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At least 91 records · Page 5Linked to original sources
PubMed1996

Pharmacokinetics and biodistribution of samarium-153-labelled OC125 antibody coupled to CITCDTPA in a xenograft model of ovarian cancer.

The use of samarium-153 in the context of radioimmunotherapy of cancers has been limited by the instability of antibody labelling, which produces high uptake concentrations in liver and bone. This study compares the pharmacokinetics and biodistribution of 153Sm-labelled OC125 monoclonal antibody, in whole or F(ab')2 fragment form and with diethylene triamine penta-acetic acid (DTPA) or 6-p-isothiocyanatobenzyl diethylene triamine penta-acetic acid (CITCDTPA) coupling, in nude mice grafted subcutaneously with an ovarian adenocarcinoma line (SHIN-3) expressing CA125 antigen. The specific activity of the immunoconjugates was 18.5-55.5 MBq/mg, and their immunoreactivity exceeded 65%. With 153Sm-DTPA-OC125F(ab')2, the stability study in serum indicated that 50% of the metal remained bound to the antibody. The pharmacokinetic study showed a retention half-life of 25.1 h and blood clearance of 0.72 ml/h. The biodistribution study indicated tumour uptake of 4.53%+/-0.49% of injected activity per gram (%ID/g) at 24 h and tumour-to-liver and tumour-to-bone ratios of 0.23+/-0.02 and 1.54+/-0.49 respectively at 24 h. With 153Sm-CITCDTPA-OC125F(ab')2, serum stability was greater (87% of the metal remaining bound to the antibody), retention half-life was 22.25 h and blood clearance was 2.23 ml/h. Tumour was better targeted (8.30%+/-3.56%ID/g at 24 h), and tumour-to-liver and tumour-to-bone ratios were 1.17+/-0.36 and 7.08+/-3.09 respectively at 24 h. However, renal retention remained elevated (29.76%+/-9. 41%ID/g at 24 h). With intact IgG, renal uptake decreased (1.41%+/-0. 49%ID/g at 24 h), but tumour uptake was lower than with fragments (1. 46%+/-0.58%ID/g at 24 h). Liver uptake was higher (tumour-to-liver ratio 0.10+/-0.05), and blood clearance was slower. The stability and distribution of 153Sm-CITCDTPA were more favourable than those of 153Sm-DTPA for application in radioimmunotherapy. Quantitative analysis performed using digitized images obtained by conventional autoradiography and the imaging plate system indicated that the latter system is suitable for biodistribution studies of immunoconjugates.

Animals↗
PubMed1999

Multicentre trial on the efficacy and toxicity of single-dose samarium-153-ethylene diamine tetramethylene phosphonate as a palliative treatment for painful skeletal metastases in China.

A multicentre trial was organized in China as part of an international coordinated research project to study the efficacy and toxicity of single-dose samarium-153 ethylene diamine tetramethylene phosphonate (EDTMP) as a palliative treatment for painful skeletal metastases. One hundred and five patients with painful bone metastases from various primaries were treated with 153Sm-EDTMP at a dose of 37 MBq/kg(group I) or 18.5 MBq/kg (group II). The effects were evaluated according to change in daily analgesic consumption, pain score, sum of effect product (SEP), Physician's Global Assessment (PGA), blood counts, and organ function tests conducted regularly for 16 weeks. Fifty-eight of 70 patients in group I and 30 of 35 in group II had a positive response, with SEPs of 22.29+/-14. 47 and 20.13+/-13.90 respectively. Of 72 patients who had been receiving analgesics, 63 reduced their consumption. PGA showed that the Karnofsky score (KS) increased from 58.54+/-25.90 to 71.67+/-26. 53, indicating improved general condition, but the difference was not significant. Among subgroups of patients, only those with breast cancer showed a significant change in the Karnofsky score after treatment. Inter-group differences were found for net change in KS between patients with lung and patients with breast cancer, and between patients with lung and patients with oesophageal cancer. Seventeen patients showed no response. No serious side-effects were noted, except for falls in the white blood cell (nadir 1.5x10(9)/l) and platelet (nadir 6.0x10(10)/l) counts in 44/105 and 34/105 cases, respectively. Ten patients had an abnormal liver function test. Response and side-effects were both independent of dose. In conclusion, 153Sm-EDTMP provided effective palliation in 83.8% of patients with painful bone metastases; the major toxicity was temporary myelosuppression. Further studies are needed to identify better ways of determining the appropriate dose in the individual case and the efficacy of treatment.

