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Tumor amplified protein expression therapy: salmonella as a tumor-selective.

Attenuated strains of Salmonella typhimurium, VNP20009 and YS7212, when injected systemically to tumor-bearing mice, accumulated preferentially in tumors at levels at least 200-fold and, more commonly, 1000-fold greater than in other normal tissues. This selectivity occurred in subcutaneously implanted murine tumors, including Bl6FIO melanoma, M127 lung carcinoma, and colon 38 carcinoma. The preferential accumulation was also manifested in animals bearing human tumor xenografts, including Lox, C8186, DLDl. SW620, HCT l l6. HTB 177, DU145. MDA-MB-231, and Caki. Four to five days after a single IV injection of l x lO' colony-forming unit (cfu)/mouse, we routinely detected VNP20009 proliferation and accumulation at levels ranging from l x 10" to 2 x to'' cfu/g tumor. The amount of VNP20009 accumulated in the liver ranged from 3 x 10' to 2 x 10" cfu/g. The distribution of Salmonella in tumors was homogenous; YS72l2 cnuld he detected from the periphery to the interior portion of the tumors. Using mice with various immunodeficiencies. we also discoverd the same preferential accumulation of Salmonella in tumors implanted in these mice. The use of Salmonella as a protein delivery vector was shown by IV administration of the bacteria expressing either green f1uorescent protein (GFP) or cytosine deaminase (CD) into tumor-bearing mice. GFP and CD were detected in tumors, but not in livers, taken from mice inoculated with Salmonella carrying these genes. Bacteria accumulation and CD expression persisted in the tumors for up to 14 days after a single bolus IV administration of bacteria to tumor- bearing mice.

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