HPLC analysis of indium-111 diethylenetriaminepentaacetic acid (111In-DTPA) radiopharmaceutical

Indium-111 diethylenetriaminepentaacetic acid (¹¹¹In-DTPA) was analyzed by reversed-phase HPLC. On-line u.v. (220 mm) and radioactivity (NaI) detectors allowed simultaneous detection and quantitation of ¹¹¹In-DTPA radiopharmaceutical and free DTPA. The optimum HPLC conditions were derived from systematic study of the effect of various mobile phase parameters on retention characteristics of ¹¹¹In-DTPA and DTPA. The method was applied in stability study and routine quality control of ¹¹¹In-DTPA radiopharmaceutical.     

Significance of (111)In-DTPA chelate in renal radioactivity levels of (111)In-DTPA-conjugated peptides

Metabolic studies of (111)In-DTPA-labeled polypeptides and peptides showed that the radiolabeled (poly)peptides generated (111)In-DTPA-adducts of amino acid that possess long residence times in the lysosomal compartment of the tissues where (poly)peptides accumulated. However, a recent study suggested that metal-chelate-methionine (Met) might possess in vivo behaviors different from metal-chelate adducts of other amino acids. In this study, to elucidate whether some biological characteristics of Met may accelerate the renal elimination rate of (111)In-DTPA-adduct of Met into urine, (111)In-DTPA-Met(1)-octreotide was synthesized and the renal handling of (111)In-DTPA-Met was investigated using (111)In-DTPA-L-Phe(1)-octreotide (Phe represents phenylalanine), which was reported previously, as a reference. Both (111)In-DTPA-conjugated octreotide analogs were stable against 3-h incubation in murine serum at 37 degrees C. Both (111)In-DTPA-octreotide analogs also showed rapid clearance of the radioactivity from the blood and similar accumulation of the radioactivity in the kidney. No significant differences were observed in the renal radioactivity levels from 10 min to 24 h postinjection between the two. Metabolic studies indicated that (111)In-DTPA-Met(1)-octreotide and (111)In-DTPA-L-Phe(1)-octreotide generated (111)In-DTPA-adducts of Met and Phe, respectively, as the final radiometabolites at similar rates. These findings suggested that the long residence times of the radioactivity in tissues after administration of (111)In-DTPA-labeled peptides and polypeptides would be attributed to inherent characteristics of (111)In-DTPA chelate.     

Biokinetics of 111In-DTPA-D-Phe(1)-octreotide in nude mice transplanted with a human carcinoid tumor

The long time biokinetics of the radiolabeled somatostatin analogues 111In-DTPA-D-Phe(1)-octreotide was studied in nude mice transplanted with the human carcinoid tumor, GOT1. The results were compared with those from the patient with the original tumor. This patient has been diagnosed and later treated with 111In-DTPA-D-Phe(1)-octreotide. The animals received about 2 MBq 111In-DTPA-D-Phe(1)-octreotide (0.1 microg) by injection into a tail vein. The animals were killed 0.5 h-14 d after injection of the radiopharmaceutical. Tumor tissue and normal tissues were collected and weighed and measured for 111In activity. The 111In uptake in the tumor was higher than in all normal tissues except the kidneys. The tumor-to-normal-tissue activity concentration, TNC, increased with time for all normal tissues studied. These data were similar to those observed for the original tumor in the patient. The similar biokinetics for 111In-DTPA-D-Phe(1)-octreotide in the tumor-bearing mice and the patient makes this animal model suitable as a model for evaluation of therapy of somatostatin receptor (sstr) expressing tumors with radiolabeled somatostatin analogues. Furthermore, the increase with time of TNC both in mice and the patient indicates that long-lived radionuclides are preferred for therapy with radiolabeled somatostatin analogues.     

