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Systemic administration of new therapeutic radioisotopes, including phosphorus, strontium, samarium, and rhenium.

New advances in systemic radionuclide therapy have increased the number of treatment options available for patients with painful osseous metastases. This form of therapy has three major appeals: 1) it addresses all sites of involvement; 2) selective absorption into bone limits irradiation of normal tissues; and 3) as a result, toxicity may be reduced and the therapeutic ratio improved. The clinical experience with radioactive phosphorus, strontium, samarium, and rhenium are reviewed. To date, the best studied and the only Food and Drug Administration approved agent is strontium-89. About 60% to 90% of patients treated with strontium-89 respond with complete or partial relief of pain for a median duration of 6 months. Large, prospectively randomized clinical trials have established the efficacy of strontium-89 as a first-line therapy and as an adjuvant to external-beam radiotherapy. Particularly advantageous is its usefulness in situations in which external-beam radiotherapy options have been exhausted and normal tissue tolerance has been reached. Newer radiopharmaceuticals are still under investigation.

Bone Neoplasms↗

Toxicological and pharmacological effects of gadolinium and samarium chlorides.

A study has been made of the toxicology and pharmacology of gadolinium and samarium chlorides. The symptoms of acute toxicity following intraperitoneal injection are described. The chronic oral ingestion of both chemicals for 12 weeks produced no effects on growth or the blood picture, and only the male rats receiving gadolinium chloride showed liver damage. The pharmacological responses to both chemicals were mainly depressant on all systems studied, and death was associated with cardiovascular collapse coupled with respiratory paralysis. The greatest damage seen was on abraded skin, where non-healing ulcers were produced by both chemicals, whereas irritation of intact skin and ocular tissues was only transient in nature.

Animals↗

Double blind glucocorticoid controlled trial of samarium-153 particulate hydroxyapatite radiation synovectomy for chronic knee synovitis.

BACKGROUND: Samarium-153 particulate hydroxyapatite (Sm-153 PHYP) is a relatively new radiation synovectomy agent developed for the treatment of chronic synovitis. Although it has been shown that the levels of unwanted extra-articular radiation are lower after intra-articular injection of Sm-153 PHYP than yttrium-90 colloid, its clinical efficacy has not been rigorously studied. OBJECTIVES: To establish whether Sm-153 PHYP radiation synovectomy results in a clinically useful benefit sustained at one year. METHODS: In a randomised double blind study, patients received either intra-articular 40 mg triamcinolone hexacetonide alone or 40 mg triamcinolone hexacetonide combined with Sm-153 PHYP in an outpatient clinic. RESULTS: Sixty patients (28 male, 32 female), median age 51 (18-75) with chronic knee synovitis were studied. Diagnoses included: rheumatoid arthritis (n=29); psoriatic arthritis (n=9); ankylosing spondylitis (n=3); reactive arthritis (n=2); undifferentiated seronegative oligoarthritis (n=13) and miscellaneous inflammatory conditions (n=4). More patients who received Sm-153 PHYP/triamcinolone hexacetonide sustained clinical benefit a year after treatment compared with patients who received corticosteroid alone (12 of 31 (39%) v 6 of 29 (21%), a difference of 18% more patients (95% CI -5% to 41%)) though the difference was not significant (chi(2)=2.31, 0.2>p>0.1, n=60). Despite the variation in injected activity (median 563 MBq, range 218-840 MBq), there was no obvious relation between low levels of injected activity (<555 MBq) and relapse within 12 months of treatment (chi(2) =2.61, 0.2>p>0.1, n=31). CONCLUSIONS: There was no clear beneficial clinical effect of combined Sm-153 PHYP/triamcinolone hexacetonide injection over triamcinolone hexacetonide alone a year after treatment for chronic knee synovitis.

Administration, Topical↗

Body composition analysis by DEXA by using dynamically changing samarium filtration.

Dual-energy X-ray absorptiometry (DEXA) has a high accuracy for body composition analysis but is influenced by beam hardening and other error sources in the extremes of measurement. To compensate for beam hardening, the Norland XR-36 introduces a dynamically changing samarium filtration system, which depends on the current-absorber thickness. With this system we found a good agreement (r = 0.99) between reference and measured amounts of tissue or fat percentages in a plastic phantom and in smaller (approximately 0.5-4 kg) and larger (approximately 5-20 kg) piles of tissue (ox muscle and lard). Scans of six healthy volunteers covered with combinations of beef and lard (approximately 5-15 kg) showed a good agreement (r = 0.99) between reference and DEXA values of added soft tissue mass and fat percentage. We conclude that the DEXA method (and, in particular, the Norland XR-36 using dynamic filtration) has a high accuracy for body composition analysis. It has a potential for gaining status as a reference method in the future and may presently be used as a supplement to the traditional methods for body composition analysis.

