title: Induction of thymidine phosphorylase as a pharmacodynamic end-point in patients with advanced carcinoma treated with 5-fluorouracil, folinic acid and interferon alpha.
abstract: Thymidine phosphorylase (TP) is an essential enzyme for the biochemical activation of 5-fluorouracil (5-FU). Interferon upregulates TP in vivo, although the dose and schedule of interferon for optimal biomodulation of 5-FU is not known. In this study, TP activity was measured in peripheral blood lymphocytes (PBLs) from patients with advanced carcinoma receiving treatment with 5-FU and folinic acid. Cohorts of patients were treated with interferon alpha (IFNalpha), immediately prior to 5-FU/folinic acid, at doses of 3 MIU m(-2), 9 MIU m(-2) and 18 MIUm(-2). IFNalpha was administered on day 0 cycle two, day-1 and day 0 cycle three and day-2, day-1 and day 0 cycle four. A fourth cohort was treated with IFNalpha 9 MIU m(-2) three times per week from cycle 2 onwards. Twenty-one patients were entered into the study with 19 evaluable for response. Six patients (32%) had stable disease and 13 (68%) progressive disease. There were no grade-IV toxicities. TP activity was detected in PBLs from all patients with wide interpatient variability in constitutive TP activity prior to chemotherapy, and in response to IFNalpha. 5-FU/folinic acid alone did not induce TP activity but a single dose of IFNalpha led to upregulation of TP within 2 h of administration with a further increase by 24 h (signed rank test, P = 0.006). TP activity remained elevated for at least 13 days (signed rank test, P= 0.02). There were no significant differences in TP activity between schedules or with additional doses of IFNalpha. A single dose of IFNalpha as low as 3 MIU m(-2) can cause sustained elevation of PBL TP activity in vivo indicating that biochemical markers are important pharmacodynamic endpoints for developing optimal schedules of IFNalpha for biomodulation of 5-FU.
authors.affiliation: ICRF Medical Oncology Unit, Churchill Hospital, Oxford, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Braybrooke
authors.forename: D J
authors.initials: DJ
authors.lastname: Propper
authors.forename: K J
authors.initials: KJ
authors.lastname: O'Byrne
authors.forename: M I
authors.initials: MI
authors.lastname: Koukourakis
authors.forename: A V
authors.initials: AV
authors.lastname: Patterson
authors.forename: S
authors.initials: S
authors.lastname: Houlbrook
authors.forename: S D
authors.initials: SD
authors.lastname: Love
authors.forename: S
authors.initials: S
authors.lastname: Varcoe
authors.forename: M
authors.initials: M
authors.lastname: Taylor
authors.forename: T S
authors.initials: TS
authors.lastname: Ganesan
authors.forename: D C
authors.initials: DC
authors.lastname: Talbot
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D013939:Thymidine Phosphorylase / Q000096:biosynthesis*
chemical_list: D016898:Interferon-alpha; D013939:Thymidine Phosphorylase; D002955:Leucovorin; D005472:Fluorouracil