High relative biologic effectiveness of carbon ion radiation on induction of rat mammary carcinoma and its lack of H-ras and Tp53 mutations.
OBJECTIVE
The high relative biologic effectiveness (RBE) of high-linear energy transfer (LET) heavy-ion radiation has enabled powerful radiotherapy. The potential risk of later onset of secondary cancers, however, has not been adequately studied. We undertook the present study to clarify the RBE of therapeutic carbon ion radiation and molecular changes that occur in the rat mammary cancer model.


METHODS
We observed 7-8-week-old rats (ACI, F344, Wistar, and Sprague-Dawley) until 1 year of age after irradiation (0.05-2 Gy) with either 290 MeV/u carbon ions with a spread out Bragg peak (LET 40-90 keV/mum) generated from the Heavy-Ion Medical Accelerator in Chiba or (137)Cs gamma-rays.


RESULTS
Carbon ions significantly induced mammary carcinomas in Sprague-Dawley rats but less so in other strains. The dose-effect relationship for carcinoma incidence in the Sprague-Dawley rats was concave downward, providing an RBE of 2 at a typical therapeutic dose per fraction. In contrast, approximately 10 should be considered for radiation protection at low doses. Immunohistochemically, 14 of 18 carcinomas were positive for estrogen receptor alpha. All carcinomas examined were free of common H-ras and Tp53 mutations. Importantly, lung metastasis (7%) was characteristic of carbon ion-irradiated rats.


CONCLUSIONS
We found clear genetic variability in the susceptibility to carbon ion-induced mammary carcinomas. The high RBE for carbon ion radiation further supports the importance of precise dose localization in radiotherapy. Common point mutations in H-ras and Tp53 were not involved in carbon ion induction of rat mammary carcinomas.
Imaoka
Tatsuhiko
T
Experimental Radiobiology for Children's Health Research Group, Anagawa, Chiba, Japan. t_imaoka@nirs.go.jp
Nishimura
Mayumi
M
Kakinuma
Shizuko
S
Hatano
Yukiko
Y
Ohmachi
Yasushi
Y
Yoshinaga
Shinji
S
Kawano
Akihiro
A
Maekawa
Akihiko
A
Shimada
Yoshiya
Y
D000818:Animals; D002244:Carbon / Q000009:adverse effects*; D002588:Cesium Radioisotopes; D004307:Dose-Response Relationship, Radiation; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D020022:Genetic Predisposition to Disease; D020450:Heavy Ions / Q000009:adverse effects*; D018499:Linear Energy Transfer; D008325:Mammary Neoplasms, Experimental / Q000737:chemistry / Q000209:etiology* / Q000235:genetics; D009363:Neoplasm Proteins / Q000032:analysis; D009376:Neoplasms, Hormone-Dependent / Q000737:chemistry; D009381:Neoplasms, Radiation-Induced / Q000737:chemistry / Q000235:genetics; D017354:Point Mutation; D011835:Radiation Protection; D051381:Rats; D011912:Rats, Inbred ACI; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000032:analysis; D012062:Relative Biological Effectiveness; D013045:Species Specificity
D002588:Cesium Radioisotopes; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; D002244:Carbon