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We aimed to determine the effect of carbon ion irradiation on the uptake of N-benzyl-N-11C-methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([11C]DAC), a positron emission tomography (PET) ligand for the peripheral-type benzodiazepine receptor (PBR), in tumor cells and tumor-bearing mice. Spontaneous murine fibrosarcoma (NFSa) cells were implanted into the right hind legs of syngeneic C3H male mice. Conditioning irradiation with 290 MeV/u carbon ions was delivered to the 7- to 8-mm tumors In vitro uptake of [11C]DAC was measured in single NFSa cells isolated from NFSa-bearing mice after irradiation. In vivo biodistribution of [11C]DAC in NFSa-bearing mice was determined by small animal PET scanning and dissection. In vitro autoradiography was performed using tumor sections prepared from mice after PET scanning. In vitro and in vivo uptake of [11C]DAC in single NFSa cells and NFSa-bearing mice was significantly reduced by carbon ion irradiation. The decrease in [11C]DAC uptake in the tumor sections was mainly due to the change in PBR expression. In conclusion, [11C]DAC PET responded to the change in PBR expression in tumors caused by carbon ion irradiation in this study. Thus, [11C]DAC is a promising predictor for evaluating the effect of carbon ion radiotherapy.

A radiobiological method was developed to measure the initial growth of clonogenic tumor cells metastasizing to lung. Thorax of mice was externally irradiated by gamma rays after an intravenous transplantation of syngeneic fibrosarcoma cells. Lung colonies developed 11 days after irradiation were counted and provided surviving fractions. Survival curves moved downward when time interval between transplantation and radiation delayed from 1 to 21 hr, but shifted upward at 48 hr or later. Survival ratios at given doses and the extrapolation number of survival curves fitted to multi-target model were calculated, and plotted against time after the intravenous transplantation. Doubling times of 13.3 and 13.1 hr were obtained by use of the survival ratio and of the extrapolation number, respectively. This method is useful to measure growth dynamics of clonogenic tumor cells at the site of metastasized organ.

The biological effectiveness of carbon ions relative to γ rays (RBE) was compared between the tumor growth delay and an early skin reaction of syngeneic mice. The RBE was larger for a tumor than skin when irradiated with large doses of high-LET (linear energy transfer) carbon ions. The intra-track damage (a term of a linear quadratic model) of a tumor and skin increased equally with an increase of the LET, while the inter-track damage (β term) of skin alone increased with the LET. These data provide evidence that high-LET radiotherapy could achieve therapeutic gain by minimizing the difference in response to fractionated irradiation between the tumor and normal tissue.

We performed dynamic MRI to reveal the characteristic gadopentetate dimeglumine (Gd-DTPA) uptake in carbon-ion irradiated tumor and compare it with photon irradiation. Fibrosarcomas in C3H mice legs were irradiated with either 16 Gy of carbon ions (74 keV/mm) or an equivalent dose (30 Gy) of Cs-137 gamma-rays. Dynamic MRI was performed 1 or 6 days after irradiation when the tumors showed an initial growth delay or incipient regrowth, respectively. The enhancement pattern was visualized by mapping the maximum enhanced time (Tmax), relative signal intensity maximum (SImax), and time delay of starting enhancement (Td). Significantly larger Tmax and Td values were observed in the tumors 1 day after carbon-ion irradiation than in the nonradiated tumors (No-R) and tumors 1 day after gamma-ray irradiation. Among the selected pixels in the tumors 6 days after carbon irradiation, 77% had Tmax values of less than 120 sec, significantly more than in the No-R group. The Tmax maps for the tumors irradiated with gamma-rays showed a similar tendency to the carbon-irradiated ones, and only a significant difference was obtained between tumors 1 and 6 days after irradiation. Tmax and Td in the carbon-ion irradiated tumors were different from those in the gamma-ray-irradiated tumors. These treatment-specific kinetics may be useful in predicting the therapeutic efficacy of carbon-ion treatment.