Induction of thymidine phosphorylase as a pharmacodynamic end-point in patients with advanced carcinoma treated with 5-fluorouracil, folinic acid andinterferon alpha

Thymidine phosphorylase (TP) is an essential enzyme for the biochemical act ivation of 5-fluorouracil (5-FU). Interferon upregulates TP in vivo, althou gh 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 lym phocytes (PBLs) from patients with advanced carcinoma receiving treatment w ith 5-FU and folinic acid. Cohorts of patients were treated with interferon alpha (IFN alpha), immediately prior to 5-FU/folinic acid, at doses of 3 M IU m(-2), 9 MIU m(-2) and 18 MIUm(-2). IFN alpha 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 IFN alpha 9 MIU m(-2) three times pe r week from cycle 2 onwards. Twenty-one patients were entered into the stud y with 19 evaluable for response. Six patients (32%) had stable disease and 13 (68%) progressive disease. There were no grade-IV toxicities. TP activi ty was detected in PBLs from all patients with wide interpatient variabilit y in constitutive TP activity prior to chemotherapy, and in response to IFN alpha. 5-FU/folinic acid alone did not induce TP activity but a single dos e of IFN alpha led to upregulation of TP within 2h of administration with a further increase by 24 h (signed rank test, P = 0.006). TP activity remain ed elevated for at least 13 days (signed rank test, P = 0.02). There were n o significant differences in TP activity between schedules or with addition al doses of IFN alpha. A single dose of IFN alpha as low as 3 MIU m(-2) can cause sustained elevation of PBL TP activity in vivo indicating that bioch emical markers are important pharmacodynamic endpoints for developing optim al schedules of IFN alpha for biomodulation of 5-FU. (C) 2000 Cancer Resear ch Campaign.