Analgesics, Non-Narcotic↗
PubMed1987

The standardization of samarium-153.

Samarium-153 has been standardized by 4 pi beta liquid-scintillation counting, with an uncertainty of 0.4%. The probability per decay for the 103.2-keV gamma ray was measured, using two germanium detectors, to be 0.298 +/- 0.004. The half life, based on liquid-scintillation measurements over 6.4 half lives and pressurized-ionization-chamber measurements over four half lives, was found to be 46.27 +/- 0.02 h. The uncertainties given are one estimated standard deviation (of the mean when applicable) for random and non-random components.

Gamma Rays↗
PubMed2006

Samarium(II) promoted stereoselective synthesis of antiproliferative cis-beta-alkoxy-gamma-alkyl-gamma-lactones.

Samarium(II) iodide promotes the stereoselective synthesis of cis-beta-alkoxy-gamma-alkyl-gamma-lactones under mild conditions starting from linear precursors. The in vitro antiproliferative activities were examined in the human solid tumor cell lines from diverse origin A2780, SW1573, and WiDr. From the growth inhibition data a structure-activity relationship was obtained. Overall the results point to the relevant role of cis-beta-alkoxy-gamma-alkyl-gamma-lactones as novel scaffolds for the development of new anticancer drugs.

Antineoplastic Agents↗
PubMed2004

Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer.

OBJECTIVES: A Phase III randomized trial was designed to assess the effectiveness of samarium-153 (153Sm)-lexidronam for palliation of bone pain in patients with hormone-refractory prostate cancer. METHODS: A total of 152 men with hormone-refractory prostate cancer and painful bone metastases were enrolled in a prospective, randomized, double-blind trial comparing radioactive (153Sm) versus nonradioactive (152Sm) lexidronam complexes. Patients were randomized (2:1) to the radioactive (153Sm) agent. Patient diaries recording daily pain and analgesic use were completed during a planned 16-week evaluation period. Nonresponders were informed of the treatment received after 4 weeks of treatment and, if initially treated with placebo, were allowed to receive 153Sm-lexidronam in an open-label fashion. Pain was measured using validated patient-derived visual analog scales and pain descriptor scales. RESULTS: 153Sm-lexidronam had positive effects on measures of pain relief compared with placebo within 1 to 2 weeks. Reductions in opioid use were recorded at weeks 3 and 4. Because nonresponders were unblinded at week 4, statistical comparisons between the arms beyond week 4 were not possible. Mild, transient bone marrow suppression was the only adverse event associated with 153Sm-lexidronam administration. The mean nadir white blood cell and platelet count (3 to 4 weeks after treatment) was 3800/microL and 127,000/microL, respectively. Counts recovered to baseline after approximately 8 weeks. No grade 4 decreases in either platelets or white bloods cells were documented. CONCLUSIONS: These findings demonstrate that 1 mCi/kg 153Sm-lexidronam is both safe and effective for the palliation of painful bone metastases in patients with hormone-refractory prostate cancer.

Aged↗
PubMed1997

Dose response relationship and multiple dose efficacy and toxicity of samarium-153-EDTMP in metastatic cancer to bone.

