title: Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase.
abstract: The gene encoding cytosine deaminase (CD) has been expressed in the human colorectal carcinoma cell line WiDr. Metabolism studies confirm that tumor cells expressing CD convert the very nontoxic prodrug 5-fluorocytosine (5FCyt) to 5-fluorouracil (5FUra) and 5FUra metabolites. Tumor xenografts composed of CD-expressing cells can selectively generate tumor levels of > 400 microM 5FUra when the host mouse is dosed with nontoxic levels of 5FCyt. The selective metabolic conversion of 5FCyt to 5FUra in CD-expressing tumor cells results in the inhibition of thymidylate synthase and incorporation of 5FUra into RNA. 5FUra is also liberated into the surrounding environment when CD-expressing tumor cells are treated with 5FCyt. The liberated 5FUra is able to kill neighboring, non-CD-expressing tumor cells in vitro and in vivo. Most importantly, when only 2% of the tumor mass contains CD-expressing cells (98% non-CD-expressing cells), significant regressions in all tumors are observed when the host mouse is dosed with nontoxic levels of 5FCyt.
authors.affiliation: Division of Cell Biology, Wellcome Research Laboratories, Research Triangle Park, NC 27709.
authors.forename: B E
authors.initials: BE
authors.lastname: Huber
authors.forename: E A
authors.initials: EA
authors.lastname: Austin
authors.forename: C A
authors.initials: CA
authors.lastname: Richards
authors.forename: S T
authors.initials: ST
authors.lastname: Davis
authors.forename: S S
authors.initials: SS
authors.lastname: Good
mesh_terms: D000818:Animals; D001711:Biotransformation; D002455:Cell Division; D002470:Cell Survival; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D043525:Cytosine Deaminase; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005437:Flucytosine / Q000378:metabolism*; D005472:Fluorouracil / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D009700:Nucleoside Deaminases / Q000096:biosynthesis / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D013997:Time Factors; D014183:Transplantation, Heterologous; D014316:Tritium; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D014316:Tritium; D005437:Flucytosine; D013940:Thymidylate Synthase; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil