Yasuko Hyodo-Taguchi, Shinji Fushiki¡ö, Chikako Kinoshita¡ö, Yuji Ishikawa and Tomohisa Hirobe (¡öKyoto Prefectural University of Medicine, Kyoto 602)
- Keywords: mouse brain, neuronal migration, prenatal chronic irradiation
It is well known that the development of the cerebral cortex in mammals can be severely affected by exposure to ionizing radiation at critical periods during gestation. Quantitative studies of low dose radiation effects on migration of neuronal progenitor cells in the cerebral mantle are required in experimental animals in order to contribute to pathogenic analysis of mental retardation seen among A-bomb survivors exposed in utero. In particular, long-term effects on neuronal allocation in adult animals after prenatal irradiation at different neurogenic stages should be evaluated. We previously reported the effects of acute exposure of developing brains to radiation at embryonic day 14 (E14) in mice. In the present experiments, we investigated effects of continuous exposure to radiation on the migration of neurons from the matrix cell zone towards the neocortical plate in mice during the period of the embryonic days 14 to 17. ¡¡Pregnant mice (C57BLxC3H) received intraperitoneal injection of bromodeoxyuridine (BrdU), 0.5 mg dissolved in 0.5 ml saline¡¿mouse on E14 of pregnancy to label S phase cells. The mice were then irradiated continuously with ¦Ã-rays at dose rates of 0.1 Gy per day, 0.3 Gy per day and 0.94 Gy per day from E14 to E17 by exposing them to a 137Cs source of 370 GBq at different distances. Brains from some embryos on E17 and some of the offspring at 3 and 8 weeks after birth from irradiated and control dames were either immersed or transcardially fixed with 4¡ó paraformaldehyde in 0.1 M phosphate buffer (pH 7.4). Four mm paraffin sections of the parietal cortex were processed for immunohistochemical examination of BrdU-labeled cells, using monoclonal anti-BrdU antibody (Becton Dickinson) followed by the peroxidase reaction visualized with 3,3'-diaminobenzidine. Immunostained sections were carefully observed under a light microscope and the locations of BrdU-labeled cells were plotted onto tracing paper using a camera lucida apparatus. ¡¡BrdU-labeled cells were densely accumulated in the deeper portion of the ventricular zone of E14 mice neocortex. At E17 more than 70¡ó of all of the BrdU-labeled cells were seen in the cortical plate of non-irradiated animals. In animals at 3 and 8 weeks after birth, most of the labeled cells (approximately 70¡ó) were located in layer IV, while some of the cells were located in layers ¢£¡¿¢£ or in layers ¢£¡¿¢£. Chronic exposure to ¦Ã-rays with dose-rates of 0.1 and 0.3 Gy¡¿day from E14 to E17 did not affect the initial migration of neurons in developing the neocortex and relative distribution of BrdU-labeled cells in cerebral cortex in young and mature mice. After continuous irradiation with dose-rate of 0.94 Gy¡¿day for 3 days, decelerated migration of neurons was observed during the period of embryonic development and some difference of distribution pattern of BrdU-labeled cells in mature cerebral cortex was found between prenatally irradiated and control mice. ¡¡We have reported previously decelerated migration of neurons in neocortex during the embryonic period and aberrantly placed neurons in the cerebral cortex in young mice after acute prenatal x-irradiation with dose of less than 1 Gy at E14. From the present results, on the contrary, it seems that deleterious effects of prenatal radiation to development of murine cerebral cortex are reduced by chronic low dose-rate irradiation.
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2¡¥Dose-Response Relationship for Induction of Hepatocellular Tumors in Mice Irradiated Neonatally with Gamma Rays
Shunsaku Sasaki
- Keywords :hepatocellular tumors, gamma rays, dose-response relationship, mice, neonatal period
¡¡Our previous studies demonstrated that mice of the early postnatal period are highly susceptible to induction of hepatocellular tumors. In this report we show the dose-response relationship for induction of hepatocellular tumors which was obtained using a new method. Data for analysis were obtained by a lifetime experiment using a total of 2,978 female B6C3F£± mice. Animals were irradiated at day 0 of the neonatal period with 0.48, 0.95, 1.43, 1.90, 2.38, 2.85, 3.80 or 5.70 Gy gamma rays from 137Cs. After natural death, macroscopic and microscopic examinations were carried out for each mouse. ¡¡Incidences of hepatocellular tumors are plotted against dose of gamma rays in Fig.1. Tumor incidences in all irradiated groups were significantly higher than that in the control group. The shape of the dose-response relationship may be described as follows: 1) rapid increase in incidence in dose range up to 1 Gy; 2) gradual increase in dose range between 1 to 3 Gy; 3) gradual decrease in dose range over 3 Gy. Dose-response relationship for induction of hepatocellular tumors was fitted to a model which was expressed as the equation: I(D) ¡á I(0) (1¡ÜaD)Ž¥(1-bD) Ž¥exp(-cD) where I(D) represents incidence of tumors in a group irradiated with dose D, I(0) incidence in the control group, parameter a the coefficient for induction of tumors, parameter b the coefficient for decrease in incidence by competing risks, and parameter c the coefficient for killing of the potentially tumorigenic cells. From regression analysis, values of the parameters were estimated asfollows: a¡á1.739¡Þ0.135, b¡á0.120¡Þ0.002, c¡á0.082¡Þ0.015. Dose-response relationship for induction of hepatocellular tumors seems to be well described by the equation. This model may be useful for analysis of dose-response relationship for induction of other tumors.
Fig.1. Dose-response relationship for induction of hepatocellular tumors in female B6C3F£± mice irradiated neonatally with gamma rays.
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3¡¥High LET Radiation-Induced Tumors In Mice : Tumor Spectrum and RBEs
Takeshi Furuse, Yuko Noda, Hiroshi Otsu£±, Hiroshi Ohara£² (£±Inst. Environmental Sciences, £²Okayama Univ.)
- Keywords:high LET radiation, radiation carcinogenesis, tumor spectrum, RBE, life shortening
¡¡It has been reported that incidence of liver tumors increased slightly among A-bomb survivors. On the other hand, many cases of radiation therapy using high LET radiation, such as fast neutrons, fission neutrons, protons, and other heavy ion beams, have been carried out during the past 20 years. There is now a fear that secondary tumors may have been induced in those who received high LET radiation therapy. We are studying the delayed carcinogenic effects of low doses of neutrons on a strain of mice relatively resistant to the carcinogenic effects of radiation . ¡¡C57BL¡¿6J male mice (4 weeks of age) were supplied by the Laboratory Plants and Animals Section of our institute. They were maintained under SPF conditions. In this study, each experimental group of mice received an examination to determine the effect of the two types of whole body irradiation on life span and carcinogenesis during their life span. Mice were housed in lucite cages with a micro-organismic barrier system that enabled the mice to breath sterilized air during neutron irradiations. ¡¡Cyclotron-accelerated deuterons up to a mean energy of 30MeV were bombarded on to a thick 10Be target. It radiated neutrons with a mean energy of 13MeV and an averaging LET of 10.7keV¡¿¦Ìm. Gamma-ray contamination was estimated to be less than 4¡ó of the beams. The dose rate was 33cGy¡¿min. ¡¡Daily death checks were carried out, and ordinary autopsies and histological examinations were made on all mice. The life shortening effect of the radiation was analyzed by a life shortening ratio calculated from 50¡ó survival periods obtained from survival curves using the Kaplan-Meire's method. ¡¡All groups of mice and the numbers of their tumors observed are shown in Table 7. The fast neutrons induced a wide variety of tumors, including tumors of the endocrine organs, such as thyroid gland, pituitary gland, and adrenal gland, and soft tissues. Two to five different