Azidothymidine enhances fluorodeoxyuridine-mediated radiosensitization.
OBJECTIVE
To examine the role of DNA repair and altered thymidine analogues in altering the response to radiation during thymidine deprivation.


METHODS
Mismatch repair-deficient and -proficient cell lines HEC59 and HC-2.4 were treated with fluorodeoxyuridine (FUdR), azidothymidine (AZT), and irradiation either alone or in combination, and outcomes of clonogenic survival and cell-cycle distributions were determined.


RESULTS
Survival outcomes for all treatments were similar for both cell lines, suggesting that hMSH2 does not significantly influence thymidine deprivation toxicity or radiosensitization. The chain-terminating thymidine analogue AZT increased the toxicity of FUdR and increased DNA fragmentation. The combination of FUdR and AZT afforded greater radiosensitization than either drug alone. Drug enhancement ratios, the degree of excess radiation-induced cell death in drug-treated cultures compared with radiation alone for HEC59, were 1.2, 1.4, and 1.8 for AZT, FUdR, and the combination, respectively. Enhancement ratios for HC-2.4 were 1.3, 1.5, and 1.8 for AZT, FUdR, and the combination, respectively.


CONCLUSIONS
Azidothymidine, a chain-terminating thymidine analogue, can enhance the radiosensitizing affects of thymidine deprivation. Deoxyribonucleic acid strand breaks may play an important role in the mechanism of thymidine deprivation-induced radiosensitization.
Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 55805, USA.
Chang-Ming
CM
Chen
Monika
M
Johnson
Brian J
BJ
Smith
Ken
K
Dornfeld
D000963:Antimetabolites / Q000378:metabolism / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D003114:Colony-Forming Units Assay / Q000379:methods; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage; D053843:DNA Mismatch Repair / Q000502:physiology; D003856:Deoxyuracil Nucleotides / Q000378:metabolism; D004357:Drug Synergism; D005434:Flow Cytometry; D005467:Floxuridine / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D016012:Poisson Distribution; D011836:Radiation Tolerance / Q000187:drug effects* / Q000235:genetics; D013936:Thymidine / Q000378:metabolism*; D013942:Thymine Nucleotides / Q000378:metabolism; D015215:Zidovudine / Q000378:metabolism / Q000494:pharmacology*
D000963:Antimetabolites; D003856:Deoxyuracil Nucleotides; D013942:Thymine Nucleotides; D005467:Floxuridine; C027078:deoxyuridine triphosphate; D015215:Zidovudine; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein; C024157:thymidine 5'-triphosphate; D013936:Thymidine