Intrahepatic tumor recurrence after partial hepatectomy: value of percutaneous radiofrequency ablation

PURPOSE: To determine the risks and benefits of percutaneous radiofrequency (RF) ablation of recurrent hepatic tumors in patients who have undergone hepatic resection. MATERIALS AND METHODS: Retrospective review of the institutional RF ablation database yielded 35 patients with recurrent hepatic tumor after hepatectomy. Sixty-one recurrent hepatic tumors (mean diameter +/- SD, 1.7 +/- 1.1 cm; range, 0.5-5.3 cm) were ablated percutaneously under sonographic guidance or combined guidance with sonographic and fluoroscopic computed tomography (CT). Follow-up CT, magnetic resonance imaging, or both were used for assessment of the primary and secondary therapeutic effectiveness rate and failure of RF ablation. Patients' survival status was determined by contacting the primary care physician or searching the Social Security Death Index. RESULTS: Complete ablation was accomplished in 54 of 61 hepatic tumors (primary therapeutic effectiveness rate, 88.5%). During a mean follow-up time of 18 months (range, 1-65 months), 14.8% of the tumors (n = 9) were incompletely ablated. Three of the nine incompletely ablated tumors were treated with a second RF ablation, all three of which failed (secondary therapeutic effectiveness rate, 0%). Distant intrahepatic tumor progression appeared in 23 of 35 patients (65.7%). One major complication (2.1%, one of 48 sessions) and eight minor complications (16.7%, eight of 48 sessions) were reported. The major complication was hepatic abscess formation. The overall survival rates for all patients at 1, 2, and 3 years were 76%, 68%, and 45%, respectively. For patients with metastases from colorectal cancer (n = 14), the overall survival rates were 72%, 60%, and 60% at 1, 2, and 3 years, respectively; and for patients with hepatocellular carcinoma (n = 8), the overall survival rates were 72%, 58%, and 44% at 1, 2, and 3 years, respectively. CONCLUSION: Percutaneous RF ablation offers a safe and effective treatment option for recurrent hepatic tumors after previous partial hepatectomy.     

Nuclear localization of 111In after intravenous injection of [111In-DTPA-D-Phe1]-octreotide in patients with neuroendocrine tumors.

Treatment with tumor-targeting substances is currently being evaluated in clinical trials. For patients with neuroendocrine tumors expressing somatostatin receptors, the 111In-labeled somatostatin analog [diethylenetriaminepentaacetic acid (DTPA)-DPhe1]-octreotide has been used with promising results. To further investigate the clinical effect of the injected conjugate, we analyzed the cellular distribution of 111In by ultrastructural autoradiography. METHODS: Seven patients with somatostatin receptor-expressing midgut carcinoid tumors scheduled for abdominal surgery were investigated by somatostatin receptor scintigraphy. During operation, tumor tissue samples and samples of normal intestine were collected, fixed, and processed for electron microscopy. A thin layer of film emulsion was applied on sections and after the exposure film was developed. The cellular distribution of silver precipitations indicating the presence of isotope was evaluated. RESULTS: Cell surface receptor binding and internalization of [111In-DTPA-D-Phe1]-octreotide in the tumor cells was easily revealed by silver precipitations in the film. Multiple silver grains were seen at the plasma membrane, in the cytoplasmic area among secretory granules and vesicular compartments, and in the perinuclear area. Silver grains were also regularly located in the nucleus. For all patients, the silver precipitation patterns from 111In decay were identical in all examined cells from removed tumors, and in most cells 111In could be seen in the nucleus. The specificity of the silver reaction products is supported by the observation that enterocytes in intestinal tissue specimens from near the tumor did not show any silver grains and no background labeling was seen in the plastic. CONCLUSION: After internalization through the somatostatin receptor system, 111In is translocated to the perinuclear area and into the nucleus. Whether the nuclide is still conjugated to the intact somatostatin analog or to part of it cannot be evaluated in this study. Despite the short irradiation range of 111In, the nuclear localization can explain its clinical effectiveness. The results from this study suggest that [111In-DTPA-D-Phe1]-octreotide may act as a powerful tumor cell-targeting substance.     

Comparison of 111In-DOTA-Tyr3-octreotide and 111In-DTPA-octreotide in the same patients: biodistribution, kinetics, organ and tumor uptake.

Scintigraphy with [111In-diethylenetriamine pentaacetic acid0-D-Phe1]-octreotide (DTPAOC) is used to demonstrate neuroendocrine and other somatostatin-receptor-positive tumors. Despite encouraging results, this 111In-labeled compound is not well suited for peptide-receptor-mediated radiotherapy of somatostatin-receptor-positive tumors. Another somatostatin analog, [1,4,7,10-tetraazacyclododecane-N,N',N",N'-tetraacetic acid0, D-Phe1, Tyr3]-octreotide (DOTATOC), can be labeled with the beta-emitter 90Y in a stable manner. METHODS: We compared the distribution, kinetics and dosimetry of 111In-DTPAOC and 111In-DOTATOC in eight patients to predict the outcomes of these parameters in patients who will be treated with 90Y-DOTATOC. RESULTS: Serum radioactivity levels for the radiopharmaceuticals did not differ significantly 2-24 h after injection (P>0.05). Up to 2 h postinjection they were slightly, but significantly, lower after administration of 111In-DOTATOC (P < 0.01 at most time points). The percentage of peptide-bound radioactivity in serum did not differ after administration of either compound. Urinary excretion was significantly lower after administration of 111In-DOTATOC (P < 0.01). The visualization of known somatostatin-receptor-positive organs and tumors was clearer after administration of 111In-DOTATOC than after administration of 111In-DTPAOC. This was confirmed by significantly higher calculated uptakes in the pituitary gland and spleen. The uptake in the tumor sites did not differ significantly (P > 0.05), although in three of the four patients in whom tumor uptake could be calculated, it was higher after administration of 111In-DOTATOC. CONCLUSION: The distribution and excretion pattern of 111In-DOTATOC resembles that of 111In-DTPAOC, and the uptake in somatostatin-receptor-positive organs and most tumors is higher for 111In-DOTATOC. If 90Y-DOTATOC shows an uptake pattern similar to 111In-DOTATOC, it is a promising radiopharmaceutical for peptide-receptor-mediated radiotherapy in patients with somatostatin-receptor-positive tumors.     

Biokinetics and dosimetry in patients administered with (111)In-DOTA-Tyr(3)-octreotide: implications for internal radiotherapy with (90)Y-DOTATOC.

Recent advances in receptor-mediated tumour imaging have resulted in the development of a new somatostatin analogue, DOTA-dPhe(1)-Tyr(3)-octreotide. This new compound, named DOTATOC, has shown high affinity for somatostatin receptors, ease of labelling and stability with yttrium-90 and favourable biodistribution in animal models. The aim of this work was to evaluate the biodistribution and dosimetry of DOTATOC radiolabelled with indium-111, in anticipation of therapy trials with (90)Y-DOTATOC in patients. Eighteen patients were injected with DOTATOC (10 microg), labelled with 150-185 MBq of (111)In. Blood and urine samples were collected throughout the duration of the study (0-2 days). Planar and single-photon emission tomography images were acquired at 0.5, 3-4, 24 and 48 h and time-activity curves were obtained for organs and tumours. A compartmental model was used to determine the kinetic parameters for each organ. Dose calculations were performed according to the MIRD formalism. Specific activities of >37 GBq/ micromol were routinely achieved. Patients showed no acute or delayed adverse reactions. The residence time for (111)In-DOTATOC in blood was 0.9+/-0.4 h. The injected activity excreted in the urine in the first 24 h was 73%+/-11%. The agent localized primarily in spleen, kidneys and liver. The residence times in source organs were: 2.2+/-1.8 h in spleen, 1.7+/-1.2 h in kidneys, 2.4+/-1.9 h in liver, 1.5+/-0.3 h in urinary bladder and 9. 4+/-5.5 h in the remainder of the body; the mean residence time in tumour was 0.47 h (range: 0.03-6.50 h). Based on our findings, the predicted absorbed doses for (90)Y-DOTATOC would be 7.6+/-6.3 (spleen), 3.3+/-2.2 (kidneys), 0.7+/-0.6 (liver), 2.2+/-0.3 (bladder), 0.03+/-0.01 (red marrow) and 10.1 (range: 1.4-31.0) (tumour) mGy/MBq. These results indicate that high activities of (90)Y-DOTATOC can be administered with low risk of myelotoxicity, although with potentially high radiation doses to the spleen and kidneys. Tumour doses were high enough in most cases to make it likely that the desired therapeutic response desired would be obtained.     

Uptake of [111In-DTPA0]octreotide in the rat kidney is inhibited by colchicine and not by fructose.

The high renal uptake of radiolabeled somatostatin analogs is dose limiting. Lowering this uptake permits higher radioactivity doses and, thus, tumor doses to be administered. We tested the effects of the microtubule drug colchicine on renal uptake of [(111)In-DTPA(0)]octreotide. Also, the effects of fructose were tested. METHODS: Organ radioactivity 24 h after injection of [(111)In-DTPA(0)]octreotide was determined in rats. RESULTS: Coinjection of 1 mg of colchicine per kilogram did not influence renal uptake of [(111)In-DTPA(0)]octreotide, whereas this dose administered 5 h before [(111)In-DTPA(0)]octreotide resulted in significant renal uptake reduction (63%). D-Lysine plus colchicine reduced the uptake by 76% (P < 0.01 vs. D-lysine alone). Liver and blood radioactivity levels were significantly elevated by colchicine. Fructose did not affect the biodistribution of [(111)In-DTPA(0)]octreotide. CONCLUSION: Renal uptake of [(111)In-DTPA(0)]octreotide is dependent on microtubule function in rats. The addition of colchicine to amino acid protocols may permit administration of higher doses, improving the therapeutic window of peptide receptor radionuclide therapy.     

Epidermal growth factor receptor inhibition modulates the nuclear localization and cytotoxicity of the Auger electron emitting radiopharmaceutical 111In-DTPA human epidermal growth factor.

(111)In-DTPA-human epidermal growth factor ((111)In-DTPA-hEGF [DTPA is diethylenetriaminepentaacetic acid]) is an Auger electron-emitting radiopharmaceutical that targets EGF receptor (EGFR)-positive cancer. The purpose of this study was to determine the effect of EGFR inhibition by gefitinib on the internalization, nuclear translocation, and cytotoxicity of (111)In-DTPA-hEGF in EGFR-overexpressing MDA-MB-468 human breast cancer cells. METHODS: Western blot analysis was used to determine the optimum concentration of gefitinib to abolish EGFR activation. Internalization and nuclear translocation of fluorescein isothiocyanate-labeled hEGF were evaluated by confocal microscopy in MDA-MB-468 cells (1.3 x 10(6) EGFRs/cell) in the presence or absence of 1 microM gefitinib. The proportion of radioactivity partitioning into the cytoplasm and nucleus of MDA-MB-468 cells after incubation with (111)In-DTPA-hEGF for 24 h at 37 degrees C in the presence or absence of 1 microM gefitinib was measured by cell fractionation. DNA double-strand breaks caused by (111)In were quantified using the gamma-H2AX assay, and radiation-absorbed doses were estimated. Clonogenic survival assays were used to measure the cytotoxicity of (111)In-DTPA-hEGF alone or in combination with gefitinib. RESULTS: Gefitinib (1 microM) completely abolished EGFR phosphorylation in MDA-MB-468 cells. Internalization and nuclear translocation of fluorescein isothiocyanate-labeled EGF were not diminished in gefitinib-treated cells compared with controls. The proportion of internalized (111)In that localized in the nucleus was statistically significantly greater when (111)In-DTPA-hEGF was combined with gefitinib compared with (111)In-DTPA-hEGF alone (mean +/- SD: 26.0% +/- 5.5% vs. 14.6% +/- 4.0%, respectively; P < 0.05). Induction of gamma-H2AX foci was greater in MDA-MB-468 cells that were treated with (111)In-DTPA-hEGF (250 ng/mL, 1.5 MBq/mL) plus gefitinib (1 microM ) compared with those treated with (111)In-DTPA-hEGF alone (mean +/- SD: 35 +/- 4 vs. 24 +/- 5 foci per nucleus, respectively). In clonogenic assays, a significant reduction in the surviving fraction was observed when (111)In-DTPA-hEGF (5 ng/mL, 6 MBq/microg) was combined with gefitinib (1 microM ) compared with (111)In-DTPA-hEGF alone (42.9% +/- 5.7% vs. 22.9% +/- 3.6%, respectively; P < 0.01). CONCLUSION: The efficacy of (111)In-DTPA-hEGF depends on internalization and nuclear uptake of the radionuclide. Nuclear uptake, DNA damage, and cytotoxicity are enhanced when (111)In-DTPA-hEGF is combined with gefitinib. These results suggest a potential therapeutic role for peptide receptor radionuclide therapy in combination with tyrosine kinase inhibitors.     

