Effects of p53 Status of Tumor Cells and Combined Treatment With Mild Hyperthermia, Wortmannin or Caffeine on Recovery From Radiation-Induced Damage

Shin-ichiro Masunaga, Keizo Tano, Yu Sanada, Minoru Suzuki, Akihisa Takahashi, Ken Ohnishi, Koji Ono


Background: The aim of the study was to examine the dependency of p53 status and the usefulness of mild hyperthermia (MHT) as an inhibitor of recovery from radiation-induced damage, referring to the response of quiescent (Q) tumor cell population.

Methods: Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector (SAS/neo) were injected subcutaneously into left hind legs of nude mice. Tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells. They received high dose-rate γ-ray irradiation (HDR) immediately followed by localized MHT (40 °C for 2 h), or caffeine or wortmannin administration, or low dose-rate gamma-ray irradiation simultaneously with localized MHT or caffeine or wortmannin administration. Nine hours after the start of irradiation, the tumor cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in cells without BrdU labeling (= Q cells) was determined using immunofluorescence staining for BrdU.

Results: SAS/neo tumor cells, especially intratumor Q cell populations, showed a marked reduction in sensitivity due to the recovery from radiation-induced damage, compared with the total or Q tumor cells within SAS/mp53 tumors that showed little recovery capacity. The recovery from radiation-induced damage was thought to be a p53-dependent event. In both total and Q tumor cells within SAS/neo tumors, especially the latter, MHT efficiently suppressed the reduction in sensitivity caused by leaving an interval between HDR irradiation and the assay and decreasing the irradiation dose-rate, as well as the combination with wortmannin administration.

Conclusions: From the viewpoint of solid tumor control as a whole, including intratumor Q-cell control, non-toxic MHT is useful for suppressing the recovery from radiation-induced damage, as well as wortmannin treatment combined with γ-ray irradiation.

World J Oncol. 2019;10(3):132-141
doi: https://doi.org/10.14740/wjon1203


Recovery from radiation-induced damage; Dose-rate effect; p53 status; Mild hyperthermia; Wortmannin; Caffeine; Quiescent cell

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