Preclinical evaluation of 5-iodo-2-pyrimidinone-2'-deoxyribose as a prodrug for 5-iodo-2'-deoxyuridine-mediated radiosensitization in mouse and human tissues.
We reported previously that p.o. administered 5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) was efficiently converted to 5-iodo-2'-deoxyuridine (IUdR) in athymic mice (T. J. Kinsella et al., Cancer Res., 54: 2695-2700, 1994). Here, we further evaluate IPdR metabolism, systemic toxicity, and percentage DNA incorporation in athymic mouse normal tissues and a human colon cancer xenograft (HT29) using higher p.o. doses of IPdR. These data are compared to results using a continuous infusion of IUdR at the maximum tolerable dose. We also evaluate IPdR metabolism in cytosolic extracts from normal human liver, normal human intestine, and human colorectal cancer specimens. Athymic mice tolerated a daily p.o. bolus of up to 2 g/kg IPdR for 6 days with minimal host toxicity (< or = 10% body weight loss). There was rapid conversion of IPdR to IUdR, with peak plasma levels of IUdR of 40-75 microM at 10 min following a p.o. IPdR bolus of 250-1500 mg/kg. The percentage IUdR-DNA in the HT29 s.c. human tumor xenografts increased 1.5 times (2.3-3.6%) with IPdR doses above 1 g/kg/day for 6 days, whereas the percentage IUdR-DNA incorporation in two proliferating normal tissues (4-4.5% in intestine; 1.6-2.2% in bone marrow) and a quiescent normal tissue (< or = 1% in liver) showed < 1.5-fold increases with the IPdR dose escalation between 1-2 g/kg/day for 6 days. In contrast, using a continuous infusion of IUdR at 100 mg/kg/day, significant systemic toxicity (> 20% body weight loss) was found by day 6 of the infusion. Steady-state plasma IUdR levels were 1.0-1.2 microM during the 6-day infusion, and percentage IUdR-DNA incorporations of 2.3, 8, 6, and 1% were measured in s.c. tumors, normal intestine, normal bone marrow, and normal liver, respectively, following the 6-day infusion. Thus, the p.o. IPdR schedule has an improved therapeutic index, based on percentage IUdR-DNA incorporation in normal and tumor tissues, compared to continuous infusion IUdR at the maximum tolerable dose in athymic mice with this human tumor xenograft. Additionally, a tumor regrowth assay to assess the radiation response of HT29 s.c. xenografts showed a 1.5-fold enhancement (time to regrow to 300% initial tumor volume) with IPdR (1000 mg/kg/day for 6 days) plus fractionated irradiation (XRT; 2 Gy/day for 4 days), compared to XRT (2 Gy/day for 4 days) alone. No enhancement in the radiation response of HT29 s.c. xenografts was found with continuous infusion IUdR (100 mg/kg/day for 6 days) plus XRT (2 Gy/day for 4 days), compared to XRT alone. Using cytosolic extracts from normal human liver specimens, we found a rapid (15-min) conversion of IPdR to IUdR. Coincubation of liver cytosol with IPdR and allopurinol, an inhibitor of xanthine oxidase, had no inhibitory effect on IPdR metabolism, whereas coincubation with IPdR and isovanillin or menadione, analogue substrates for aldehyde oxidase, effectively reduced the amount of IPdR oxidized to IUdR. Significantly less metabolism of IPdR to IUdR was seen in cytosolic extracts from normal human intestine specimens, and no metabolism of IPdR was found in cytosolic extracts from colorectal liver metastases in two patients and from the HT29 human colon cancer xenografts in athymic mice. These additional data indicate that IPdR has the potential for clinical use as a p.o. prodrug for IUdR-mediated radiosensitization of resistant human cancers.
Kinsella
T J
TJ
Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-5056, USA.
Kunugi
K A
KA
Vielhuber
K A
KA
Potter
D M
DM
Fitzsimmons
M E
ME
Collins
J M
JM
D000818:Animals; D004247:DNA / Q000378:metabolism; D005260:Female; D006801:Humans; D007065:Idoxuridine / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000532:radiotherapy; D011355:Prodrugs / Q000627:therapeutic use*; D011741:Pyrimidine Nucleosides / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D011355:Prodrugs; D011741:Pyrimidine Nucleosides; D011838:Radiation-Sensitizing Agents; C045889:ropidoxuridine; D004247:DNA; D007065:Idoxuridine