tumors often occurred simultaneously in one mouse, especially in fast neutron irradiated-mice. Tumor incidence is shown in Table 2. as crude incidence and age-adjusted incidence for each group. The life shortening effect of the radiation was analyzed by z-tests and generalized Wilcoxon tests. Fifty percent survival periods, estimated by the Kaplan-Meier's method, and life shortening effect of these two kinds of radiation on each group(life shortening ratio) are also listed. The effect of gamma-rays was lower than the effect of neutrons., and RBE was calculated as 2.4 for the neutrons. Dose dependent increases in liver tumors were observed in the groups irradiated with 0.125, 0.25, 0.5 and 1Gy of neutrons (Table 2). Higher incidences than that of the control group were observed in the 0.25 and 0.5Gy neutron groups. In this study remarkably higher incidences of liver tumors and a linear increase of the tumors were observed in the mice that received the low dose range of whole body neutron irradiation than in the mice irradiated with gamma-rays. The difference in the dose response between the two kinds of fast neutrons was small. We calculated the RBEs from the slopes of the initial rising curves of these dose response curves as 33 for 2MeV fast neutrons and 24 for 13MeV fast neutrons in our previous study, in which data from low dose gamma-ray irradiated groups was not yet available. We recalculated the RBE using these new data as 33 for 13MeV fast neutrons. RBEs concerning liver tumor were comparable between the two kinds of neutrons.
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4¡¥Effects of Calorie Restriction on Hepatoma in C3H¡¿He Mice
Kazuko Yoshida, Tohoru Inoue¡ö, Kumie Nojima and Toshihiko Sado (¡öNational institute of health sciences)
- Keywords: hepatoma, calorie restriction
Host-defense mechanisms from cancer are known to be modulated by changing an environmental factor. The spontaneous incidence of myeloid leukemia is about 1¡ó in C3H¡¿He male mice, and the incidence increases up to 23.3¡ó when whole-body irradiation is given with 3 Gy of X-rays. However, such radiation induced-increase of myeloid leukemia is significantly decreased by calorie restriction(CR), i.e., 7.9¡ó and 10.7¡ó when CR was started before irradiation(6 weeks old) and after irradiation (10 weeks old). It is well known that C3H¡¿He mice develop hepatoma spontaneously with high incidence. Then this report examined whether such spontaneous tumors would also be decreased by CR. ¡¡Diets consisted of four different calorie controlled regimens, 60, 65, 70 and 95Kcal per week per mouse. The calorie-intake was adjusted by varying the amount of carbohydrate and dextrose, but giving a constant amounts of other nutrients, such as protein, lipid, vitamins and minerals. The body weight of mice was measured weekly. Mice in the restricted groups were controlled to keep their body-weight between 25¡Á27g by an appropriate combination of the four different calorie diets, so that mice were fed with the least-sufficient amounts of calories to maintain normal growth. Animals were placed in 6 groups : the control diet without radiation (CC), the control diet with irradiation at 3Gy (3C), the restriction A group with (3RA) or without (CRA) irradiation, the restriction B group (3RB) with or without (CRB) irradiation. Control diet groups were fed the 95Kcal diet from 6 weeks old over their life span. Restriction A groups were also fed the 95Kcal diet from 6 to 10 weeks old. Restriction B groups were fed the 65Kcal diet, also from 6 to 10 weeks old. Mice in the two restricted groups had their body-weight controlled according to above described procedures. ¡¡The incidence of hepatoma in both control-diet groups, CC and 3C, were 70¡ó and 68¡ó, respectively. On the other hand, the incidence of hepatoma in all groups for calorie restriction significantly decreased, i.e., 31¡ó, 37¡ó, 36¡ó and 51¡ó in CRA, 3RA, CRB and 3RB, respectively. ¡¡The calorie restriction not only reduced the incidence but also reduced the latent period of the hepatoma (Figure1). In the control-diet groups (CC and 3C), the first hepatoma appeared at ages of 406 and 349 days, respectively, whereas, in restricted groups, it appeared at 586 days in CRA and 526 days in 3RA. Interestingly, the incidence of hepatoma was not changed with radiation, however, the onset of hepatoma in all diet groups was promoted by radiation. The calorie restriction reduced not only the myeloid leukemia, but also spontaneous hepatoma.
