Comparison of 111In-[DTPA0]Octreotide Versus Non Carrier Added 177Lu- [DOTA0,Tyr3]-Octreotate Efficacy in Patients With GEP-NET Treated Intra-arterially for Liver Metastases.

AIM: In patients with progressive, metastatic neuroendocrine tumors (NET), intra-arterial radionuclide infusions with high activities of In-[DTPA]-octreotide and more recently with non-carrier added (nca) Lu-[DOTA,Tyr]-octreotate have been performed with encouraging results. However, the affinity profiles (IC50) of these radiopeptides for human sst2 receptors are markedly different (In-[DTPA]-octreotide, 22 ± 3.6 nM and nca Lu-[DOTA,Tyr]-octreotate, 1.5 ± 4.0 nM). The total administered activity is determined by organ dose limits (kidneys and bone marrow), and our aim therefore was to compare and evaluate the therapeutic efficacy of both radiopeptides in metastatic NETs. METHODS: Thirty patients with gastroenteropancreatic (GEP) somatostatin-positive NETs with liver metastases confirmed on biopsy and In-pentetreotide scan were included. They were treated with In-[DTPA]-octreotide (n = 17) or nca Lu-[DOTA,Tyr]-octreotate (n = 13). Blood samples were collected 2, 4, 8, and 24 hours postadministration to calculate residence time in blood and in red marrow. The maximum percentage uptake in organs and tumors was estimated by region of interest analysis, and tumor dosimetry calculations were performed using OLINDA/EXM/ 1.0 software. RESULTS: ncaLu-[DOTA,Tyr3]-octreotate blood radioactivity, expressed as a percentage of the injected dose, was significantly lower than In-[DTPA]-octreotide (P < 0.05), as clearly depicted from the time-activity curves; the background-corrected tumor uptake was significantly higher than In-[DTPA]-octreotide but without any significant difference in other organs (spleen, kidneys, and liver). CONCLUSIONS: Using Lu-[DOTA,Tyr]-octreotate, a 3-fold higher absorbed dose to tumor tissue was achieved compared with In-[DTPA] octreotide. Residence time of nca Lu-[DOTA,Tyr]-octreotate results in a significantly higher absorbed dose to bone marrow compared with In-[DTPA]-octreotide. However, a drawback of In-[DTPA]-octreotide therapy is that the number of administrations would need to be almost doubled to achieve an equal therapeutic outcome as compared with Lu-[DOTA,Tyr]-octreotate.

Orally administered DTPA di-ethyl ester for decorporation of (241)Am in dogs: Assessment of safety and efficacy in an inhalation-contamination model.

PURPOSE: Currently two injectable products of diethylenetriaminepentaacetic acid (DTPA) are U.S. Food and Drug Administration (FDA)-approved for decorporation of (241)Am; however, an oral product is considered more amenable in a mass casualty situation. The di-ethyl ester of DTPA, named C2E2, is being developed as an oral drug for treatment of internal radionuclide contamination. MATERIALS AND METHODS: Single-dose decorporation efficacy of C2E2 administered 24-h post contamination was determined in beagle dogs using a (241)Am nitrate inhalation contamination model. Single and multiple dose toxicity studies in beagle dogs were performed as part of an initial safety assessment program. In addition, the genotoxic potential of C2E2 was evaluated by the in vitro bacterial reverse mutation Ames test, mammalian cell chromosome aberration cytogenetic assay and an in vivo micronucleus test. RESULTS: Oral administration of C2E2 significantly increased (241)Am elimination over untreated controls and significantly reduced the retention of (241)Am in tissues, especially liver, kidney, lung and bone. Daily dosing of 200 mg/kg/day for 10 days was well tolerated in dogs. C2E2 was found to be neither mutagenic or clastogenic. CONCLUSIONS: The di-ethyl ester of DTPA (C2E2) was shown to effectively enhance the elimination of (241)Am after oral administration in a dog inhalation-contamination model and was well tolerated in toxicity studies.

LAT1 targeted delivery of methionine based imaging probe derived from M(III) metal ions for early diagnosis of proliferating tumours using molecular imaging modalities.

