Bromodeoxyuridine-mediated radiosensitization in human glioma: the effect of concentration, duration, and fluoropyrimidine modulation.
OBJECTIVE
To define the relative influence of duration of exposure, concentration, and modulation by fluorodeoxyuridines (FdUrd) on the incorporation of 5-bromo-2-deoxyuridine (BrdUrd) into DNA of a human malignant glioma line (D-54) in vitro and in vivo.


METHODS



METHODS
an established human malignant glioma line (D-54) was exposed to a clinically achievable concentration of BrdUrd to model intravenous (1 microM BrdUrd) and intraarterial (4 microM BrdUrd) conditions. The influence of modulation was assessed using 1 nM FdUrd. Incorporation of BrdUrd, radiosensitization, and cytotoxicity were determined after 24, 72, and 120 h drug exposures. In Vivo studies: nude mice bearing D-54 xenografts were infused with BrdUrd at 100 mg/kg/day for 7 and 14 days or BrdUrd at 400 mg/kg/day for 5 days. The influence of modulation was assessed by combining 100 mg/kg/day of BrdUrd with 0.1, 0.3, and 1 mg/kg/day FdUrd for 7 days. Incorporation of BrdUrd into the DNA of tumor, gut, and marrow were determined.


RESULTS
In Vitro: thymidine replacement and radiosensitization were a function of concentration, and incorporation began to plateau after 2 to 3 population doublings. Modulation with 1 nM FdUrd significantly increased incorporation. Radiosensitization was a linear function of thymidine replacement under all conditions tested. In Vivo: infusion with 400 mg/kg/day for 5 days resulted in greater tumor incorporation (10.3 +/- 0.4% thymidine replaced) than treatment with 100 mg/kg/day for 14 days (6.0 +/- 0.6% of thymidine replaced). Infusion of FdUrd with BrdUrd increased normal tissue incorporation of BrdUrd, but failed to increase BrdUrd incorporation in tumor cells.


CONCLUSIONS
These results suggest that relatively short, high dose rate infusions may be preferable to long, low dose rate infusions. The potential benefit of FdUrd modulation demonstrated in vitro may be difficult to realize using continuous systemic infusions.
McLaughlin
P W
PW
University of Michigan Medical Center, Ann Arbor 48109.
Lawrence
T S
TS
Seabury
H
H
Nguyen
N
N
Stetson
P L
PL
Greenberg
H S
HS
Mancini
W R
WR
D000818:Animals; D001973:Bromodeoxyuridine / Q000008:administration & dosage*; D005467:Floxuridine / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy / Q000532:radiotherapy*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
D011838:Radiation-Sensitizing Agents; D005467:Floxuridine; D001973:Bromodeoxyuridine