Absorptiometry, Photon↗

Prospective evaluation of samarium-153-EDTMP radionuclide treatment for bone metastases in patients with hormone-refractory prostate cancer.

PURPOSE: Bone is a common site of metastatic disease and the most frequent site of metastatic spread in patients with prostate cancer. Most patients with bone metastases complain of bone pains. This pain may be alleviated or eliminated by administration of radiotherapy at the site of metastases. Currently, two forms of radiotherapy administration exist: external-beam irradiation or intravenous administration of bone-seeking therapeutic radiopharmacon such as samarium-153-ethylene-diamino-tetramethylene-phosphonate (EDTMP). This radiopharmacon produces beta-particles and concentrates in the areas of enhanced osteoblastic activity. The aim of this study was to assess the efficacy of (153)Sm-EDTMP therapy. MATERIALS AND METHODS: 32 men (aged 50-83, mean 70 years) with bone disseminated hormone-refractory prostate cancer and bone pain received (153)Sm-EDTMP. Mean applied dosage was 40 MBq/kg of the patient's body weight. Karnofsky performance status, pain score (numerical rating scale), analgesic score (WHO) and blood count were evaluated before, and 1 and 3 months after the treatment. RESULTS: Significant pain relief was observed in 44 and 38% of patients, mild relief in 31 and 34% and no effect in 25 and 28% of patients, 1 and 3 months after administration, respectively. Pain palliation was accompanied by an improvement in mobility and a decrease in necessary dosage of analgesics. Mild and transient bone marrow suppression was observed as a side effect of (153)Sm-EDTMP treatment. None of the patients showed hematological toxicity grade 4, and only 2 showed grade 3 (NCI CTC). The majority of the patients had hematological toxicity grade 1 or 2. CONCLUSION: After (153)Sm-EDTMP administration, bone pain palliation was observed in 72% of patients for 3 months. Hematological toxicity after (153)Sm-EDTMP treatment was mild and transient.

Aged↗

Samarium as a tool in studies on the responsiveness of the isolated guinea pig ventral taenia coli to barium.

The responsiveness of isolated guinea pig ventral taenia coli to barium in polarized (Ringer-Tris medium) and depolarized (Ringer-KCl medium) preparations was assayed in the presence of samarium (Sm3+, 6 or 8 X 10(5) M). No difference in EC50 or maximal response was observed between polarized and depolarized preparations (p greater than 0.05). The lower Sm3+ concentration increased Ba2+ EC50 in both experimental conditions (p less than 0.05) although no alteration was observed as to the maximal response (p greater than 0.05). On the other hand, maximal tension was strongly reduced by the higher Sm3+ concentration in polarized preparations (p less than 0.01) while a potentiation of the maximum response was observed on the depolarized tissues (p less than 0.05). A possible role for calcium ions in the mediation of the effects is suggested.

Animals↗

A phase I study of samarium-153 ethylenediaminetetramethylene phosphonate therapy for disseminated skeletal metastases.

Thirty-five patients with disseminated skeletal metastases from a variety of tumor types underwent clinical trial of samarium-153 ethylenediaminetetramethylene phosphonate (153Sm-EDTMP) on a day-patient basis. Individual beta radiation dosimetry was based on pharmacokinetic studies of a 20 mCi tracer dose of 153Sm-EDTMP. The retained skeletal activity varied unpredictably from 40% to 95% of the administered dose, but in all patients greater than 98% of the nonosseous activity was cleared in the urine within 6 hours. Prospective calculation of radiation dosimetry in each patient permitted an accurate dosage schedule based upon total red marrow exposure, starting at 100 cGy and escalating to 280 cGy to define the dose-limiting myelotoxicity. Pain was relieved in 22 of 34 evaluable patients (65%) for periods ranging from 4 to 35 weeks, following a single administration of 153Sm-EDTMP. Recurrence of pain responded to retreatment with 153Sm-EDTMP in five of nine patients. The dose-limiting toxicity was myelosuppression manifested particularly by delayed thrombocytopenia. Platelet counts less than 100 x 10(9)/L occurred in 42% of courses when bone marrow radiation absorbed dose exceeded 200 cGy. Myelosuppression was transient and platelet counts had recovered to pretreatment levels within 10 weeks of treatment. 153Sm-EDTMP is effective for the amelioration of pain due to disseminated skeletal metastases particularly with carcinoma of breast or prostate where 83% of patients experienced pain relief. In 15 of the 34 evaluable patients there was evidence of stabilization or regression of skeletal metastases on radiographs and follow-up technetium-99m methylene diphosphonate (99mTc-MDP) bone scans.