We investigated the potential of DTPA-bis(Methionine), a target specific amino acid based probe for detection of L-type amino acid transporters (LAT1) known to over express in proliferating tumours using multimodality imaging. The ligand, DTPA-bis(Met) was readily converted to lanthanide complexes and was found capable of targeting cancer cells using multimodality imaging. DTPA-bis(Met) complexes were synthesized and characterized by mass spectroscopy. MR longitudinal relaxivity, r1 = 4.067 ± 0.31 mM⁻¹s⁻¹ and transverse relaxivity, r2 = 8.61 ± 0.07 mM⁻¹s⁻¹ of Gd(III)-DTPA-bis(Met) were observed at pH 7.4 at 7 T. Bright, localized fluorescence of Eu(III)-DTPA-bis(Met) was observed with standard microscopy and displacement studies indicated ligand functionality. K(D) value determined for Eu(III)-DTPA-bis(Met) on U-87 MG cells was found to be 17.3 pM and showed appreciable fluorescence within the cells. Radio HPLC showed a radiochemical purity more than 95% (specific activity = 400-500 MBq/µmol, labelling efficiency 78 %) for 68Ga(III)-DTPA-bis(Met). Pre-treatment of xenografted U-87 MG athymic mice with 68Ga(III)-DTPA-bis(Met) following unlabelled L-methionine administration reduced tumour uptake by 10-folds in Micro PET. These data support the specific binding of 68Ga(III)-DTPA-bis(Met) to the LAT1 transporter. To summarize, this agent possesses high stability in biological environment and exhibits effective interaction with its LAT1 transporters giving high accumulation in tumour area, excellent tumour/non-tumour ratio and low non-specific retention in vivo.

Evaluating the toxicity of novel Zn-DTPA tablet formulation in dogs and rats.

The purpose of this research work is to evaluate toxicity of diethylenetriamine pentaacetic acid zinc trisodium salt (Zn-DTPA) tablets, a novel oral solid dosage form containing permeation enhancers in beagle dogs and Sprague Dawley rats. (Zn-DTPA) in tablet dosage form was administered once daily for 7 days to beagle dogs at low (840 mg/dog/day), mid (2520 mg/dog/day), or high (7560 mg/dog/day). On day 8, all treated and control groups were necropsied. The novel Zn-DTPA tablet formulation showed rapid absorption with the T(max) at 1 h. Plasma concentrations as high as 270 µg/mL were observed after 7 days of administration. Exposure to DTPA, based on area under the curve (AUC(last)) and maximum concentration (C(max)), was dose dependent but not dose proportional. No biologically relevant changes in hematology or clinical chemistry that were related to DTPA exposure were observed, and there were no changes in body weight in treated dogs compared with controls. Zn-DTPA was well tolerated, with minor toxicological effects of emesis and diarrhea, following oral tablet administration for 7 consecutive days. Based on the endpoints evaluated in this study, the maximum tolerated dose is considered to be greater than 7560 mg/dog/day (2535 µmol/kg/day, 1325 mg/kg/day), and the no-observed-adverse-effect level (NOAEL) is considered to be approximately 1325 mg/kg/day per oral when given to male and female beagle dogs. For rats, the NOAEL was estimated to be greater than 1000 mg/kg/day when administered by oral gavage of the crushed Zn-DTPA tablets as suspension once daily (qd) to male and female Sprague Dawley rats.

Optimizing the ventilation-perfusion lung scan for image quality and radiation exposure.

