LEUCOVORIN MODULATION OF 5-IODODEOXYURIDINE RADIOSENSITIZATION - A PHASE-I STUDY

Evidence for clinically significant radiosensitization by the halogena ted pyrimidine 5-iododeoxyuridine (IdUrd) continues to accumulate, In vitro radiosensitization has been demonstrated in human colon tumor ce ll lines following exposure to 1-10 mu M. Coadministration of leucovor in (LV) increases radiosensitization, which correlates directly with i ncreased IdUrd DNA incorporation, Clinical data regarding proliferatio n rates and thymidine kinase levels in tumors versus normal tissues su ggest selective incorporation of IdUrd into gastrointestinal tumors ma y occur, The objectives of this Phase I study were: (a) to assess the feasibility of LV modulation of IdUrd radiosensitization by determinin g the maximum tolerated dose (MTD) of IdUrd plus LV; and (b) to perfor m correlative laboratory studies to investigate the potential of IdUrd plus LV to increase radiosensitization in vivo, Seventeen patients wi th unresectable or recurrent gastrointestinal adenocarcinomas received a 14-day course of continuous i,v, infusion of IdUrd prior to initiat ion of radiotherapy, Two additional 14-day infusions of IdUrd with LV were given during the course of radiotherapy (60 Gy in 6 weeks), The i nitial dose of IdUrd was 250 mg/m(2)/day and was escalated in subseque nt patients to 400 and 600 mg/m(2)/day, The LV dose remained fixed at 250 mg/m(2)/day, Leukopenia was the dose-limiting toxicity, and 400 mg /m(2)/day was the MTD for this trial, At the MTD, the mean +/- SD stea dy-state plasma concentration of IdUrd during the infusion, measured b y high-performance liquid chromatography, was 0.66 +/- 0.23 mu M. Ther e was no significant influence of LV on IdUrd DNA incorporation in per ipheral blood granulocytes as measured by high-performance liquid chro matography, Based on toxicity data and correlative laboratory studies, a meaningful increase in radiosensitization would not be achieved wit h the IdUrd infusion schedule and dose of LV investigated compared wit h IdUrd alone.