Tumor-targeted Salmonella expressing cytosine deaminase as an anticancer agent.
The study was designed to evaluate whether TAPET-CD, an attenuated strain of Salmonella typhimurium expressing Escherichia coli cytosine deaminase (CD), was capable of converting nontoxic 5-fluorocytosine (5-FC) to the active antitumor agent 5-fluorouracil (5-FU). The antitumor effect of TAPET-CD plus 5-FC against subcutaneously implanted colon tumors was also evaluated. TAPET-CD was given to tumor-bearing mice by a single bolus intravenous administration followed with 5-FC by intraperitoneal administration. TAPET-CD accumulated in tumors at levels 1000-fold higher than that in normal tissues and high levels of 5-FU were detected in tumors in mice treated with both TAPET-CD and 5-FC. No 5-FU could be detected in normal tissues. Inhibition of tumor growth was observed in mice treated with either TAPET-CD alone or TAPET-CD in combination with 5-FC (TAPET-CD/5-FC), but not with 5-FC alone. TAPET-CD/5-FC inhibited tumor growth by 88%-96%, compared to TAPET-CD alone, which inhibited tumor growth by 38%-79%. These data suggest that tumor-targeting Salmonella could be used to deliver prodrug-converting enzyme selectively to tumors and produced anti-tumor effects when the corresponding prodrug was also given.
King
Ivan
I
Vion Pharmaceuticals, Inc., New Haven, CT 06511, USA. IKING@VIONPHARM.COM
Bermudes
David
D
Lin
Stanley
S
Belcourt
Michael
M
Pike
Jeremy
J
Troy
Kimberly
K
Le
Trung
T
Ittensohn
Martina
M
Mao
John
J
Lang
Wenshang
W
Runyan
Jacob D
JD
Luo
Xiang
X
Li
Zujin
Z
Zheng
Li-Mou
LM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001711:Biotransformation; D003110:Colonic Neoplasms / Q000628:therapy; D043525:Cytosine Deaminase; D004926:Escherichia coli / Q000201:enzymology; D005260:Female; D005437:Flucytosine / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D005819:Genetic Markers; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009700:Nucleoside Deaminases / Q000235:genetics / Q000494:pharmacology*; D009928:Organ Specificity; D012486:Salmonella typhimurium / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005819:Genetic Markers; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil