Optimization of tumor-targeted gene delivery by engineered attenuated Salmonella typhimurium.
BACKGROUND
Attenuated Salmonella typhimurium has been demonstrated as a potential gene delivery vector. Previous findings induce the necessity to optimize tumor selectivity and bacterial dosing in relation to tumor volume and intratumoral therapeutic gene expression.


METHODS
Attenuated Salmonella VNP20009 and VNP20047 (expressing cytosine deaminase) were systemically administered to tumor-bearing rats. The bacteria were quantified in tumor and normal organs. Conversion of 5-fluorocytosine to 5-fluorouracil was evaluated using thin layer chromatography.


RESULTS
Tumor colonization efficiency was dependent on Salmonella density, administration route and tumor volume. Colonization of normal tissues gradually decreased with time, while intratumoral proliferation of bacteria remained high during the follow-up period. The Optimal Therapeutic Dose (OTD) was found to be 5.10(7) cfu/rat. Intratumoral VNP20047-expressed CDase leading to the conversion of 5-FC to 5-FU was detected in vivo.


CONCLUSIONS
Our results indicate the need to define an OTD, probably for each species, when using genetically engineered Salmonella as a tumor- and species-selective vector in cancer therapy.
Mei
Shaoping
S
Laboratory of Experimental Radiobiology LEO, U.Z. Gasthuisberg K.U. Leuven, Herestraat 49, B-3000 Leuven.
Theys
Jan
J
Landuyt
Willy
W
Anne
Jozef
J
Lambin
Philippe
P
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics; D043525:Cytosine Deaminase; D005437:Flucytosine / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000493:pharmacokinetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000382:microbiology* / Q000628:therapy*; D009368:Neoplasm Transplantation; D009700:Nucleoside Deaminases / Q000235:genetics / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000382:microbiology* / Q000628:therapy*; D012486:Salmonella typhimurium / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D014018:Tissue Distribution
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil