Influence of manipulating hypoxia in solid tumors on the radiation dose-rate effect in vivo, with reference to that in the quiescent cell population.
OBJECTIVE
The aim of this study was to clarify the effect of manipulating intratumor hypoxia on radiosensitivity under reduced dose-rate (RDR) irradiation.


METHODS
Tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. They received gamma-rays or accelerated carbon-ion beams at high dose-rate (HDR) or RDR with or without tumor clamping to induce hypoxia. Some mice without clamping received nicotinamide, an acute hypoxia-releasing agent or misonidazole, a hypoxic cell radio-sensitizer before irradiation. The responses of quiescent (Q) and total (= P + Q) cells were assessed by the micronucleus frequency using immunofluorescence staining for BrdU.


RESULTS
The clearer decrease in radiosensitivity in Q than total cells after RDR gamma-ray irradiation was suppressed with carbon-ion beams, especially with a higher linear energy transfer value. Repressing the decrease in the radiosensitivity under RDR irradiation through keeping tumors hypoxic during irradiation and enhancing the decrease in the radiosensitivity by nicotinamide were clearer with gamma-rays and in total cells than with carbon-ion beams and in Q cells, respectively. Inhibiting the decrease in the radiosensitivity by misonidazole was clearer with gamma-rays and in Q cells than with carbon-ion beams and in total cells, respectively.


CONCLUSIONS
Manipulating hypoxia during RDR as well as HDR irradiation influences tumor radiosensitivity, especially with gamma-rays.
Masunaga
Shin-ichiro
S
Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Sennan-gun, Osaka, Japan. smasuna@rri.kyoto-u.ac.jp
Hirayama
Ryoichi
R
Uzawa
Akiko
A
Kashino
Genro
G
Takata
Takushi
T
Tanaka
Hiroki
H
Suzuki
Minoru
M
Kinashi
Yuko
Y
Liu
Yong
Y
Koike
Sachiko
S
Ando
Koichi
K
Ono
Koji
K
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001973:Bromodeoxyuridine / Q000008:administration & dosage; D002250:Carbon Radioisotopes / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000473:pathology* / Q000532:radiotherapy*; D015687:Cell Hypoxia; D002470:Cell Survival / Q000528:radiation effects; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005455:Fluorescent Antibody Technique; D005720:Gamma Rays / Q000627:therapeutic use; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000008:administration & dosage; D009536:Niacinamide / Q000008:administration & dosage; D011836:Radiation Tolerance / Q000528:radiation effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D014407:Tumor Cells, Cultured / Q000528:radiation effects; D014803:Vitamin B Complex / Q000008:administration & dosage
D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D011838:Radiation-Sensitizing Agents; D014803:Vitamin B Complex; D009536:Niacinamide; D008920:Misonidazole; D001973:Bromodeoxyuridine