title: Wortmannin efficiently suppresses the recovery from radiation-induced damage in pimonidazole-unlabeled quiescent tumor cell population.
abstract: Labeling of proliferating (P) cells in mice bearing EL4 tumors was achieved by continuous administration of 5-bromo-2'-deoxyuridine (BrdU). Tumors were irradiated with γ-rays at 1 h after pimonidazole administration followed by caffeine or wortmannin treatment. Twenty-four hours later, assessment of the responses of quiescent (Q) and total (= P + Q) cell populations were based on the frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of the pimonidazole-unlabeled tumor cell fractions was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. The pimonidazole-unlabeled cell fraction showed significantly enhanced radio-sensitivity compared with the whole cell fraction more remarkably in Q cells than total cells. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using an assay performed 24 hours after irradiation, was more clearly observed in Q cells than total cells. In both the pimonidazole-unlabeled and the whole cell fractions, wortmannin efficiently suppressed the reduction in sensitivity due to delayed assay. Wortmannin combined with γ-ray irradiation is useful for suppressing the recovery from radiation-induced damage especially in the pimonidazole-unlabeled cell fraction within the total and Q tumor cell populations.
authors.affiliation: Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka, 590-0494, Japan. smasuna@rri.kyoto-u.ac.jp
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Masunaga
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Minoru
authors.initials: M
authors.lastname: Suzuki
authors.forename: Natsuko
authors.initials: N
authors.lastname: Kondo
authors.forename: Masaru
authors.initials: M
authors.lastname: Narabayashi
authors.forename: Akira
authors.initials: A
authors.lastname: Maruhashi
authors.forename: Koji
authors.initials: K
authors.lastname: Ono
mesh_terms: D000730:Androstadienes / Q000008:administration & dosage*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects*; D004347:Drug Interactions; D004357:Drug Synergism; D008223:Lymphoma / Q000473:pathology / Q000503:physiopathology* / Q000532:radiotherapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009593:Nitroimidazoles / Q000008:administration & dosage*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D013194:Staining and Labeling; D016896:Treatment Outcome; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C033815:pimonidazole; D000077191:Wortmannin