Oral delivery of tumor-targeting Salmonella exhibits promising therapeutic efficacy and low toxicity

Tumor-targeting bacteria have been developed as powerful anticancer agents. Salmonella typhimurium VNP20009, a representative tumor-targeting strain, has been systemically administered as a single-agent therapy at doses of 1 x 106 to 3 x 106 colony-forming unit (cfu)/mouse, or in combination with other antitumor agents at doses of 1 x 104 to 2 x 105 cfu/mouse. Recently, we reported that oral delivery of VNP20009 at the dose of 1 x 109 cfu/mouse induced significant anticancer effects comparable to that induced by systemic administration of this strain at 1 x 104 cfu/mouse. To further address the efficacy and safety of oral administration of bacteria, here we performed a systemically comparative analysis of anticancer efficacy and toxicity of VNP20009 administered: (i) orally at a dose of 1 x 109 cfu/mouse (VNP9-oral); (ii) intraperitoneally at a dose of 1 x 104 cfu/mouse (VNP4-i.p.); or (iii) intraperitoneally at a dose of 1 x 106 cfu/mouse in tumor-free and tumor-bearing murine models. The results showed that VNP9-oral, similar to VNP4-i.p., induced significant tumor growth inhibition whereas VNP6-i.p. induced better anticancer effect in the B16F10 melanoma model. Among three treatments, VNP9-oral induced the mildest and reversible toxicity whereas VNP6-i.p. resulted in the most serious and irreversible toxicities when compared to other two treatments. Moreover, the combination of VNP9-oral with a low dose of chemotherapeutics produced comparable antitumor effects but displayed significantly reduced toxicity when compared to VNP6-i.p. The findings demonstrated that oral administration, as a novel avenue in the application of bacteria, is highly safe and effective. Moreover, the present preclinical study should facilitate the optimization of bacterial therapies with improved anticancer efficacy and reduced adverse effects in future clinical trials. (Cancer Sci 2009; 100: 2437-2443).