Fig.1 Cumulative incidence of hepatoma.
[Publications]
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5¡¥Comparison of Dose-Dependent Enhancing Effects of ¦Ã-Ray Irradiation on Urethan-Induced Lung Tumorigenesis in Athymic Nude (nu¡¿nu) Mice and Euthymic (nu¡¿¡Ü) Littermates
Shigeru Kobayashi, Hiroshi Otsu, Yuko Noda and Toshiaki Ogiu
- Keywords:lung tumors, nude mice, urethan, gamma-ray irradiation, tumor acceleration
¡¡The role of immunological surveillance in carcinogenesis is still controversial. In our previous experiments, urethan-lung tumorigenesis in athymic (nu¡¿nu) mice and euthymic (nu¡¿¡Ü) littermates was examined, and it was concluded that immunosurveillance mediated by T-cells could not be demonstrated. However, the reported enhancement of development of various tumors by ionizing radiation might be achieved through modulating host immunological conditions. In the present experiment, nu¡¿nu and littermate nu¡¿¡Ü mice were treated with 1 to 4 Gy of gamma-rays alone at 6 weeks of age or treated with 0.5 mg¡¿g body weight of urethan at 14 days followed by 1 to 4 Gy of gamma-rays 4 weeks later. Lung tumors were assessed at 6.5 months of age. Ionizing radiation itself caused a very low incidence of these lesions. On the other hand, multiplicities and incidences of lung tumors after the urethan treatment were similar between the two phenotypically different groups of mice (1.66 and 1.84 tumors¡¿mouse, 73 and 80¡ó incidences, for nu¡¿nu and nu¡¿¡Ü cases, respectively). This urethan-lung tumorigenesis was significantly enhanced by gamma-rays in both nu¡¿nu and nu¡¿¡Ü mice, and the magnitude of tumor enhancement was somewhat higher in nu¡¿¡Ü mice than in nu¡¿nu mice, especially with 2 Gy dose. In conclusion, the lung tumorigenicity of gamma-ray irradiation itself and the enhancing effect of radiation on urethan-induced tumorigenesis are scarcely influenced by the immuno-surveillance mechanism mediated by T-cells.
[Publications]1)Kobayashi,S., Otsu,H., Noda,Y., Ogiu,T.: Jpn. J. Cancer Res., 122, 231-236, 1996.
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6¡¥Bone Damages in Hind Limb by X-ray Irradiation to Parathyroid and Thyroid in Young Rats
Satoshi Fukuda and Haruzo Iida
- Keywords: x-ray irradiation, bone damage, histomorphometry, parathyroid-thyroid, rat
¡¡Bone damages which occurred after local X-ray irradiation to the neck, including the parathyroid and thyroid, in young male rats were examined and compared to those in groups irradiated to the whole body with dose of 1.25 - 5 Gy, and locally to the hind limb with doses of 5 -15 Gy at the age of 4 weeks. Five months after irradiation, the bone and serum samples were analyzed. Serum PTH level decreased significantly up to 7.5 Gy and calcitonin level was less than the detectable limit over 5 Gy. There was no significant difference in the ionized calcium level. High correlations were seen between doses and individual values such as the bone length, strength and calcium content in the femur, the values decreased significantly in the whole body irradiation group over 2.5 Gy, and those in the hind limb irradiation group at 7.5 - 15 Gy. In the histomorphometric analysis of the secondary spongiosa area in the proximal metaphysis of tibia, bone volume and trabecular thickness had a tendency to decrease up to 5 Gy in the neck and whole body irradiation groups, but to increase over 5 Gy, for the neck as well as whole body and hind limb irradiation groups. Mineral apposition and bone formation rates had a tendency to decrease with the increase of dose and decrease significantly over 7.5 Gy in the hind limb irradiation group. The results indicate that irradiation to the neck locally as well as the whole body in young rats induces damages in bones such as mineral loss and fragility at less than 5 Gy, and all of these advance with morphologic changes such as atrophy over 5 Gy. ¡¡
[Publications] Fukuda, S. and Iida H.: J. Jpn. Soc. Bone Morphom., 5, 47-51, 1995.