Evaluation of [99mTc/EDDA/HYNIC0]octreotide derivatives compared with [111In-DOTA0,Tyr3, Thr8]octreotide and [111In-DTPA0]octreotide: does tumor or pancreas uptake correlate with the rate of internalization?

Radiolabeled somatostatin analogs are important tools for the in vivo localization and targeted radionuclide therapy of somatostatin receptor-positive tumors. The aim of this study was to compare 3 somatostatin analogs designed for the labeling with (99m)Tc (where HYNIC is 6-hydrazinopyridine-3-carboxylic acid): 6-hydrazinopyridine-3-carboxylic acid(0)-octreotide (HYNIC-OC/(99m)Tc-(1)), [HYNIC(0),Tyr(3)]octreotide (HYNIC-TOC/(99m)Tc-(2)), and [HYNIC(0),Tyr(3),Thr(8)]octreotide (HYNIC-TATE/(99m)Tc-(3)), using ethylenediamine-N,N'-diacetic acid (EDDA) as a coligand. In addition, we compared the (99m)Tc-labeled peptides [(111)In-diethylenetriaminepentaacetic acid(0)]octreotide ([(111)In-DTPA]-OC) and [(111)In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid(0),Tyr(3),Thr(8)]octreotide ([(111)In-DOTA]-TATE) with regard to the rate of internalization and the biodistribution in AR4-2J (expressing the somatostatin receptor subtype 2) tumor-bearing rats. The main attention was directed toward a potential correlation between the rate of internalization and the tumor or pancreas uptake. METHODS: Synthesis was performed on solid phase using a standard Fmoc strategy. Internalization was studied in cell culture (AR4-2J) and biodistribution was studied using a Lewis rat tumor model (AR4-2J). RESULTS: The 5 radiopeptides showed a specific internalization into AR4-2J cells in culture (as shown by blocking experiments). The rate of internalization of the 5 radiopeptides differed significantly according to the following order: (99m)Tc-(1) approximately = [(111)In-DTPA]-OC < (99m)Tc-(2) < (99m)Tc-(3) approximately = [(111)In-DOTA]-TATE. All radiopeptides displayed a rapid blood clearance and a fast clearance from all somatostatin receptor-negative tissues predominantly via the kidneys. A receptor-specific uptake of radioactivity was observed for all compounds in somatostatin receptor-positive organs such as the pancreas, the adrenals, and the stomach. After 4 h, the uptake in the AR4-2J tumor was comparable for (99m)Tc-(2) (3.85 +/- 1.0 injected dose per gram tissue (%ID/g)), (99m)Tc-(3) (3.99 +/- 0.58%ID/g), and [(111)In-DOTA]-TATE (4.12 +/- 0.74%ID/g) but much lower for [(111)In-DTPA]-OC (0.99 +/- 0.08%ID/g) and (99m)Tc-(1) (0.70 +/- 0.13%ID/g). The specificity was determined by blocking experiments using a large excess of [Tyr(3)]octreotide. (99m)Tc-(3) displayed the highest tumor-to-kidney ratio (2.5:1), followed by (99m)Tc(2) (1.9:1) and [(111)In-DOTA]-TATE (1.7:1). CONCLUSION: These data show that the 5 radiopeptides are specific radioligands for the somatostatin receptor subtype 2. The rate of internalization correlates with the uptake in the tumor (R(2) = 0.75; P = 0.026) and pancreas (R(2) = 0.98; P = 7.4.10(-5)). [Tyr(3),Thr(8)]octreotide derivatives show superiority over the corresponding octreotide and [Tyr(3)]octreotide derivatives, indicating that [(111)In-DOTA]-TATE and [(99m)Tc/EDDA/HYNIC]-TATE are suitable candidates for clinical studies.     