INTRODUCTION: The optimal dose of samarium-153-EDTMP (153Sm-EDTMP) for effective palliation of painful metastases to bone is under investigation. It is not known whether increased doses of 153Sm EDTMP will lead to better and longer pain and tumour control and survival. Multiple dose efficacy and toxicity is of importance as most Patients will require prolonged support for pain. METHODS: Twenty-eight (28) patients were treated with 0.75 mCi/kg, 35 patients with 1.5 mCi/kg and 19 patients with 3 mCi/kg in three sequential Phase I-II trials. Multiple doses were given to patients on the 0.75 mCi/kg and 1.5 mCi/kg dose levels. RESULTS: At all dose levels adequate pain control was achieved in 78-95% of patients. The duration of pain control was 40-56 days with the best results in the 1.5 mCi/kg group (56 days). There is no evidence that increasing dose leads to better and longer pain control, tumour response and survival, but toxicity is increased. Multiple doses can be given with acceptable toxicity and pain control, however, only 38% of patients will qualify for multiple treatments. CONCLUSION: 153Sm-EDTMP provides adequate and safe palliation but multiple doses can only be given in 38% of patients. There is not a clear dose-response relationship. The length of pain control is satisfactory but not ideal and hospitalisation for 4 days every 6-8 weeks is a disadvantage. Further research is required to combine 153Sm-EDTMP with cytostatics and to administer it on an out patient basis.

Bone Neoplasms↗
PubMed1992

Samarium-153-labelled EDTMP for bone metastases from cancer of the prostate.

A Phase I dose-escalation trial of a bone seeking phosphonate labelled with Samarium-153 was conducted on heavily pretreated patients with widespread bony metastases from cancer of the prostate. The bone marrow dose was calculated initially on a 4:1 uptake of cortical to cancellous bone, but subsequent information suggested the distribution was approximately equal so that the marrow received about three times the dose that has been prescribed. As a result, what were at first thought to be doses of 0.5 Gy, 1.0 Gy and 1.5 Gy were probably 1.5 Gy, 3.0 Gy and 4.5 Gy respectively. Three patients were treated at each dose level. The dose was repeated in the first three. Pain relief was delayed for 2 weeks, and was maximal by 4 weeks. All but one patient gained some benefit but this was transitory, lasting only 4-6 weeks in most. A recalculated dose of 3 Gy proved the most effective. The major toxicity was to platelets. Thrombocytopenia was fatal in four cases (two with repeat doses). All patients died but three survived more than 6 months with the help of third line hormonal measures and local radiotherapy to maintain comfort. A second group of five patients, not previously irradiated, were given 153Sm-EDTMP to a marrow dose of 3 Gy and all have survived for more than 4 months and achieved minimal to excellent relief of pain. The technique is recommended as initial therapy in unirradiated patients with good bone marrow function and with significant pain above and below the diaphragm, making half-body irradiation less likely to be a useful palliative procedure.

Aged↗
PubMed2000

Preparation and evaluation of samarium (III) phosphate [(153)Sm] colloid (SMPC) for possible therapeutic use.

A simple method of preparation of a new therapeutic colloid, samarium(III) phosphate-(153)Sm (SMPC), is reported involving the reaction of carrier-added (153)SmCl(3) with phosphoric acid. Recovery of the colloid was accomplished by dialysis leading to purification and a radiochemical (RC) yield of more than 90%. The RC purity of purified colloid formulated in isotonic phosphate buffer was more than 99% as assessed by paper chromatography. The product retained its RC purity throughout the period of stability study of 7 days. Complete retention of radioactivity instilled in the rabbit knee joint was observed over the study period of 6 days, with radioactivity in the blood being indistinguishable from the natural background activity. Ninety-six percent of colloidal particles were in the size range of 0.3-2 microm. The promising results demonstrated warrant further studies on SMPC for assessing the suitability for therapy.

Animals↗
PubMed1996

Evaluation of samarium-153 and holmium-166-EDTMP in the normal baboon model.

Bone-seeking radiopharmaceuticals such as ethylenediaminetetramethylene phosphonate (EDTMP) complexes of samarium-153 and holmium-166 are receiving considerable attention for therapeutic treatment of bone metastases. In this study, using the baboon experimental model, multicompartmental analysis revealed that with regard to pharmacokinetics, biodistribution, and skeletal localisation, 166Ho-EDTMP was significantly inferior to 153Sm-EDTMP and 99mTc-MDP. A more suitable 166Ho-bone-seeking agent should thus be sought for closer similarity to 153Sm-EDTMP to exploit fully the therapeutic potential of its shorter half-life and more energetic beta radiation.

