Non-invasive 19F MR spectroscopy of 5-fluorocytosine to 5-fluorouracil conversion by recombinant Salmonella in tumours.
The aim of this study was to evaluate the applicability of fluorine-19 magnetic resonance spectroscopy ((19)F MRS) for monitoring in vivo the conversion of 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU) after using an attenuated Salmonella Typhimurium strain recombinant to provide cytosine deaminase (TAPET-CD). The (19)F MRS measurements were done on mice bearing the human colon tumour xenograft (HCT116). The intratumoural conversion is greater when TAPET-CD/5-FC is delivered intratumourally (i.tu.) than when TAPET-CD is delivered intravenously (i.v.) and 5-FC intraperitoneally (i.p.). Repeat measurements of the same tumour also yielded important information on the tumour colonization by TAPET-CD through the correlated 5-FC to 5-FU conversion efficacy. The in vivo MRS spectra were confirmed by in vitro (19)F MRS of perchloric acid extracts of the tumour tissue. No 5-FU metabolites were detectable in vivo in the tumours. However, the in vitro measurements revealed, besides 5-FC and 5-FU, the presence of small amounts of catabolites. Finally, spectra obtained in vitro from liver extracts of tumour-bearing mice treated i.tu. with TAPET-CD/5-FC showed no 5-FU and only little amounts of catabolites. Our data illustrate most importantly the potential of (19)F MRS to monitor biologically-based treatments involving cytosine deaminase.
Biomedical NMR Unit, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
T
T
Dresselaers
J
J
Theys
S
S
Nuyts
B
B
Wouters
E
E
de Bruijn
J
J
Anné
P
P
Lambin
P
P
Van Hecke
W
W
Landuyt
D000818:Animals; D043525:Cytosine Deaminase / Q000008:administration & dosage / Q000378:metabolism; D005437:Flucytosine / Q000008:administration & dosage / Q000378:metabolism*; D005462:Fluorine Radioisotopes; D005472:Fluorouracil / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D015552:Injections, Intralesional; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000378:metabolism*; D012486:Salmonella typhimurium; D019737:Transplants; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D005462:Fluorine Radioisotopes; D011355:Prodrugs; D005437:Flucytosine; D043525:Cytosine Deaminase; D005472:Fluorouracil