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7¡¥Bone Histomorphometric Analysis in the Dahl-Iwai Salt-sensitive Rat (DIS¡¿Eis)
Satoshi Fukuda, Haruzo Iida, Kazuto Yamazaki¡ö and Tsuneo Wakabayashi¡ö (¡öEisai Co., Ltd)
- Keywords:bone histomorphometry, Dahl-Iwai salt-sensitive rat, ospetopenia, osteoporosis
Effects of salt loading on the bones in Dahl-Iwai salt sensitive (DIS¡¿Eis) and resistant (DIR¡¿Eis) rat were examined. Both strains were divided into two groups, and fed on 8.0 ¡ó and 0.3 ¡ó salt diets for 6 weeks after being fed on a 0.3 ¡ó salt diet until 5 weeks old. In the 8.0 ¡ó salt diet group of DIS¡¿Eis rats, there were significant differences in the decrease of body weight, elevation of systolic blood pressure, increase of excreted calcium in urine, decrease of alkalinephosphatase activity, and also in the results on histomorphometric examination for the secondary spongiosa area of undecalcified tibial proximal metaphysis, decrease of bone volume, trabecular number and osteoid volume, and increase of trabecular separation, as compared to those in 0.3 ¡ó salt diet group of DIS¡¿Eis (Fig.1). In the DIR¡¿Eis rats , no significant changes were seen, except for the increase of calcium in plasma between 0.3 ¡ó and 8.0 ¡ó salt diet groups. These results indicate that excessive salt intake is accompanied by osteopenia or osteoporosis and hypertension in rats having a genetic salt sensitive factor. ¡¡
[Publications]Fukuda, S ., Iida, H. Yamazaki, K. and Wakabayashi, Y.: J. Jpn. Soc. Bone Morphom., 5, 135-139, 1995.Fig.1. Bone volume¡¿tissue volume(BV¡¿TV) in each group.
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8¡¥Intestinal Calcium Absorption and Response of Calcium Regulating Hormones in Stroke-prone Spontaneously Hypertensive Rat (SHRSP) as a model of Osteoporosis
Satoshi Fukuda, Satoru Tsuchikura, Haruzo Iida, Katsumi Ikeda¡ö, Yasuo Nara¡ö and Yukio Yamori¡ö (¡öKyoto Univ.)
- Keywords:intestinal calcium absorption, SHRSP, osteoporosis
Because of low levels of serum calcium (Ca) in SHRSP, intestinal Ca absorption and urinary Ca excretion were examined. Intestinal Ca absorption rate from diets was lower in SHRSP than in the normotensive WKY(Wistar Kyoto) and WM(Wistar Mishima) strains at all ages. Urinary Ca excretion was 3-5 times greater and increased with age in SHRSP. With oral administration of vitamin D, the intestinal Ca absorption rate increased significantly in SHRSP at 6 months and in WKY at 12 months. The urinary Ca excretion increased significantly in WKY and SHRSP at 6 months and in WKY at 12 months. ¡¡Absorption rates for various chemical forms of Ca were lower in SHRSP than in WKY and WM, and decreased in the order of oxide ¡ä carbonate ¡ä chloride in SHRSP and WM rats. The absorption rate of CaCl2 was lower in SHRSP than in WM. Ca transport rate was lower and increased with age in SHRSP. Serum Ca levels elevated significantly 15 min after pCa injection in both TPTX and intact groups and the levels were TPTX ¡ä intact, WM ¡ä SHRSP, but these did not change in the intact group and were lower than the base line in the TPTX group after CaCO3 injection in SHRSP and WM rats. In the intact SHRSP group, PTH levels were suppressed, decreasing rather significantly (p¡ã0.001), by pCa at 6 and 12 months, while the levels did not change at 6 months and decreased slightly at 12 months for CaCO3. Calcitonin levels were elevated significantly for CaCO3 (p¡ã0.05) at 6 months and pCa (p¡ã0.001) at 6 and 12 months. Serum Ca levels after intravenous injection were lower in SHRSP than in WM and decreased with age in SHRSP. The results indicate that SHRSP has lower intestinal Ca absorption and higher urinary Ca excretion, but with a latent function for intestinal Ca absorption which is able to respond to Ca regulating hormones for Ca loading in the aged. ¡¡
[Publications]Fukuda, S., Tsuchikura, S., Iida, H., Ikeda, K., Nara, Y. and Yamori, Y.: Clin. Exper, Pharmacol. Physiol. Suppl. 1, S240-241, 1995.
