Tomio Inoue

Development of new markers for hypoxic cells: 131I]Iodomisonidazole and [131I]Iodoerythronitroimidazole

This study was aimed at developing ligands to evaluate tumor hypoxia by planar scintigraphy. Two 2-nitroimidazole analogues were developed as precursor compounds to image hypoxic tumors. Both tosylmisonidazole (Ts MISO) and tosylerythronitroimidazole (Ts ETNIM) were labeled with 131I. The biodistribution and autoradiographic evaluations by planar scintigraphy of 131I-IMISO and 131I-IETNIM were conducted at 1, 2 and 4 hours after administration to rats bearing 13762 breast tumors. Biodistribution of 131I-IMISO was also evaluated in Madison lung tumor-bearing mice. Intratumoral oxygen tension was measured by the Eppendorf system. Biodistribution showed similar tumor/blood and tumor/muscle count density ratios for both compounds. The thyroid uptake of both analogues was increased with time, suggesting in vivo deiodination probably occurred. Autoradiographs of 131I-IMISO and 131I-IETNIM revealed good visualization of the neoplasms. The tumor oxygen tension was 3-6 mmHg as compared to the normal tissue oxygenation of 30-40 mmHg. The findings indicate that these analogues can localize in the hypoxic region of solid tumors and may assist with quantitation of the hypoxic fraction of tumor for proper selection and evaluation of appropriate radiotherapy and chemotherapy.

Evaluation of In-111 DTPA-paclitaxel scintigraphy to predict response on murine tumors to paclitaxel.

Our goal was to determine whether scintigraphy with111In-DTPA-paclitaxel could predict the response to chemotherapy with paclitaxel.Methods: Ovarian carcinoma (OCA 1), mammary carcinoma (MCA-4), fibrosarcoma (FSA) and squamous cell carcinoma (SCC VII) were inoculated into the thighs of female C3Hf/Kam mice. Mice bearing 8 mm tumors were treated with paclitaxel (40 mg/kg). The growth delay, which was defined as the time in days for tumors in the treated groups to grow from 8 to 12 mm in diameter minus the time in days for tumors in the untreated control group to reach the same size, was measured to determine the effect of paclitaxel on the tumors. Sequential scintigraphy in mice bearing 10 to 14 mm tumors was conducted at 5, 30, 60, 120, 240 min and 24 hrs postinjection of111In-DTPA-paclitaxel (3.7MBq) or111In-DTPA as a control tracer. The tumor uptakes (% injection dose/pixel) were determined.Results: The growth delay of OCA 1, MCA-4, FSA and SCC VII tumors was 13.6, 4.0, −0.02 and −0.28 days, respectively. In other words, OCa 1 and MCA-4 were paclitaxel-sensitive tumors, whereas FSA and SCC VII were paclitaxel-resistant tumors. The tumor uptakes at 24 hrs postinjection of In-111 DTPA paclitaxel of OCA 1, MCA-4, FSA and SCC VII were 1.0 × 10−3, 1.6 × 10−3,2.2 × 10−3 and 9.0 × 10−3 % injection dose/ pixel, respectively. There was no correlation between the response to chemotherapy with paclitaxel and the tumor uptakes of111In-DTPA-paclitaxel.Conclusions: Scintigraphy with111In-DTPA-paclitaxel could not predict the response to paclitaxel chemotherapy. Although there was significant accumulation of the paclitaxel in the tumor cells, additional mechanisms must be operative for the agent to be effective against the neoplasm.111In-DTPA-paclitaxel activity is apparently different from that of paclitaxel with Cremophor.