Cellular processing of (125)I- and (111)in-labeled epidermal growth factor (EGF) bound to cultured A431 tumor cells

Low molecular weight of epidermal growth factor (EGF) enables better intratumoral penetration in comparison with larger targeting proteins, but the cellular retention of EGF-associated radioactivity is poor for directly iodinated EGF. An attempt was made to improve intracellular retention by the use of metal-diethylenetriaminepentaacetic acid or nonphenolic linker (N-succinimidyl-para-iodobenzoate) as labeling agents. The use of nonphenolic linker did not improve retention of the radioactivity in A431 carcinoma cell line. The use of the radiometal label provided an appreciable prolongation of radioactivity residence inside the cell.     

Recurrent hepatocellular carcinoma after partial hepatectomy: value of treatment with transcatheter arterial chemoembolization.

The usefulness of transcatheter arterial chemoembolization (TACE) of the hepatic artery was retrospectively evaluated in 66 patients who underwent the procedure for treatment of hepatocellular carcinoma that recurred after partial hepatectomy. The materials infused were Gelfoam sponge or Gelfoam sponge plus Lipiodol and an anticancer agent. A control group of 15 patients with recurrent tumor received oral anticancer agents alone. The cumulative survival rate for the TACE group was 88% for the first year, 57% for 2 years, 42% for 3 years, and 27% for 5 years, whereas that of the control group was 80% for the first year, 27% for 2 years, and 18% for 3 years. Thus, the prognosis of the TACE group was significantly better (p less than or equal to .01, log-rank test) than that of the control group. The survival rate was inversely correlated with the ratio of the volume of the recurrent tumor to the volume of the whole residual liver. These results suggest that TACE is more effective than oral chemotherapy for treatment of hepatocellular carcinoma that recurs after partial hepatectomy.     

The inhibitory effect of meadowsweet (Filipendula ulmaria) on radiation-induced carcinogenesis in rats

Purpose: To examine the ability of the meadowsweet preparation to inhibit carcinogenesis induced by ionizing radiation in female rats.

Materials and methods: The chemical composition of meadowsweet (Filipendula ulmaria) raw material (ethanol and aqueous extracts of meadowsweet flowers) has been studied for the presence of flavonoids, tannins and catechins. Adult female LIO strain rats were subjected to a single whole body γ-irradiation at a dose of 4?Gy in animal experiments. One group of irradiated rats served as control while the other group, starting from the 10th day after irradiation and until the end of the experiment, was given meadowsweet as a decoction of the flowers instead of drinking water. The average daily intake of meadowsweet (dry raw material) was 1?g/kg body weight. Rats were observed for 16 months.

Results: The analyzed meadowsweet extracts showed a sufficiently high content of flavonoids and tannins. In irradiated rats after 16 months the overall incidence of tumors was 79.6% (in 82 of 103 rats), the incidence of malignant tumors was 43.7% and the overall tumor multiplicity was 1.48. Most tumors were localized in the mammary gland – 57.3%. In rats that received meadowsweet, the incidence of all malignant tumors and overall multiplicity of tumors were significantly decreased by 1.5 and 1.3 times, respectively. The greatest reduction of many parameters has been identified for breast tumors: the overall incidence was decreased by 1.5 (p?=?0.0174) and the overall multiplicity and multiplicity of malignant tumors – by 1.6 (p?=?0.0002) and 2.2 (p?=?0.0383) times, respectively.

Conclusions: Meadowsweet preparation showed inhibiting activity on radiation carcinogenesis.     

A human transferrin-vascular endothelial growth factor (hnTf-VEGF) fusion protein containing an integrated binding site for (111)In for imaging tumor angiogenesis.