Absorption↗
PubMed1998

Samarium-153 and lutetium-177 chelation properties of selected macrocyclic and acyclic ligands.

We describe a simple in vitro characterization of chelation that is useful when choosing an appropriate ligand-metal combination for clinical applications. These properties include the effect of concentration on chelation efficiency, time to maximum chelation, and stability in acidic and serum environments. The macrocyclic ligands nitro-DOTA and nitro-PADOTA, the acyclic ligands nitro-CHX-A-DTPA, nitro-MX-DTPA, DTPA, and a novel terpyridine ligand, TMT-amine, were evaluated as chelate complexes of both intermediate energy beta-emitting lanthanides lutetium-177 and samarium-153. The data were compared to results obtained in a previously published study with yttrium-90. Acid lability, time to achieve maximum chelation, and stability in human serum are properties unique to each ligand-metal combination and should be evaluated prior to choosing an appropriate combination for therapeutic applications. Concentration dependence and duration of chelation are general properties of lanthanide and yttrium chelation that can be applied to an appropriate ligand-metal combination to achieve optimum chelation efficiencies.

Chelating Agents↗
PubMedDate not supplied

Samarium-153 for intravascular irradiation therapy with liquid-filled balloons to prevent restenosis: acute and long-term results in a hypercholesterolemic rabbit restenosis model.

BACKGROUND: It has been shown that irradiation with either beta and gamma sources inhibit neointimal formation. Samarium-153 ((153)Sm) is an isotope with 0.8 MeV, subdivided in three different beta energies and 103 keV of gamma energy. This compound has been tested and used in humans for palliation of pain from bone metastases. The aim of the present study was to evaluate the feasibility and efficacy of brachytherapy with (153)Sm-filled balloon to inhibit neointimal formation in rabbits after balloon overstretch injury. METHODS: Nineteen rabbits underwent balloon injury in their iliac arteries. In 12 animals (control), oversized balloons filled with saline solution were inflated up to 5 atm for a period of 5 min. In 7 rabbits, the same procedure was performed but using balloons filled with (153)Sm. In all cases, both iliac arteries were treated. The prescribed radiation dose was 15 Gy at 1 mm depth. After 30 days, the animals were sacrificed and their arterial segments were analyzed. Radiation exposure at the animal chest to the table and at a distance of 1 m from the table was measured. RESULTS: Histopathologic analysis showed a striking reduction in the amount of neointima in the irradiated arteries compared with control vessels (0.36+/-0.21 vs. 1.07+/-0.56 mm(2), P<.01). The dose delivered to the animal chest was 21.5 mR/h, whereas only 1.9 mR/h was measured at the table and virtually no radiation could be detected at a distance of 1 m from the table. CONCLUSIONS: Brachytherapy with (153)Sm was feasible with minimal personnel exposure radiation and effectively inhibited neointimal formation in this experimental model. These results warrant further experimental and clinical investigations.

Animals↗
PubMedDate not supplied

An improved method for labeling monoclonal antibodies with samarium-153: use of the bifunctional chelate 2-(p-isothiocyanatobenzyl)-6- methyldiethylenetriaminepentaacetic acid.

Samarium-153 (153Sm) radioimmunoconjugates of the monoclonal antibody K-1-21 were produced using the bifunctional chelate 2-(p-isothiocyanatobenzyl)-6- methyldiethylenetriaminepentaacetic acid (Mx-DTPA). The specific activity (up to 150 MBq mg-1) and percent retained immunoreactivity (greater than 75%) were similar to that of 153Sm-K-1-21 conjugates formed with cyclic DTPA anhydride (cDTPAa). In vivo biodistribution studies showed specific localization of 153Sm-Mx-DTPA-K-1-21 to target antigen implants and higher blood pool and lower uptake in liver, spleen, kidney, and bone when compared to 153Sm-cDTPAa-K-1-21. The improved in vivo distribution of 153Sm-Mx-DTPA-K-1-21 should result in lower radiotoxicity to nontarget tissues when used for radioimmunotherapy purposes.