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9¡¥Prevention of Cilia-Associated Respiratory Bacillus by Antibiotics and Its Diagnosis by Polymerase Chain Reaction
Satoru Matsushita, Akihiro Kawano, Tsuneya Matsumoto£±, Kazuo Goto£², Ryoko Nozu£², Akira Takakura£² and Toshio Itoh£² (£±Institute for Environmental Sciences, Rokkasho, £²Central Institute for Experimental Animals, Kawasaki)
- Keywords:CAR bacillus, antibiotics, sulfamerazine, RT-PCR
¡¡The cilia-associated respiratory (CAR) bacillus, a gram-negative filamentous bacterium, was identified in 1985. Since then it has been recognized as one of the causative agents of murine chronic respiratory disease (CRD). Recent reports have shown that CAR bacillus may be potentially widespread in many species of la-boratory and domestic animals. However, little is known yet concerning this disease. The present studies describe prevention and eradication by treatment using antibiotics (Experiment A) and diagnosis by the reverse transcription (RT)-polymerase chain reaction (PCR) (Experiment B). ¡¡Experiment A: Specific-pathogen-free female BALB¡¿c mice, 10 to 11 weeks old, were used. The mice were orally administrated sulfamerazine, ampicillin, and chlortetracycline at a rate of 500 mg¡¿L of drinking water. They were infected by intranasal inoculation with 10£¶ bacilli of the SMR strain of CAR bacillus, and treated with the antibiotics starting 1 week before, 1 week after, or 4 weeks after the inoculation, for 5, 3, or 4 weeks respectively, then were examined. Only the mice administered sulfamerazine starting 1 week before the inoculation had no antibody titers to the bacilli and no pathologic respiratory tract lesions or bacterial colonization. These findings suggest that prevention and eradication of CAR bacillus infection is possible by treatment with sulfamerazine. ¡¡Experiment B: Experimentally infected female Jcl: ICR mice, 4 weeks old, and naturally infected rats were used. In the experimental infection, the mice were in contact with infective mice previously inoculated with 7.5X10£µ bacilli of the CB-M strain. The designs of primers and probe for RT-PCR amplification were based on the 16S rRNA sequences described previously. CAR bacillus was detected in oral swab samples from mice by RT-PCR on day 3 post-contact infection. In the naturally infected rats, infectious rate by RT-PCR corresponded to serum antibody-positive rate by enzyme-linked immunosorbent assay. These findings suggest that the RT-PCR is a specific, highly sensitive and reliable procedure for detecting CAR bacillus in mice and rats. ¡¡
[Publications]1)Matsushita, S. and Suzuki, E.: Lab. Anim. Sci., 45, 503-507, 1995. 2)Goto, K., Nozu, R., Takakura, A., Matsushita, S. and Itoh, T.: Exp. Anim. , 44, 333-336, 1995.