UNLABELLED: Our purpose was to compare the performance of an initial ventilation-perfusion (V/Q) scan protocol with that of a data-driven modified protocol to improve diagnostic quality without increasing radiation dose to the patient. METHODS: The initial V/Q scan protocol consisted of a ventilation scan after inhalation of (99m)Tc-diethylenetriaminepentaacetic acid (DTPA) aerosol for 5 min followed by a (99m)Tc-macroaggregated albumin perfusion scan. Interim analysis after 34 scans under an initial protocol included calculations of ventilation efficiency, perfusion efficiency, and perfusion-to-ventilation counting rate ratio (Q:V). Ventilation efficiency was defined as ventilation counting rate divided by ventilation dose, perfusion efficiency as perfusion counting rate divided by perfusion dose, and Q:V as perfusion counting rate divided by ventilation counting rate. From these data, the protocol was modified to improve the Q:V ratio and was applied to 60 patients. Results from the 94 scans were tabulated, and a comparison of ventilation efficiency, perfusion efficiency, and Q:V between the 2 protocols was statistically analyzed. RESULTS: The initial protocol returned a mean ventilation efficiency of 7.8% (SD, 4.6%; range, 1.4%-19%), mean perfusion efficiency of 100% (SD, 31%; range, 39%-160%), and mean Q:V of 2.4 (SD, 1.9; range, 0.51-9.0). All 3 parameters displayed a wide range. Fifty-four percent of these cases demonstrated an unacceptable Q:V (≤2) indicating that the perfusion dose did not overwhelm the ventilation dose. To improve Q:V, options included decreasing ventilation dose, increasing perfusion dose, or performing the ventilation scan with a much higher dose after the perfusion scan. To minimize radiation, the protocol was modified to decrease the ventilation from 5 min to 2.5 min. The modified protocol yielded a mean ventilation efficiency of 5.1% (SD, 1.8; range, 2.0-11), mean perfusion efficiency of 120% (SD, 27%; range, 65%-170%), and mean Q:V of 3.6 (SD, 1.7; range, 1.2-12). Differences between protocols were statistically significant for ventilation efficiency, perfusion efficiency, and Q:V (P < 0.02). Less than 8% of cases under the modified protocol exhibited an unacceptable Q:V. CONCLUSION: The initial V/Q scan protocol was successfully modified to improve image quality with less radiation. By decreasing the ventilation time by half, the percentage of studies with an unacceptable Q:V decreased from 54% to 8%. This analysis may help others to optimize their V/Q protocols.

Actinide handling after wound entry with local or systemic decorporation therapy in the rat.

BACKGROUND: Treatment of actinide-contaminated wounds may be problematic because of contaminant physicochemical properties, dissemination and anatomical localization. This study investigates different chelation/resection protocols after contamination of rats with americium (Am) or plutonium (Pu) nitrate or mixed oxide (MOX; uranium (U), Pu oxide). METHODS: Anesthetized rats were contaminated with Am or Pu nitrate (moderately soluble) or MOX (insoluble) following wounding of hind leg muscle. DTPA (diethylene triamine pentaacetic acid) treatment (30 µmol/kg) was immediate or delayed, systemic or local and combined or not with wound resection. Actinide urinary and tissue levels were measured. RESULTS: Comparison of Pu nitrate and MOX dissemination at the wound site indicated a more heterogeneous localization of MOX particles. In all cases DTPA treatment reduced target tissue (bone, liver) activity levels even if DTPA treatment was started 7 days after contamination. Surgery alone increased urinary excretion suggesting release from the wound site but no subsequent increases in organ retention (bone, liver) were observed. The combination of surgery and DTPA increased Pu excretion and reduced tissue levels markedly. CONCLUSION: This rodent model of actinide wound contamination has been used to test different treatments. It provides evidence of activity release as a result of surgery that seems not to lead to increased organ retention.

¹¹¹In-DTPA°-octreotide (Octreoscan), ¹³¹I-MIBG and other agents for radionuclide therapy of NETs.

This paper is a critical review of the literature on NET radionuclide therapy with (111)In-DTPA(0)-octreotide (Octreoscan) and (131)I-MIBG, focusing on efficacy and toxicity. Some potential future applications and new candidate therapeutic agents are also mentioned. Octreoscan has been a pioneering agent for somatostatin receptor radionuclide therapy. It has achieved symptomatic responses and disease stabilization, but it is now outperformed by the corresponding ß-emitter agents (177)Lu-DOTATATE and (90)Y-DOTATOC. (131)I-MIBG is the radionuclide therapy of choice for inoperable or metastatic phaeochromocytomas/paragangliomas, which avidly concentrate this tracer via the noradrenaline transporter. Symptomatic, biochemical and tumour morphological response rates of 50-89%, 45-74% and 27-47%, respectively, have been reported. (131)I-MIBG is a second-line radiopharmaceutical for treatment of enterochromaffin carcinoids, mainly offering the benefit of amelioration of hormone-induced symptoms. High specific activity, non-carrier-added (131)I-MIBG and meta-astato((211)At)-benzylguanidine (MABG) are tracers with potential for enhanced therapeutic efficacy, yet their integration into clinical practice awaits further exploration. Amongst other promising agents, radiolabelled exendin analogues show potential for imaging and possibly therapy of insulinomas, while preclinical studies are currently evaluating DOTA peptides targeting the CCK-2/gastrin receptors that are overexpressed by medullary thyroid carcinoma cells.