Our objective was to synthesize a recombinant protein (hnTf-VEGF [VEGF is vascular endothelial growth factor]) composed of VEGF(165) fused through a flexible polypeptide linker (GGGGS)(3) to the n-lobe of human transferrin (hnTf) for imaging angiogenesis. The hnTf domain allowed labeling with (111)In at a site remote from the VEGF receptor-binding domain. METHODS: DNA encoding hnTf, peptide linker (GGGGS)(3), and VEGF(165) genes were cloned into the Pichia pastoris vector pPICZalphaB to generate the pPICZalphaB-hnTF-VEGF plasmid. The expression vector was transformed into P. pastoris KM71H strain. The protein was purified using Co(2+) metal affinity resin. The growth-stimulatory effects of hnTf-VEGF on human umbilical vascular endothelial cells (HUVECs) and its binding to porcine aortic endothelial cells (PAECs) transfected with VEGF receptors were evaluated. hnTf-VEGF protein was labeled with (111)InCl(3) in 10 mmol/L HEPES/15 mmol/L NaHCO(3) buffer, pH 7.4 (HEPES is N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid). The loss of (111)In in vitro from (111)In-hnTf-VEGF to transferrin in human plasma and to diethylenetriaminepentaacetic acid (DTPA) in buffer was determined. Tumor and normal tissue distributions of (111)In-hnTf-VEGF were evaluated in athymic mice implanted subcutaneously with U87MG human glioblastoma xenografts. Tumor imaging was performed. RESULTS: Sodium dodecylsulfate-polyacrylamine gel electrophoresis under reducing and nonreducing conditions showed bands for hnTf-VEGF monomer (M(r) of 65 kDa) and dimer (M(r) of 130 kDa). hnTf-VEGF stimulated the growth of HUVECs 3-fold and demonstrated binding to PAECs displaced by a 50-fold excess of VEGF(165) but not by apotransferrin. There was 21.3% +/- 3.4% loss of (111)In per day from (111)In-hnTf-VEGF to transferrin in plasma, but <5% loss to DTPA over 4 h. (111)In-hnTf-VEGF accumulated in U87MG tumors (6.7% injected dose per gram at 72 h after injection) and its tumor uptake decreased 15-fold by coadministration of a 100-fold excess of VEGF but not by apotransferrin. The tumor-to-blood ratio was 4.9:1 at 72 h after injection and tumors were imaged at 24-72 h after injection. CONCLUSION: (111)In-hnTf-VEGF is a promising radiopharmaceutical for imaging tumor angiogenesis and represents a prototypic protein harboring the metal-binding site of transferrin for labeling with (111)In without introducing DTPA metal chelators.     

腹腔神经丛阻滞对肝部分切除术后肝细胞凋亡的影响

目的观察腹腔神经丛阻滞（NCPB）对肝部分切除术（PH）大鼠残余肝细胞凋亡的影响。方法60只清洁雄性sD大鼠,构建大鼠70％PH模型,随机分为对照组和NCPB组。NCPB组在术后12h开始给予双侧0．5％利多卡因经皮NCPB,1次／d,而对照组以0．9％生理盐水替换。分别于术后第1、3、7d测定残肝功能、血流量和凋亡相关蛋白Bcl-2相关x蛋白（BAX）和B细胞淋巴瘤／白血病-2（Bcl-2）的表达。结果NCPB组大鼠的谷草转氨酶（AST）和谷丙转氨酶（AI卫）在PH术后第1、3、7d均不同程度地低于对照组（P〈0．叭或P〈0．05）;对照组PH术后肝细胞出现明显的脂肪变性,且较多见小灶性肝细胞坏死和小片状肝细胞坏死,而NCPB组肝组织变性坏死明显减轻;与对照组相比,NCPB组大鼠的肝脏血流量在各个时间点均显著高于对照组（P〈0．01）;PH术后两组肝组织BAX均逐渐下降,但在相应时间点NCPB组显著低于对照组（P〈0．05或P〈0．01）,而Bcl-2显著升高,但NCPB组却显著高于对照组（P〈0．01）,在第3d和第7dNCPB组的BAX／Bcl-2比值显著低于对照组（P〈0．01）。结论NCPB减轻大鼠PH术后早期肝功能损害,可能与抑制PH术后早期肝细胞凋亡有关。     

Patient-specific dosimetry calculations using mathematic models of different anatomic sizes during therapy with 111In-DTPA-D-Phe1-octreotide infusions after catheterization of the hepatic artery.

