AN IN-VIVO COMPARISON OF ORAL 5-IODO-2'-DEOXYURIDINE AND 5-IODO-2-PYRIMIDINONE-2'-DEOXYRIBOSE TOXICITY, PHARMACOKINETICS, AND DNA INCORPORATION IN ATHYMIC MOUSE-TISSUES AND THE HUMAN COLON-CANCER XENOGRAFT, HCT-116

5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) was recently reported to b e converted to 5-iodo-2'-deoxyuridine (IUdR) by an aldehyde oxidase, m ost concentrated in liver tissue. We questioned whether IPdR could be used as a p.o. hepatotropic prodrug to increase the percentage of IUdR -DNA incorporation into liver tumors compared to normal liver with acc eptable systemic toxicity. Athymic nude mice with human colon cancer ( HCT-116) xenograft tumors as liver metastases and s.c. flank tumors re ceived daily p.o. boluses (via gastric tubes) of IUdR or IPdR for 6 da ys. The maximum tolerated dose of IUdR was 250 mg/kg/day and was assoc iated with a >10% weight loss and a high percentage of IUdR-DNA incorp oration (>5%) into normal bone marrow and intestine. In contrast, anim als tolerated escalating doses of IPdR to 1 gm/kg/day without weight l oss and with less (1.5-4%) IUdR-DNA incorporation in normal tissues. P harmacokinetic analysis of p.o. IPdR showed peak plasma levels of IPdR and IUdR within 15-45 min, suggesting efficient conversion of IPdR to IUdR. Aldehyde oxidase activity was found in normal liver tissue but not in other normal or tumor tissues. Additionally, we found a 2-3 tim es greater percentage of IUdR-DNA incorporation in tumor with IPdR tha n IUdR at the highest doses used. However, no differential effect in t he percentage of IUdR-DNA incorporation was noted between liver metast ases and s.c. tumors with either IPdR or IUdR. We conclude that p.o. I PdR offers a greater therapeutic index for tumor incorporation (and pr esumably radiosensitization) than a similar schedule of IUdR.