Animals↗
PubMed2001

Sequenced reactions with samarium(II) iodide. Sequential intramolecular Barbier cyclization/Grob fragmentation for the synthesis of medium-sized carbocycles.

Samarium(II) iodide was used to access eight-, nine-, and ten-membered carbocycles via a domino reaction composed of a cyclization/fragmentation process. 2-(Iodoalkyl)-, 2-(iodomethyl)allyl-, and 2-(2-iodomethyl)benzyl-2-methyl-3-(methanesulfonyloxy)cycloalkanones were subjected to Barbier-type reductive coupling conditions. Intermediate cycloalkanedione derivatives were also treated under similar conditions, providing bicyclic hydroxy ketones with complete diastereoselectivity and high yields. This method represents a general and efficient approach to a variety of highly functionalized, stereodefined carbocycles.

Alkanes↗
PubMed2002

Sequenced reactions with samarium(II) iodide. Sequential intramolecular Reformatsky/nucleophilic acyl substitution reactions for the synthesis of medium-sized carbocycles.

Samarium(II) iodide was used to access eight- and nine-membered carbocycles via a domino reaction comprised of a Reformatsky reaction followed by a nucleophilic acyl substitution reaction. This method represents a general and efficient approach to a variety of highly functionalized, stereodefined carbocycles.

Alkanes↗
PubMed2003

One-step highly diastereoselective synthesis of gamma-aminoalkyl-substituted gamma-butyrolactones by an asymmetric samarium-mediated ketyl-alkene coupling reaction.

The samarium(II) iodide mediated reaction of N,N-dibenzyl-protected (S)-alpha-amino aldehydes with (1S,2R)-N-methylephedrinyl acrylate gave the (4R,1'S)-gamma-(aminoalkyl)-gamma-butyrolactones in good yields with high diastereoselectivities (up to 80% de); (4R,1'S)-gamma-amino-(2-phenylethyl)-gamma-butyrolactone (6a), which should be a potent precursor for gamma-secretase inhibitors, was obtained with high de value.

4-Butyrolactone↗
PubMed2002

Samarium(II) iodide-mediated intramolecular conjugate additions of alpha,beta-unsaturated lactones.

Samarium(II) iodide, in the presence of catalytic amounts of nickel(II) iodide, has been used to promote intramolecular conjugate additions of alkyl halides onto alpha,beta-unsaturated lactones. This process has been shown to be applicable to a number of alpha,beta-unsaturated lactones, including tetrasubstituted olefins, and has been demonstrated to be quite general for the formation of saturated bicyclic and tricyclic lactones. The method presented herein provides a mild, efficient process to form structurally complex lactones from simple precursors.

Cyclization↗
PubMed2003

Total synthesis of (+)-isoschizandrin utilizing a samarium(II) iodide-promoted 8-endo ketyl-olefin cyclization.

The 13-step synthesis of (+)-isoschizandrin reported herein features a samarium(II) iodide-promoted 8-endo ketyl-olefin coupling to assemble the eight-membered ring present in the target concomitantly with the required functionality and stereochemistry. In constructing (+)-isoschizandrin as a single atropisomer, the synthesis utilizes a kinetic resolution of a seven-membered lactone using a CBS-oxazaborolidine.

Alkenes↗
PubMed2005

Ketyl-allene cyclizations promoted by samarium(II) iodide.

[reaction: see text] Samarium(II) iodide has proven to be an effective reagent for intramolecular reductive coupling reactions. Previous investigations of intramolecular ketyl-olefin coupling reactions provided carbocycles in excellent yield and good diastereoselectivity. This method has been extended to ketyl cyclizations with allenes. Substrates leading to both carbocycles and heterocycles in a selective manner are explored.

Iodides↗