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 be converted to 5-iodo-2'-deoxyuridine (IUdR) by an aldehyde oxidase, most 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 acceptable systemic toxicity. Athymic nude mice with human colon cancer (HCT-116) xenograft tumors as liver metastases and s.c. flank tumors received daily p.o. boluses (via gastric tubes) of IUdR or IPdR for 6 days. The maximum tolerated dose of IUdR was 250 mg/kg/day and was associated with a > 10% weight loss and a high percentage of IUdR-DNA incorporation (> 5%) into normal bone marrow and intestine. In contrast, animals tolerated escalating doses of IPdR to 1 gm/kg/day without weight loss and with less (1.5-4%) IUdR-DNA incorporation in normal tissues. Pharmacokinetic 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 times greater percentage of IUdR-DNA incorporation in tumor with IPdR than IUdR at the highest doses used. However, no differential effect in the percentage of IUdR-DNA incorporation was noted between liver metastases and s.c. tumors with either IPdR or IUdR. We conclude that p.o. IPdR offers a greater therapeutic index for tumor incorporation (and presumably radiosensitization) than a similar schedule of IUdR.
Kinsella
T J
TJ
Department of Human Oncology, University of Wisconsin Medical School, Madison 53792.
Kunugi
K A
KA
Vielhuber
K A
KA
McCulloch
W
W
Liu
S H
SH
Cheng
Y C
YC
D000284:Administration, Oral; D000818:Animals; D003110:Colonic Neoplasms / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D005260:Female; D006801:Humans; D007065:Idoxuridine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary; D051379:Mice; D009368:Neoplasm Transplantation; D011741:Pyrimidine Nucleosides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D014018:Tissue Distribution
D011741:Pyrimidine Nucleosides; C045889:ropidoxuridine; D004247:DNA; D007065:Idoxuridine