Diethylenetriamine pentaacetic acid derivative of toremifene and in vitro evaluation in human breast cancer cell line MCF-7.

Cytotoxic and apoptotic effects of toremifene-diethylenetriamine pentaacetic acid (TOR-DTPA), formed by conjugation of TOR and DTPA, on the MCF-7 cell line were evaluated. TOR-DTPA was synthesized and qualified via gas chromatography-mass spectrometry system, thin layer chromatography, and high performance liquid chromatography methods. To screen the biological properties of TOR-DTPA at determined concentrations, our ongoing effort was to evaluate apoptotic and cytotoxic effects on the MCF-7 cell line. Trypan blue dye exclusion test, XTT, ELISA, and TUNEL assays were utilized to evaluate cytotoxicity and apoptosis. TOR-DTPA has no cytotoxic and limited apoptotic effect on the MCF-7 cell line according to the results of in vitro studies. It is concluded that the lack of obvious apoptotic and cytotoxic effects allows the already proposed ligand, TOR-DTPA, to be improved as a novel hydrophilic ligand for breast imaging.

Experimental facts supporting a red marrow uptake due to radiometal transchelation in 90Y-DOTATOC therapy and relationship to the decrease of platelet counts.

PURPOSE: The aim of this study was to retrospectively evaluate whether the red marrow (RM) takes up (111)In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe(1)-octreotide and (86)Y-DOTATOC and to assess the correlation between the RM absorbed doses and platelet count reduction as a biological dose estimate. METHODS: Data from 12 patients who underwent at 24 h p.i. high statistics (111)In single photon emission computed tomography (SPECT) and (86)Y positron emission tomography (PET) acquisitions of the chest were analysed. Uptake was measured on >7 cm spine length and converted to total RM uptake using standard RM distribution in man. RM absorbed doses were calculated assuming specific RM uptake and using the plasma and remainder of the body models. RM doses were correlated with the platelet count reduction at 4 weeks. In vitro experiments explored the metabolism of (111)In-DTPA-D-Phe(1)-octreotide and (90)Y-DOTATOC in plasma. RESULTS: The correlation between the uptake of both tracers was excellent (R = 0.80), indicating that RM uptake of (86)Y-DOTATOC reflects a real physiological process and not reconstruction artefacts. The kinetics of (86)Y-DOTATOC RM activity was different than that in blood and tumours, with no activity at 4 h p.i. indicating that the uptake is not somatostatin receptor dependent. In vitro experiments showed a transchelation of both radiometals to free transferrin that could explain the RM uptake. In patients without chemotherapy and with a normal platelet count recovery, a good correlation (R = 0.96) was found between the RM doses and the platelet count reduction at the nadir. CONCLUSION: These experimental facts support the existence of a true RM uptake likely related to transchelation of the radiometal to transferrin. RM uptake correlates well with the observed acute RM toxicity.

Treatment of peritoneal carcinomatosis by targeted delivery of the radio-labeled tumor homing peptide bi-DTPA-[F3]2 into the nucleus of tumor cells.

