrow the nonarchived LT2 population, but also clear zones appeared at edges of encounters from which phage fels-1 and fels-2 (but not gifsy-1 nor gifsy-2) were recovered. However, in competitions of an archived strain with S. Typhimurium ATCC 14028, phage emerged that had a DNA base sequence segment of prophage ST64B but the sequence differed from the reported homologous segment in ST64B.
Despite significant progress in the development of new drugs and radiation, deaths due to cancer remain high. Many novel therapies are in clinical trials and offer better solutions, but more innovative approaches are needed to eradicate the various subpopulations that exist in solid tumors. Since 1997, the use of bacteria for cancer therapy has gained increased attention. Salmonella Typhimurium strains have been shown to have a remarkably high affinity for tumor cells. The use of bacterial strains to target tumors is a relatively new research method that has not yet reached the point of clinical success. The first step in assessing the effectiveness of bacterial tumor therapy will require strain development and preclinical comparisons of candidate strains, which is the focus of this chapter. Several investigators have developed strains of Salmonella with reduced toxicity and capacity to deliver anti-tumor agents. Although methods for obtaining safe therapeutic strains have been relatively successful, there is still need for further genetic engineering before successful clinical use in human patients. As described by Forbes et al. in 2003, the main stumbling block is that, while bacteria preferentially embed within tumor cells, they fail to spread within the tumor and finish the eradication process. Further engineering might focus on creating Salmonella that remove motility limitations, including increased affinity toward tumor-generated chemotactic attractants and induction of matrix-degrading enzymes.
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