IN-VIVO MODULATION OF IODODEOXYURIDINE METABOLISM AND INCORPORATION INTO CELLULAR DNA BY 5'-AMINO-5'-DEOXYTHYMIDINE IN NORMAL MOUSE-TISSUESAND 2 HUMAN COLON-CANCER XENOGRAFTS

This in vivo study examines the ability of 5'-amino-5'-deoxythymidine (5'-AdThd) to modulate 5-iododeoxyuridine (IdUrd) cellular metabolism in two human colon cancer xenografts (HT 29 and HCT-116), two actively proliferating normal mouse tissues (bone marrow and intestine), and a quiescent normal mouse tissue (liver), 5'-AdThd is a thymidine analog ue that at low concentrations (< 30 mu M) can increase thymidine kinas e activity, which is the rate-limiting enzyme for activation of IdUrd, We reported recently that the in vitro incubation of HT 29 and HCT-11 6 cells in 5'-AdThd + IdUrd resulted in an enhancement of 5-iodo-2'-dU TP pools, IdUrd DNA incorporation, and subsequent radiosensitization c ompared with incubation with IdUrd alone (Clin, Cancer Res., 1: 407-41 6, 1995), These in vitro effects were more significant in the radiores istant cell line HT 29, Using a 6-day continuous infusion of IdUrd (50 or 100 mg/kg/day) and/or 5'-AdThd (200 mg/kg/day), no increase in sys temic toxicity (percentage of body weight loss) was observed in athymi c nude mice with 5'-AdThd alone or when combined with IdUrd, There was significant dose-dependent, systemic toxicity with IdUrd, which was r eversible within 3 days of completing the lower-dose IdUrd infusion. H owever, a comparison of plasma levels during the 6-day continuous infu sion of IdUrd a 5'-AdThd showed a significant interaction of IdUrd and 5'-AdThd, resulting in higher plasma levels by day 6 of both compound s and the principal metabolites, iodouracil and deoxyuridine, which is consistent with nonlinear saturating effects on dihydrouracil dehydro genase, Coadministration of IdUrd and 5'-AdThd resulted in an increase in the percentage of IdUrd DNA incorporation in the two proliferating normal tissues, which was significant only with the lower IdUrd dose, No effect on IdUrd DNA incorporation was found in normal liver at eit her IdUrd dose a 5'-AdThd, Similar to our in vitro data, the continuou s infusion of IdUrd and 5'-AdThd showed a significant effect by increa sing the percentage of IdUrd DNA incorporation in HT-29 xenografts at both IdUrd doses, whereas coadministration of 5'-AdThd had no such eff ect in HCT-116 xenografts.