The aim of the study was to provide dosimetric data on intrahepatic (111)In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe(1)-octreotide therapy for neuroendocrine tumors with overexpression of somatostatin receptors. METHODS: A dosimetric protocol was designed to estimate the absorbed dose to the tumor and healthy tissue in a course of 48 treatments for 12 patients, who received a mean activity of 5.4 +/- 1.7 GBq per session. The patient-specific dosimetry calculations, based on quantitative biplanar whole-body scintigrams, were performed using a Monte Carlo simulation program for 3 male and 3 female mathematic models of different anatomic sizes. Thirty minutes and 2, 6, 24, and 48 h after the radionuclide infusion, blood-sample data were collected for estimation of the red marrow radiation burden. RESULTS: The mean absorbed doses per administered activity (mGy/MBq) by the critical organs liver, spleen, kidneys, bladder wall, and bone marrow were 0.14 +/- 0.04, 1.4 +/- 0.6, 0.41 +/- 0.08, 0.094 +/- 0.013, and (3.5 +/- 0.8) x 10(-3), respectively; the tumor absorbed dose ranged from 2.2 to 19.6 mGy/MBq, strongly depending on the lesion size and tissue type. CONCLUSION: The results of the present study quantitatively confirm the therapeutic efficacy of transhepatic administration; the tumor-to-healthy-tissue uptake ratio was enhanced, compared with the results after antecubital infusions. Planning of treatment was also optimized by use of the patient-specific dosimetric protocol.     

Tumor response after [(90)Y-DOTA(0),Tyr(3)]octreotide radionuclide therapy in a transplantable rat tumor model is dependent on tumor size.

A promising application of radiolabeled somatostatin analogs is peptide receptor-targeted radionuclide therapy of somatostatin receptor-expressing tumors. A suitable radionuclide is (90)Y, which emits high-energy beta-particles with a pathlength of several millimeters in tissue, making it especially promising for treatment of large tumors. METHODS: We investigated the radiotherapeutic effect of different activities (111 and 370 MBq) of [(90)Y-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)(0),Tyr(3)]octreotide in Lewis rats bearing somatostatin receptor-positive rat pancreatic CA20948 tumors of different size (0.08-15 cm(2)) in their flank. RESULTS: Dose-dependent radiotherapeutic effects of (90)Y-labeled octreotide in this rat tumor model were found. Tumor control (100% complete response) was found in animals bearing tumors of 3-9 cm(2) (mean, 7.8 cm(2)) after intravenous injection of the highest activity (370 MBq [(90)Y-DOTA(0),Tyr(3)]octreotide). In rats bearing tumors of < or =1 cm(2) or > or =14 cm(2), the effects were less pronounced (50% and 0% complete response, respectively). In tumors of < or =1 cm(2) the (90)Y radiation energy will not be absorbed completely in the tumor, whereas in tumors of > or =14 cm(2) the increased number of clonogenic and probably hypoxic tumor cells may explain the failure to reach a cure. CONCLUSION: This study shows the ability of [(90)Y-DOTA(0),Tyr(3)]octreotide to control tumor growth, especially in medium-sized tumors. The effect of radionuclide therapy appeared to be dependent on tumor size at the onset of therapy.     

Hepatocellular carcinoma: Efficacy of transcatheter oily chemoembolization in relation to macroscopic and microscopic patterns of tumor growth among 100 patients with partial hepatectomy

Purpose: To evaluate the efficacy of transcatheter oily chemoembolization (TOCE) for hepatoceliular carcinoma (HCC) on the basis of microscopic and macroscopic findings postembolization. Methods: HCCs ranging in size from 0.5 to 13 cm (mean 3.6 cm) were obtained from partial hepatectomies of 100 consecutive patients who had undergone TOCE between 20 and 246 days (mean 59.5 days) prior to surgery. The efficacy of TOCE was assessed on the basis of the necrotic to live cell ratio of the tumors. The microscopic pattern of tumor growth was grouped into expanding type (complete capsule formation) and replacing type (incomplete or no capsule). There were five types of macroscopic groupings: single nodule, single nodule with extranodular growth (SNE), contiguous and noncontiguous multinodular, and massive growth type. Results: Among 79 cases with the expanding type, 29 (37%) had 100% HCC necrosis, but none with 100% necrosis were in the replacing type. By macroscopic grouping, the efficacy of TOCE decreased from the single nodule type (50% of patients had 100% necrosis) to the SNE type (21%), and the other types (9%).