Iododeoxyuridine radiosensitization of human glioblastoma cells exposed to acute and chronic gamma irradiation: mechanistic implications and clinical relevance.
OBJECTIVE
Iododeoxyuridine (IdUrd) is a recognized sensitizer of sparsely and some densely ionizing radiations. The mechanism of sensitization remains uncertain. Sensitization is likely to involve increased production of DNA damage and/or inhibition of DNA damage repair. To test these possibilities, we have characterized acute and chronic radiosensitization, and the sublethal damage repair capacity of two human glioblastoma cell lines, with or without clinically relevant concentrations of IdUrd.


METHODS
Exponentially growing human glioblastoma cell lines, G18 and U251, were irradiated with acute (1.4 Gy/min) and chronic (20, 40, and 80 cGy/hr) cobalt 60 exposures in the presence and absence of 0 to 10 microM IdUrd. Clonogenic survival was determined. Sensitizer enhancement ratios and global survival curve comparisons were determined with and without IdUrd. Repair half-times for chronic exposures with and without IdUrd were calculated. Split-dose recovery following acute fractions of 5 Gy separated by 0, 0.5, 1, 2, and 5 hours was evaluated.


RESULTS
Following acute exposure, a sensitizer enhancement ratio at 10% survival of 1.85 and 1.75 was observed at concentrations of 10 microM IdUrd for the G18 and U251 cell lines, respectively. A global comparison of the survival curves similarly revealed significant sensitization at 10 microM IdUrd. Sensitizer enhancement ratios and global comparisons of the chronic exposures showed significant sensitization in the presence of 2 microM IdUrd for both lines. No significant interaction between dose rate and IdUrd effect could be shown using a global comparison. Repair half-times for chronic exposures were similar in the presence or absence of IdUrd. Both cell lines demonstrate capacity for sublethal damage repair in the presence of 2 microM IdUrd in split-dose experiments.


CONCLUSIONS
The results of the chronic clonogenic and split-dose studies suggest that increased DNA damage production contributes to the mechanism of IdUrd radio-sensitization, perhaps more so than repair inhibition. A capacity for sublethal damage repair is not necessarily a prerequisite for sensitization. IdUrd remains an attractive sensitizer of ionizing irradiation delivered at high or low dose rates, particularly for actively growing tumors located in quiescent normal tissues.
Schultz
C J
CJ
Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee 53226, USA.
Gaffney
D K
DK
Lindstrom
M J
MJ
Kinsella
T J
TJ
D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D005720:Gamma Rays; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D006801:Humans; D007065:Idoxuridine / Q000494:pharmacology*; D066298:In Vitro Techniques; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011859:Radiography; D014407:Tumor Cells, Cultured
D019384:Nucleic Acid Synthesis Inhibitors; D011838:Radiation-Sensitizing Agents; D007065:Idoxuridine