Radiosensitization of human tumor cells by alpha-difluoromethylornithine.
The effect of polyamine depletion on the radiosensitivity of a human tumor cell line was investigated. CAL 18 A cells, derived from a breast carcinoma, were incubated with alpha-difluoromethylornithine (DFMO)--a specific and irreversible inhibitor of ornithine decarboxylase (ODC)--at a 1 mM or 10-mM concentration for either 1 hr or 24 hr and irradiated thereafter. Survival curves of exponentially growing cells revealed a moderate but significant enhancement of radiosensitivity as compared to untreated irradiated cells. Maximum radiosensitization was observed at a concentration of 10 mM after 1 hr incubation. Plateau-phase cells were used to study the effect of polyamine inhibition on repair of radiation-induced potentially lethal damage (PLD). DFMO enhanced the radiation response and significantly inhibited PLD repair in these cells. Measurement of ODC indicated that this enzyme was markedly inactivated upon brief incubation of CAL 18 A cells with DFMO, reflecting a depletion of polyamine synthesis. These results extend findings that have demonstrated enhancement of drug-induced cytotoxicity, and raise the possibility of clinical use of this substance for potentiation of radiation response.
D001943:Breast Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D002455:Cell Division / Q000528:radiation effects; D002460:Cell Line; D002470:Cell Survival / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000528:radiation effects; D000518:Eflornithine; D006801:Humans; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000096:biosynthesis; D011838:Radiation-Sensitizing Agents
D004273:DNA, Neoplasm; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D011838:Radiation-Sensitizing Agents; D009952:Ornithine; D000518:Eflornithine