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
Tj. Kinsella et al., 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, CLIN CANC R, 6(4), 2000, pp. 1468-1475
In anticipation of an initial clinical Phase I trial in patients with high-
grade gliomas of p.o. administered 5-iodo-2-pyrimidinone-2'-deoxyribose (IP
dR) given daily for 14 days as a prodrug for 5-iodo-2'-deoxyuridine (IUdR)-
mediated tumor radiosensitization, we determined the systemic toxicities an
d 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 radi
osensitization with this IPdR-dosing schedule to radiation therapy (XRT) al
one (2 Gy/day for 4 days) or to XRT after continuous infusion IUdR for 14 d
ays 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 cel
ls 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 infusio
n IUdR for 14 days (1.4 +/- 0.1%). Compared to XRT alone, a significant sen
sitizer 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 xenograf
ts. 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 wer
e 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 res
ults in no significant systemic toxicity in athymic mice and is associated
with significant radiosensitization using this human glioblastoma multiform
e xenograft model. Based on these data and our previously published data us
ing shorter IPdR dosing schedules, which also demonstrate an improved thera
peutic index for IPdR compared to IUdR, an initial clinical Phase I and pha
rmacokinetic study of p.o. IPdR daily for 14 days is being designed.