Treatment of isografted 9L rat brain tumors with beta-5-o-carboranyl-2'-deoxyuridine neutron capture therapy.
beta-5-o-Carboranyl-2'-deoxyuridine (D-CDU) is a nontoxic pyrimidine nucleoside analogue designed for boron neutron capture therapy of brain tumors. In vitro studies indicated that D-CDU accumulates to levels 92- and 117-fold higher than the extracellular concentration in rat 9L and human U-251 glioma cells, respectively, and persists for several hours at levels 5-fold higher than the extracellular concentration. Furthermore, D-CDU was not toxic to rats injected i.p. with up to 150 mg/kg. On the basis of these studies, D-CDU was evaluated as a neutron capture therapy agent using rats bearing stereotactically implanted intracranial 9L tumors at single i.p. doses of 30 mg/kg and 150 mg/kg of D-CDU (20% 10B enriched), given 2 h before irradiation with thermal neutrons. Boron concentrations in tumors 2 h after dosing were 2.3 +/- 1.6 and 7.4 +/- 1.3 micrograms boron/g tissue (mean +/- SD), corresponding to tumor/brain ratios of 11.5 +/- 3.6 and 6.8 +/- 2.0 micrograms boron/g tissue for the low and high doses, respectively. All untreated animals died within 28 days, whereas half survived at days 32, 55, and 38 for groups receiving neutrons only, 30 mg/kg D-CDU, and 150 mg/kg D-CDU, respectively. Odds ratios of all treatment groups differed significantly from the untreated group (P < 0.002; logrank test). The median survival time for the 30 mg/kg-treated group but not for the 150 mg/kg-treated group was significantly longer than for rats treated with neutrons only (P = 0.036), which may correlate with the decreased tumor selectivity for D-CDU observed at the higher dose. Additional pharmacodynamic studies are warranted to determine optimal dosing strategies for D-CDU.
Schinazi
R F
RF
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA. rschina@emory.edu
Hurwitz
S J
SJ
Liberman
I
I
Juodawlkis
A S
AS
Tharnish
P
P
Shi
J
J
Liotta
D C
DC
Coderre
J A
JA
Olson
J
J
D000818:Animals; D001896:Boron Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D016754:Boron Neutron Capture Therapy; D001932:Brain Neoplasms / Q000532:radiotherapy*; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D008297:Male; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D014185:Transplantation, Isogeneic; D014407:Tumor Cells, Cultured
D001896:Boron Compounds; D011838:Radiation-Sensitizing Agents; C087057:5-carboranyl-2'-deoxyuridine; D003857:Deoxyuridine