BACKGROUND: Alpha-particle emitting isotopes are effective novel tools in cancer therapy, but targeted delivery into tumors is a prerequisite of their application to avoid toxic side effects. Peritoneal carcinomatosis is a widespread dissemination of tumors throughout the peritoneal cavity. As peritoneal carcinomatosis is fatal in most cases, novel therapies are needed. F3 is a tumor homing peptide which is internalized into the nucleus of tumor cells upon binding to nucleolin on the cell surface. Therefore, F3 may be an appropriate carrier for alpha-particle emitting isotopes facilitating selective tumor therapies. PRINCIPAL FINDINGS: A dimer of the vascular tumor homing peptide F3 was chemically coupled to the alpha-emitter (213)Bi ((213)Bi-DTPA-[F3](2)). We found (213)Bi-DTPA-[F3](2) to accumulate in the nucleus of tumor cells in vitro and in intraperitoneally growing tumors in vivo. To study the anti-tumor activity of (213)Bi-DTPA-[F3](2) we treated mice bearing intraperitoneally growing xenograft tumors with (213)Bi-DTPA-[F3](2). In a tumor prevention study between the days 4-14 after inoculation of tumor cells 6x1.85 MBq (50 microCi) of (213)Bi-DTPA-[F3](2) were injected. In a tumor reduction study between the days 16-26 after inoculation of tumor cells 6x1.85 MBq of (213)Bi-DTPA-[F3](2) were injected. The survival time of the animals was increased from 51 to 93.5 days in the prevention study and from 57 days to 78 days in the tumor reduction study. No toxicity of the treatment was observed. In bio-distribution studies we found (213)Bi-DTPA-[F3](2) to accumulate in tumors but only low activities were found in control organs except for the kidneys, where (213)Bi-DTPA-[F3](2) is found due to renal excretion. CONCLUSIONS/SIGNIFICANCE: In conclusion we report that (213)Bi-DTPA-[F3](2) is a novel tool for the targeted delivery of alpha-emitters into the nucleus of tumor cells that effectively controls peritoneal carcinomatosis in preclinical models and may also be useful in oncology.

Neuroendocrine tumors. Peptide receptor radionuclide therapy.

Peptide receptor radionuclide therapy with radiolabelled somatostatin analogues is an emerging and convincing treatment modality for patients with unresectable, somatostatin-receptor-positive neuroendocrine tumours. Using radiolabelled somatostatin analogues for imaging became the gold standard for staging of neuroendocrine tumours. The somatostatin receptor is strongly over-expressed in most tumours, resulting in high tumour-to-background ratios. Consequently, the next step was to try to treat these patients by increasing the radioactivity of the administered radiolabelled somatostatin analogue in an attempt to bring about tumour cure. Many patients have been treated successfully with this approach, roughly 25% of them achieving objective tumour shrinkage >50%. Serious side-effects have been rare. This article reviews the effectiveness and safety of the different radiolabelled somatostatin analogues used. Furthermore, clinical issues--including indication and timing of therapy--are discussed. Finally, important directions for future research are mentioned to illustrate new strategies for increasing therapy efficacy.

Are gadolinium-based contrast media nephrotoxic? A renal biopsy study.

Gadolinium-based contrast media were originally introduced as alternatives to iodinated media for magnetic resonance imaging. Although originally thought to be nonnephrotoxic, gadolinium-based contrast media have recently been reported to be associated with acute renal failure; the mechanism and the underlying renal injury are not completely understood. We report what is, to our knowledge, the first renal biopsy in this context. A 56-year-old patient underwent 2 consecutive vascular imaging procedures in conjunction with gadolinium-based contrast medium administration. A few days later, the patient developed acute renal failure. A renal biopsy showed acute tubular cell injury including patchy tubular cell necrosis, tubular cell degeneration, and marked proliferation of tubular cells, together with mild interstitial edema and interstitial inflammation, but without significant glomerular or vascular changes. During supportive therapy, renal function was partially regained. This case emphasizes the potential nephrotoxicity of gadolinium-based contrast media and suggests that the nephrotoxicity is related to potentially reversible acute tubular cell injury.

Preclinical pharmacokinetic, biodistribution, toxicology, and dosimetry studies of 111In-DTPA-human epidermal growth factor: an auger electron-emitting radiotherapeutic agent for epidermal growth factor receptor-positive breast cancer.

