The effects of leucovorin and dipyridamole on fluoropyrimidine-induced radiosensitization.
The biomodulators leucovorin and dipyridamole potentiate the cytotoxicity of 5-fluorodeoxyuridine (FdUrd) and 5-fluorouracil (5-FU), respectively. It was hypothesized that these biomodulators would increase fluoropyrimidine-mediated radiosensitization. This hypothesis was tested using cultured HT29 human colon cancer cells. As was predicted, leucovorin increased both FdUrd-mediated cytotoxicity and radiosensitization. The increase in radiation sensitivity was associated with a decrease in the repair of radiation-induced DNA double strand breaks (DSB's). Dipyridamole potentiated the cytotoxicity produced by 5-FU. However, dipyridamole appeared to confer slight protection from irradiation, thus decreasing 5-FU-mediated radiosensitization. This demonstrates that the simple fact that a biomodulator can increase fluoropyrimidine-induced cytotoxicity does not guarantee a corresponding increase in radiation sensitivity. Clinical trials combining fluoropyrimidines and their biomodulators will need to take these potentially complex interactions into account.
Lawrence
T S
TS
Dept. of Radiation Oncology, University of Michigan Medical Center, Ann Arbor 48109-0582.
Heimburger
D K
DK
Shewach
D S
DS
D000230:Adenocarcinoma / Q000532:radiotherapy*; D003110:Colonic Neoplasms / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D004260:DNA Repair / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000528:radiation effects; D004176:Dipyridamole / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
D004273:DNA, Neoplasm; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; D004176:Dipyridamole; C029269:5-fluoropyrimidine; D002955:Leucovorin