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Objective: Gefitinib (N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine, Iressa) is an approved anticancer drug. In this study, we labeled gefitinib with carbon-11 and evaluated [(11)C]gefitinib to explore its specific binding in intact fibrosarcoma (NFSa)-bearing mice.Methods: [(11)C]Gefitinib was synthesized by the reaction of desmethyl precursor (1) with [(11)C]CH(3)I. In vitro uptake of [(11)C]gefitinib into NFSa, human-A431 epidermoid carcinoma, and Jurkat T cells was determined. Positron emission tomography (PET) imaging using [(11)C]gefitinib was performed for NFSa-bearing mice.Results: [(11)C]Gefitinib accumulated into NFSa cells with 2.1 uptake ratio (UR)/mg protein in cells. Addition of nonradioactive gefitinib decreased uptake in a concentration-dependent manner. [(11)C]Gefitinib also had high uptake (2.6 UR/mg protein) into epidermal growth factor receptor/tyrosine kinase (EGFR/TK)-rich A431 cells but low uptake (0.2 UR/mg protein) into EGFR/TK-poor Jurkat cells. In vivo distribution study on NFSa-bearing mice by the dissection method revealed that [(11)C]gefitinib specifically accumulated into the tumor. The ratio of radioactivity in tumors to that in blood and muscle as two comparative regions increased from 0.4 to 6.0 and from 0.6 to 5.0 during this experiment (0-60 min), respectively. PET for NFSa-bearing mice produced a clear tumor image, although high radioactivity was distributed throughout the body. Treatment with nonradioactive gefitinib (100 mg/kg) decreased uptake in the tumor. In vivo metabolite analysis demonstrated that [(11)C]gefitinib was stable in the tumor, liver, kidney, and blood.Conclusion: These results demonstrated the promising potential of [(11)C]gefitinib to serve as a PET ligand for in vivo imaging of NFSa-bearing mice. [ABSTRACT FROM AUTHOR]

To elucidate the effect of tumor oxygenation status on recovery from damage following γ-ray or accelerated carbon ion irradiation in vivo, including in quiescent (Q) cells. SCC VII tumor-bearing mice were continuously given 5-bromo-2′-deoxyuridine (BrdU) to label all proliferating (P) cells. They received γ-ray or accelerated carbon ion irradiation with or without tumor clamping for inducing hypoxia. Immediately after irradiation, cells from some tumors were isolated, or acute hypoxia-releasing nicotinamide was loaded to the tumor-bearing mice. For 9 h after irradiation, some tumors were kept aerobic or hypoxic. Then isolated tumor cells were incubated with a cytokinesis blocker. The response of Q cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for BrdU. That of the total (=P + Q) tumor cells was determined from BrdU non-treated tumors. Clearer recovery in Q cells than total cells and after aerobic than hypoxic γ-ray irradiation was efficiently suppressed with carbon ion beams. Inhibition of recovery through keeping irradiated tumors hypoxic after irradiation and promotion of recovery by nicotinamide loading were observed more clearly with γ-rays, after aerobic irradiation and in total cells than with carbon ion beams, after hypoxic irradiation and in Q cells, respectively. Tumor oxygenation status following irradiation can manipulate recovery from radiation-induced damage, especially after aerobic γ-ray irradiation in total cells. Carbon ion beams are promising because of their efficient suppression of the recovery. [ABSTRACT FROM AUTHOR]

The aim of this study was to clarify the radiosensitivity of intratumor total cells and quiescent (Q) cells in vivo to accelerated carbon ion beams compared with γ-ray irradiation. Squamous cell carcinoma (SCC) VII tumor-bearing mice received continuous administration of 5-bromo-2′-deoxyuridine (BrdU) to label all intratumor proliferating (P) cells. They then were exposed to carbon ions (290 MeV/u) or γ-rays. Immediately after and 12 h after irradiation, immunofluorescence staining for BrdU was used to assess the response of Q cells in terms of micronucleus frequency. The response of the total (P + Q) tumor cells was determined from the tumors not treated with BrdU. The apparent difference in radiosensitivity between total and Q cell populations under γ-ray irradiation was markedly reduced with carbon ion beams, especially with a higher linear energy transfer (LET) value. Clearer recovery in Q cells than in total cells through delayed assay under γ-ray irradiation was efficiently inhibited by carbon ion beams, especially those with a higher LET. In terms of the tumor cell-killing effect as a whole, including intratumor Q cells, carbon ion beams, especially with higher LET values, were extremely useful for suppressing the dependence on the heterogeneity within solid tumors as well as depositing the radiation dose precisely. [ABSTRACT FROM AUTHOR]

The effect of rolipram, a selective phosphodiesterase type 4 inhibitor, on the uptake of 18F-fluorodeoxyglucose (18F-FDG) in tumor tissue was examined in mice transplanted with NFSa fibrosarcoma. The uptake indexes of 18F-FDG in the heart, skeletal muscle and brain remarkably decreased after treatment with 3 mg/kg of rolipram (heart: 13%, skeletal muscle: 14%, brain: 31%), but fibrosarcoma tissue showed only a 50% reduction in the uptake index of 18F-FDG. The tumor/muscle ratio of radioactivity 30 min after 18F-FDG injection was consequently enhanced from 1.9 to 6.5 by rolipram. This indicates the possible use of rolipram to enhance the sensitivity of tumor detection, as well as characterization of tumors in 18F-FDG PET. [ABSTRACT FROM AUTHOR]

The effect of rolipram, a selective phosphodiesterase type 4 inhibitor, on the uptake of18F-fluorodeoxyglucose (18F-FDG) in tumor tissue was examined in mice transplanted with NFSa fibrosarcoma. The uptake indexes of18F-FDG in the heart, skeletal muscle and brain remarkably decreased after treatment with 3 mg/kg of rolipram (heart: 13%, skeletal muscle: 14%, brain: 31%), but fibrosarcoma tissue showed only a 50% reduction in the uptake index of18F-FDG. The tumor/muscle ratio of radioactivity 30 min after18F-FDG injection was consequently enhanced from 1.9 to 6.5 by rolipram. This indicates the possible use of rolipram to enhance the sensitivity of tumor detection, as well as characterization of tumors in18F-FDG PET. [ABSTRACT FROM AUTHOR]