UNLABELLED: Our objective was to evaluate the pharmacokinetics, normal tissue distribution, radiation dosimetry, and toxicology of human epidermal growth factor (hEGF) labeled with (111)In ((111)In-diethylenetriaminepentaacetic acid [DTPA]-hEGF) in mice and rabbits. METHODS: (111)In-DTPA-hEGF (3.6 MBq; 1.3 or 13 microg) was administered intravenously to BALB/c mice. The blood concentration-time data were fitted to a 3-compartment model. Acute toxicity was studied with female BALB/c mice at 42 times the maximum planned human dose (MBq/kg) or with New Zealand White rabbits at 1 times the maximum planned human dose (MBq/kg) for a phase I clinical trial. Toxicity was evaluated by monitoring body weight, by determination of hematology and clinical biochemistry parameters, and by morphologic examination of tissues. Radiation dosimetry projections in humans were estimated on the basis of the residence times in mice by use of the OLINDA version 1.0 computer program. RESULTS: The largest amounts of radioactivity were taken up by the liver (41.3 +/- 7.8 [mean +/- SD] percentage injected dose [%ID] at 1 h after injection and decreasing to 4.9 +/- 0.3 %ID at 72 h after injection) and kidneys (18.6 +/- 0.8 %ID at 1 h and decreasing to 4.5 +/- 0.2 %ID at 72 h after injection). (111)In-DTPA-hEGF was cleared rapidly from the blood, with a half-life at alpha-phase of 2.7-6.2 min and a half-life at beta-phase of 24.0-36.3 min. The half-life of the long terminal phase could not be accurately determined. The volume of distribution of the central compartment was 340-375 mL/kg, and the volume of distribution at steady state was 430-685 mL/kg. There was no significant difference in the ratio of body weight at 15 d to pretreatment weight for mice administered (111)In-DTPA-hEGF (1.02 +/- 0.01) and mice administered unlabeled DTPA-hEGF (1.01 +/- 0.01). Erythrocyte, leukocyte, and platelet counts and serum alanine aminotransferase and creatinine levels remained in the normal ranges. No morphologic changes were observed by light microscopy in any of 19 tissues sampled. Minor morphologic changes in the liver were observed by electron microscopy. The projected whole-body dose in humans was 0.19 mSv.MBq(-1). The projected doses to the liver, kidneys, and lower large intestine were 0.76, 1.82, and 1.12 mSv.MBq(-1), respectively. CONCLUSION: (111)In-DTPA-hEGF was safely administered to mice and rabbits at multiples of the maximum dose planned for a phase I trial in breast cancer patients.

DTPA Fe(III) decreases cytokines and hypotension but worsens survival with Escherichia coli sepsis in rats.

OBJECTIVE: Nonselective inhibition of nitric oxide (NO) with NO synthase antagonists decreases hypotension but worsens outcome clinically. We investigated whether iron (III) complex of diethylenetriaminepentaacetic acid [DTPA Fe(III)], a scavenger of NO as well as other oxidant mediators, has similar divergent effects in E. coli challenged rats. METHODS: Animals with venous and arterial catheters and challenged with intrabronchial or intravenous E. coli were randomized to treatment with DTPA Fe(III) in doses from 3 to 800 mg/kg or placebo. Mean blood pressure (MBP) was measured in all animals and plasma NO, cytokines, and blood and lung leukocyte and bacteria counts in animals administered intrabronchial E. coli and DTPA Fe(III) 50 mg/kg or placebo. Animals received antibiotics and were observed 168 h. RESULTS: Independent of drug regimen or infection site, compared to placebo, DTPA Fe(III) increased MBP although this was greater with high vs. lower doses. Despite increased MBP, DTPA Fe(III) worsened the hazards ratio of survival . At 6 and 24 h DTPA Fe(III) decreased NO but not significantly and decreased four cytokines (tumor necrosis factor-alpha, interleukins 1 and 10, and macrophage inflammatory protein 3alpha) and lung lavage neutrophils. From 6 to 24 h DTPA Fe(III) increased blood bacteria. CONCLUSIONS: DTPA Fe(III) while increasing blood pressure has the potential to worsen outcome in sepsis. Further preclinical testing is required before this agent is applied clinically.

Treatment of accidental intakes of plutonium and americium: guidance notes.

