Preclinical toxicity and efficacy study of a 14-day schedule of oral 5-iodo-2-pyrimidinone-2'-deoxyribose as a prodrug for 5-iodo-2'-deoxyuridine radiosensitization in U251 human glioblastoma xenografts.
In anticipation of an initial clinical Phase I trial in patients with high-grade gliomas of p.o. administered 5-iodo2-pyrimidinone-2'-deoxyribose (IPdR) given daily for 14 days as a prodrug for 5-iodo-2'-deoxyuridine (IUdR)-mediated tumor radiosensitization, we determined the systemic toxicities and the percentage IUdR-DNA incorporation in normal athymic mouse tissues and a human glioblastoma xenograft (U251) after this dosing schedule of IPdR. Using a tumor regrowth assay of s.c. U251 xenografts, we also compared radiosensitization with this IPdR-dosing schedule to radiation therapy (XRT) alone (2 Gy/day for 4 days) or to XRT after continuous infusion IUdR for 14 days at the maximum tolerated dose in mice (100 mg/kg/day). Athymic mice with and without U251 s.c. xenografts tolerated 750 or 1500 mg/kg/day of p.o. IPdR (using gastric lavage) for 14 days without weight loss or activity level changes during treatment and for a 28-day posttreatment observation period. The percentage IUdR-DNA incorporation in U251 tumor cells was significantly higher after p.o. IPdR (750 and 1500 mg/kg/day) for 14 days (3.1 +/- 0.2% and 3.7 +/- 0.3%, respectively) than continuous infusion IUdR for 14 days (1.4 +/- 0.1%). Compared to XRT alone, a significant sensitizer enhancement ratio (SER) was found with the combination of p.o. IPdR (1500 mg/kg/d) + XRT (SER = 1.31; P = 0.05) but not for the combination of continuous infusion IUdR + XRT (SER = 1.07; P = 0.57) in the U251 xenografts. The percentage IUdR-DNA incorporation after IPdR at 1500 mg/kg/day for 14 days in normal bone marrow, normal small intestine, and normal liver were 1.2 +/-0.2%, 3.3 +/- 0.3%, and 0.2 +/- 0.1%, respectively. We conclude that a 14-day p.o. schedule of IPdR at up to 1500 mg/kg/day results in no significant systemic toxicity in athymic mice and is associated with significant radiosensitization using this human glioblastoma multiforme xenograft model. Based on these data and our previously published data using shorter IPdR dosing schedules, which also demonstrate an improved therapeutic index for IPdR compared to IUdR, an initial clinical Phase I and pharmacokinetic study of p.o. IPdR daily for 14 days is being designed.
Kinsella
T J
TJ
Department of Radiation Oncology, Case Western Reserve University School of Medicine and University Hospitals of Cleveland/Ireland Cancer Center, Ohio 44106-6068, USA.
Vielhuber
K A
KA
Kunugi
K A
KA
Schupp
J
J
Davis
T W
TW
Sands
H
H
D000284:Administration, Oral; D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007065:Idoxuridine / Q000378:metabolism / Q000627:therapeutic use*; D008110:Liver Extracts / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D011355:Prodrugs / Q000627:therapeutic use*; D011741:Pyrimidine Nucleosides / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D008110:Liver Extracts; D011355:Prodrugs; D011741:Pyrimidine Nucleosides; D011838:Radiation-Sensitizing Agents; C045889:ropidoxuridine; D004247:DNA; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase; D007065:Idoxuridine