PATTERNS OF HEPATIC AND SPLENIC COLONIZATION BY AN ATTENUATED STRAIN OF SALMONELLA-TYPHIMURIUM CONTAINING THE GENE FOR HUMAN INTERLEUKIN-2 - A NOVEL ANTITUMOR AGENT

Currently, there is no effective treatment for unresectable hepatic ma lignancies. Salmonella sp. are known to naturally track to the liver d uring active infection. A live biological vector was developed for del ivery of Interleukin-2 (IL-2) to the liver for anti-tumor purposes. Th e avirulent and highly immunogenic c4550 strain of Salmonella typhimur ium was used to express the IL-2 protein [renamed c4550(pIL-2)]. We ha ve previously demonstrated the the c4550(pIL-2) produces biologically active IL-2 gene or non-treated controls. The goal of the current stud ies was to determine the pattern of splenic and hepatic colonization o f Salmonella-IL-2. Hepatic and splenic colonization was determined fol lowing administration of 10(7) cfu of c4550(pIL-2) and c4550(pYA292) v ia a single gavage feeding to C57BL/6 mice. Five experiments of antibi otic regimens administration were conducted where splenic and hepatic homogenates were cultured after 14 days of parenteral and/or oral anti biotics. The natural history of hepatic and splenic colonization was a lso determined for animals without antibiotic treatment. Despite admin istration of various antibiotic regimens using different routes, eradi cation of salmonella with and without IL-2 was not achieved. Salmonell a, however, was not cultured from hepatic and splenic tissue at 4 mont hs after a single gavage feeding of salmonella with no specific treatm ent. In conclusion, oral administration of c4550(pIL-2) may represent a novel form of in vivo biotherapy for unresectable hepatic malignanci es. Antibiotics do not accelerate eradication of this bacteria and its appears that c4550(pIL-2) follows the natural pathophysiological of s almonella infection in which eradication from the splenic and hepatic tissue occurs over a period of 2-4 months.