The scientific basis for the treatment of the contamination of the human body by plutonium, americium and other actinides is reviewed. Guidance Notes are presented for the assistance of physicians and others who may be called upon to treat workers or members of the public who may become contaminated internally with inhaled plutonium nitrate, plutonium tributyl phosphate, americium nitrate or americium oxide.

The role of combined imaging in metastatic medullary thyroid carcinoma: 111In-DTPA-octreotide and 131I/123I-MIBG as predictors for radionuclide therapy.

PURPOSE: The medical treatment of metastatic medullary thyroid carcinoma (MTC) is still questionable. The aim of this study was to evaluate a combined imaging protocol using 111In-DTPA-octreotide and 131I/123I-MIBG to decide whether targeted radiotherapy would be useful, and which radiopharmaceutical (90Y-DOTATOC or 131I-MIBG) would be more effective. METHODS: Eight patients (four men, four women; mean age 61 years) with metastatic MTC were included. Treatments were performed with 3,330 MBq 90Y-DOTATOC at 6-week intervals, or 11.1 GBq 131I-MIBG with a minimum interval of 3 months. RESULTS: The imaging procedure was positive in all eight patients: 111In-DTPA-octreotide imaging in five patients, 131I/123I-MIBG imaging in four patients. With respect to the number of metastatic lesions, MIBG imaging was less effective than octreotide. According to the results of combined imaging, we identified one patient to be treated with 90Y-DOTATOC, and three patients with 131I-MIBG. An overall antitumor effect was observed in all four patients, one with partial remission and three with stable disease. No relevant toxicity was observed. CONCLUSIONS: The combined imaging can increase the detection rate of metastatic foci in patients with MTC and identify more patients for effective radionuclide treatment. The treatment with 90Y-DOTATOC or 131I-MIBG is well tolerated and may improve the fate of patients with metastatic MTC.

Effect of DTPA on the nephrotoxicity induced by uranium in the rat.

The only treatment proposed after human contamination with MOX (mixed oxide of uranium and plutonium) is diethylenetriaminepentaacetic acid (DTPA), because plutonium is considered to be the major risk. However, both DTPA and uranium are nephrotoxic at high dosages and DTPA has been shown to increase in vitro the cytotoxicity induced by uranium on cultured epithelial tubular cells. This work aimed to test this effect in vivo. Rats were injected with subtoxic (57 microg kg(-1)) to toxic (639 microg kg(-1)) amounts of uranium as nitrate at 0 h, they received two DTPA injections (30 micromol kg(-1)) at 2 min and 24 h and were euthanased at 48 h. The nephrotoxic effects were evaluated by measurement of the body weight gain, food and water intake, measurement of biochemical parameters in urine and blood, and histological examination of one kidney. The main result was that DTPA did not increase the nephrotoxicity induced by uranium in the range of concentrations tested, which was inconsistent with the in vitro results.

Preclinical studies of [(99m)Tc]DTPA-mannosyl-dextran .

We report the preclinical testing of a synthetic receptor-binding macromolecule, [(99m)Tc]DTPA-mannosyl-dextran (36 kDa, 8 DTPA and 55 mannosyl units per dextran, K(D) = 0.12 nM), for sentinel node detection. Nonclinical safety studies included cardiac pharmacology safety studies, acute toxicology and pathology studies at 50 and 500 times the scaled human dose in both rats and rabbits after foot pad administration, and perivascular irritation studies in rabbits following intra-muscular administration at 100 and 1000 times the scaled human dose. Biodistribution studies in rabbits at 15 m, 1 h, and 3 h indicated that [(99m)Tc]DTPA-mannosyl-dextran cleared the hind foot pad with a biological half-life of 2.21 +/- 0.27 h. Other than mild hepatocyte hypertrophy in rabbits, no abnormalities in toxicology or pathology were found. Intravenous administration had no effect on survival, any clinical observations, electrocardiograms, or blood pressures. Intramuscular injection had no effect on survival, clinical observations, injection site observations, or injection site histopathology. The estimated absorbed radiation dose to the affected breast was 0.15 mGy/MBq and the effective dose was 1.06 x 10(-2) mSv/MBq. This preclinical study demonstrates that [(99m)Tc]DTPA-mannosyl-dextran has no toxicities and has an acceptable biodistribution and radiation dose.