title: Biochemical modification of the toxicity and the anti-tumour effect of 5-fluorouracil and cis-platinum by WR-2721 in mice.
abstract: WR-2721 (ethiofos) was tested on Balb/c mice for its chemoprotective capacity against 5-fluorouracil (5FU) monotherapy. In this combination WR-2721 was not active, but WR-2721 pretreatment allowed an elevation of the cisplatin (CDDP) dose in 5FU/CDDP combination therapy in these mice. Thrombocytopenia caused by the 5FU/CDDP (100 and 7 mg/kg, respectively) therapy was prevented by WR-2721 (200 mg/kg) and a partial protection against leukopenia was observed in C57Bl/6 mice. Various WR-2721/CDDP/5FU combinations were tested on two murine colon tumour models. The best antiproliferative effect against Colon 26 (in Balb/c mice) and the lowest toxicity were found with 5FU (100 mg/kg) and CDDP (5.5 mg/kg) delivered together 30 min after WR-2721 (200 mg/kg). The increased efficacy of WR-2721/CDDP/5FU both in Colon 26 and Colon 38 (in C57Bl/6 mice) compared to single 5FU or 5FU/CDDP treatment at the same dose could not be explained by enhanced inhibition of thymidylate synthase (TS), the 5FU target enzyme. The protection by WR-2721 against toxicity of CDDP/5FU might enable the use of high doses of CDDP in this combination.
authors.affiliation: Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: C L
authors.initials: CL
authors.lastname: van der Wilt
authors.forename: J A
authors.initials: JA
authors.lastname: van Laar
authors.forename: F
authors.initials: F
authors.lastname: Gyergyay
authors.forename: K
authors.initials: K
authors.lastname: Smid
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D004999:Amifostine / Q000627:therapeutic use*; D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects*; D003110:Colonic Neoplasms / Q000188:drug therapy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects*; D007970:Leukopenia / Q000139:chemically induced / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013921:Thrombocytopenia / Q000139:chemically induced / Q000517:prevention & control; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D013997:Time Factors; D015431:Weight Loss / Q000187:drug effects
chemical_list: D013940:Thymidylate Synthase; D004999:Amifostine; D002945:Cisplatin; D005472:Fluorouracil