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10¡¥Enhanced Metastasis After Local Irradiation to a Murine Neuroblastoma
Koichi Ando, Sachiko Koike, Mayumi Iwakawa¡ö, Yu-Jan Chen, Reiko Okudaira¡öand Haruo Ohkawa¡ö (¡öTsukuba Univ.)
- Keywords:liver metastasis, surgery, N-methylformamide
¡¡This study was carried out,using a murine model, to determine the effects of local therapy by either surgery or local irradiation on the enhancing pattern of distant metastasis. Transplanted C-1300 neuroblastomas in hind legs of syngeneic mice were treated either by surgery or local irradiation. These local treatments had adverse effects on establishment of distant metastasis. Liver metastasis was found 14 to 18 days after local treatment,but the tumors without treatment did not develop metastasis. Metastatic incidence depended on the size of the primary tumors: amputation of hind legs with primary tumors 9 or 12 mm in diameter produced more liver metastasis than amputation of legs with tumors ¡å 7 mm in diameter. Radiation doses ranging from 22 to 51 Gy completely eradicated 7-mm tumors, but failed to reduce liver metastasis. When systemic drug therapy with N-methylformamide, a maturational agent, was combined with amputation, a remarkable reduction was observed in the number of liver metastases. However, local control by irradiation combined with N-methylformamide treatment did not have any effect on the incidence of liver metastasis. The ineffectiveness of local control by radiotherapy on distant liver metastasis in this neuroblastoma animal model suggests that primary tumors, even those which diminish after irradiation, might keep supplying tumor cells with enhanced metastatic ability toward distant metastatic sites. ¡¡
[Publications]Iwakawa, M., Ando,K., Koike,S., Chen,Y. -J., Okudaira, R. and Ohkawa, H. :Int. J. Pediatric Hematol¡¿Oncol. 2, 433-439, 1995
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11¡¥Mouse Skin Reaction after Fractionated Irradiations with 290 MeV¡¿u Carbon Ions
Koichi Ando, Sachiko Koike, Yu-Jau Chen, Kumie Nemoto, Soichiro Ando, Nobuyoshi Kobayashi, Tohru Ohbuchi, Wakako Shimizu and Tatsuaki Kanai
- Keywords:skin reaction, LET, recovered dose, Fe plot
¡¡Use of heavy particle radiotherapy for malignant disease has recently started in Japan employing carbon-12 beams produced by the HIMAC synchrotron. Current clinical trials of phases ¢£ and ¢£ use a standard protocol of 18 fractions in 6 weeks with dose escalation. This protocol is based on some biological findings and past experience in our institute using fast neutrons. However, the optimum fractionation schedule must be established for more effective treatment. We have investigated carbon-dose responses of skin reactions after daily fractionations to the mouse leg (Fig.1). Irradiations with 1, 2 and 4 fractions indicated that the isoeffective doses for radiation with LETs lower than 20 keV¡¿¦Ìm increased with an increase in the number of fractions, but not the isoeffective dose for radiation with 100 keV¡¿¦Ìm. The recovered dose from 1 to 2 fractions reached a maximum at 40 keV¡¿¦Ìm while the recovered dose per fraction from 2 and 4 fractions decreased with an increase in the LET. The Fe plot was linear at the LETs lower than 20 keV¡¿¦Ìm and at the LET of 100 keV¡¿¦Ìm, but curved slightly at the LETs between 40 keV¡¿¦Ìm and 80 keV¡¿¦Ìm. These results suggest that the Fe plot is not valid at intermediate LETs of 40 keV¡¿¦Ìm through 80 keV¡¿¦Ìm.
Fig.1 Isoeffective doses of carbon ions to produce an averaged skin reaction score of 2.5.¡¡LETs less than 20keV¡¿¦Ìm were located at the entrance plateau while those than 40 keV¡¿¦Ìm were located at the 6¢£cm higher Spread¢£Out¢£Bragg¢£Peak. ¡¡
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