Lipid A mutant Salmonella with suppressed virulence and TNFα induction retain tumor-targeting in vivo

KB Low, M Ittensohn, T Le, J Platt, S Sodi… - Nature …, 1999 - nature.com
KB Low, M Ittensohn, T Le, J Platt, S Sodi, M Amoss, O Ash, E Carmichael, A Chakraborty…
Nature biotechnology, 1999nature.com
Systemically administered tumor-targeted Salmonella has been developed as an anticancer
agent, although its use could be limited by the potential induction of tumor necrosis factor α
(TNFα)-mediated septic shock stimulated by lipid A. Genetic modifications of tumor-targeting
Salmonella that alter lipid A and increase safety must, however, retain the useful properties
of this bacteria. We report here that disruption of the Salmonella msbB gene reduces TNFα
induction and increases the LD 50 of this pathogenic bacteria by 10,000-fold …
Abstract
Systemically administered tumor-targeted Salmonella has been developed as an anticancer agent, although its use could be limited by the potential induction of tumor necrosis factor α (TNFα)-mediated septic shock stimulated by lipid A. Genetic modifications of tumor-targeting Salmonella that alter lipid A and increase safety must, however, retain the useful properties of this bacteria. We report here that disruption of the Salmonella msbB gene reduces TNFα induction and increases the LD 50 of this pathogenic bacteria by 10,000-fold. Notwithstanding this enormous difference, Salmonella retains its tumor-targeting properties, exhibiting tumor accumulation ratios in excess of 1000: 1 compared with normal tissues. Administration of this bacteria to mice bearing melanoma results in tumors that are less than 6% the size of tumors in untreated controls at day 18. Thus, the antitumor activity previously demonstrated using tumor-targeting Salmonella with normal lipid A is retained. Lipid modification of tumor-specific bacterial vectors provides a means for reducing septic shock and further suggests that the antitumor activity of these bacteria may be independent of TNFα.
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