Differences in sodium fluoride-18 uptake in the normal skeleton depending on the location and characteristics of the bone

AIM The aim of this study was to evaluate the normal distribution of sodium fluoride-18 (NaF-18) and to clarify the differences in uptake according to location and the type of the bone using positron emission tomography (PET) / computed tomography (CT). METHODS We retrospectively reviewed NaF-18 PET/CT images from 30 patients with hip joint disorders. PET/CT scans were performed 40 min after injection of approximately 185 MBq of NaF-18. To evaluate the relationship between the distribution of NaF-18 uptake and bone density, we compared the maximum standardised uptake values (SUVmax) on PET and the Hounsfield Units (HUs) on CT of the lumbar vertebra, ilium, and proximal and distal femurs. Regions of interests were defined both outside and inside the cortical bone to measure whole bone and cancellous bone only, respectively. RESULTS The distribution of NaF-18 differed according to the skeletal site. The lumbar vertebra showed the highest SUVmax for both whole bone and cancellous bone, followed by the ilium, proximal femur, and distal femur. The bones differed significantly in SUVmax. The distal femur showed the highest HU, followed by the proximal femur, ilium, and vertebra. Profile curve analyses demonstrated that the cancellous bones showed higher SUVmax and lower HU than the cortical bones. CONCLUSIONS Our results demonstrate the difference in NaF-18 uptake between cancellous and cortical bones, which may explain differences in uptake by location. NaF-18 uptake does not appear to be strongly correlated with bone density, but rather with bone turnover and blood flow.

Evaluation of [131I]iodoerythronitroimidazole as a predictor for the radiosensitizing effect

The aim of this study was to evaluate whether radiolabeled iodoerythronitroimidazole (IETNIM) could predict the radiosensitization effect on tumors. Tumor-bearing mice were irradiated at a dose of 25, 31 and 37 Gy after the injection of IETNIM. They were also exposed to 37 Gy radiation at 35, 70, 140 and 240 min after the i.p. injection of IETNIM. After the irradiation, tumor growth assays were conducted and the effect of IETNIM as a radiosensitizer was estimated as enhancement factor (EF). Tumor uptake was measured at 35, 70, 140 and 240 min after i.p. injection of [131I]IETNIM, which were the same intervals used in the radiosensitization study. EF of IETNIM in mice treated with 25, 30 and 37 Gy irradiation was 0.72, 0.98 and 1.28, respectively. EF of IETNIM in mice irradiated at 35, 70, 140 and 240 min after the injection was 1.50, 1.69, 1.46 and 1.08, which corresponded to the tumor uptake and blood clearance of [131I]IETNIM. [131I]IETNIM may be a suitable radiopharmaceutical to predict the radiosensitization effect of misonidazole analogs on tumors.

Radiopharmaceuticals for Tumor-Targeted Imaging: Overview

Improvement of scintigraphic tumor diagnosis, prognosis, planning, and monitoring of cancer treatment is clearly determined by development of more tumor-specific radiopharmaceuticals. Application of molecular targets for cancer imaging, therapy, and prevention are the major focus of research projects. Radionuclide imaging modalities (positron emission tomography, PET; single photon emission computed tomography, SPECT) are diagnostic cross-sectional imaging techniques that map the location and concentration of radionuclidelabeled radiotracers. Although computed tomography (CT) and magnetic resonance imaging (MRI) provide considerable anatomical information about the location and the extent of tumors, these imaging modalities cannot adequately differentiate invasive lesions from edema, radiation necrosis, or gliosis.

Evaluation of intratumoral injection of poly(d,l-lactide) cisplatin microspheres in rats with breast tumors using [131I]iodomisonidazole (IMISO)

AbstractThis study utilized [131I]iodomisonidazole (IMISO) to examine changes in tumor hypoxia after therapy of breast cancer with poly(d,l-lactide) cisplatin microspheres (PLA-CDDP MSs) by an intratumoral injection technique. PLA-CDDP MSs were prepared by a solvent evaporation process. Breast tumor cells were inoculated into the thighs of rats. After therapy with CDDP or PLA-CDDP MSs (6 mg/kg, subcutaneously, single injection), the tumor volume and blood chemistry of breast tumor-bearing rats were measured and compared daily with those of a control group given saline alone for 16 days. A group of rats were administered [131I]IMISO (50 μCi per rat, intravenously, n = 3) on day 5 and planar scintigraphy was then acquired at 2 h after injection. The percentage of tumor uptake (region of interest) was quantitated by a computer image analyzer and expressed as percentage of injected dose (ID) per pixel. PLA-CDDP microspheres (50-100 (Jim) contained 40.04% (w/w) cisplatin and produced sustained-release properti...