title: Therapeutic efficacy of fluoropyrimidines depends on the duration of thymidylate synthase inhibition in the murine colon 26-B carcinoma tumor model.
abstract: 5-Fluorouracil (FUra) and 5-fluoro-2'-deoxyuridine (FdUrd) are common chemotherapeutic drugs for the treatment of advanced colorectal cancer. Two recognized mechanisms of action of these agents are inhibition of thymidylate synthase (TS) and incorporation of fluorinated UTP into cellular RNA. In previous studies on drug scheduling of both fluoropyrimidines, we observed the highest therapeutic efficacy by using a weekly i.v. push schedule. Furthermore, weekly 400-mg/kg FdUrd is superior to equitoxic weekly 80-mg/kg FUra in murine Colon 26-B carcinoma. We evaluated the most important pharmacokinetic and pharmacodynamic effects of both fluoropyrimidines to delineate the biochemical mechanisms underlying their differences in therapeutic activity in this tumor model. FUra concentrations and elimination in tumors after FdUrd or FUra administration were comparable, and the level of FUra incorporation into cellular RNA following treatment with FUra or FdUrd was similar. Free tumoral 5-fluoro-dUMP levels were initially 3-fold higher after FdUrd but diminished rapidly thereafter. The number of free [3H]5-fluoro-dUMP-binding sites decreased to about 25 and 15% of control values within 2 h after treatment with equitoxic doses of FUra and FdUrd and remained low for 72 h. The duration of TS inhibition was significantly longer following treatment with FdUrd compared with FUra, 168 and 72 h, respectively. The superiority of the antitumor activity of an i.v. push of FdUrd over FUra in the treatment of Colon 26-B tumors correlates with maintenance of TS inhibition and repeated drug administration when TS remains low, whereas FUra incorporation into RNA does not appear to distinguish the antitumor response of FdUrd from that of FUra in this tumor model.
authors.affiliation: Department of Oncology, Free University Hospital, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: J A
authors.initials: JA
authors.lastname: van Laar
authors.forename: C L
authors.initials: CL
authors.lastname: van der Wilt
authors.forename: Y M
authors.initials: YM
authors.lastname: Rustum
authors.forename: P
authors.initials: P
authors.lastname: Noordhuis
authors.forename: K
authors.initials: K
authors.lastname: Smid
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005467:Floxuridine / Q000378:metabolism / Q000627:therapeutic use*; D005468:Fluorodeoxyuridylate / Q000032:analysis; D005472:Fluorouracil / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D012313:RNA / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D005467:Floxuridine; D005468:Fluorodeoxyuridylate; D012313:RNA; D013940:Thymidylate Synthase; D005472:Fluorouracil