Bone Neoplasms↗

High-dose samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases.

PURPOSE: Samarium-153 ethylene diamine tetramethylene phosphonate ((153)Sm-EDTMP), a bone-seeking radiopharmaceutical, provides therapeutic irradiation to osteoblastic bone metastases. Because the dose-limiting toxicity of (153)Sm-EDTMP is thrombocytopenia, a dose-escalation trial using peripheral-blood progenitor cells (PBPCs) or marrow support was conducted to treat metastatic bone cancer. PATIENTS AND METHODS: Patients with locally recurrent or metastatic osteosarcoma or skeletal metastases avid on bone scan were treated with 1, 3, 4.5, 6, 12, 19, or 30 mCi/kg of (153)Sm-EDTMP. RESULTS: Thirty patients were treated with (153)Sm-EDTMP. Transient symptoms of hypocalcemia were seen at 30 mCi/kg. Estimates of radioisotope bound to bone surfaces and marrow radiation dose were linear with injected amount of (153)Sm-EDTMP. Cytopenias also occurred in all subjects and were dose-related. At day +13 after (153)Sm-EDTMP, residual whole-body radioactivity was 1% to 65% of whole-body radioactivity considered safe for PBPC infusion, 3.6 mCi. After PBPC or marrow infusion on day +14 after (153)Sm-EDTMP, recovery of hematopoiesis was problematic in two patients at the 30 mCi/kg dose infused with less than 2 x 10(6) CD34(+)/kg on day +14, but not in other patients. Reduction or elimination of opiates for pain was seen in all patients. Patients had no adverse changes in appetite or performance status. CONCLUSION: (153)Sm-EDTMP with PBPC support can provide bone-specific therapeutic irradiation (estimates of 39 to 241 Gy). Hematologic toxicity at 30 mCi (153)Sm-EDTMP/kg requires PBPC grafts with more than 2 x 10(6) CD34(+)/kg to overcome myeloablative effects of skeletal irradiation. Nonhematologic side effects are minimal.

Adolescent↗

Reduction of acetals with samarium diiodide in acetonitrile in the presence of Lewis acids.

Transformation of acetals into ethers by partial reduction using a samarium diiodide-Lewis acids-acetonitrile system is described. The reaction with aromatic acetals occurred in good yields in the presence of aluminum chloride (2 eq) whereas the corresponding aliphatic, vinylic, and alkynyl derivatives did not afford ethers under the same conditions. Beta-elimination to give an enol ether becomes predominant when aliphatic acetals that possess a hydrogen at the 2-position are treated with iodotrimethylsilane in the presence of SmI2 or SmI3.

Acetals↗

Facile deoxygenation of dicarbonyl compounds using a samarium diiodide-additive system.

The reduction of alpha- and beta-dicarbonyl compounds was investigated with samarium diiodide in the presence of additive. Diketones and ketocarboxylic acids were easily reduced at room temperature to give the mono-alcohols in good to excellent yield, and ketoester afforded the saturated ester as the major product in moderate yield. These reductions containing the reductive deoxygenation can be rapidly performed under the facile and mild conditions by this method.

Carboxylic Acids↗

Vascular radiolesion as a deleterious effect of high-dose-rate intraarterial brachytherapy with samarium-153 in hypercholesterolemic rabbits.

OBJECTIVE: This study was designed to evaluate vascular morphological and morphometric changes induced by brachytherapy with samarium-153 (Sm-153) at high doses in hypercholesterolemic rabbits. METHODS: Forty-three New Zealand White hypercholesterolemic rabbits were analyzed, and the total of 86 iliac arteries underwent balloon angioplasty injury. The rabbits were divided into three different groups: two irradiation groups (IG) assigned to 15 Gy (n=14) and 60 Gy (n=36) irradiation doses, respectively, and a control group (n = 36). Histomorphometric and qualitative histological analyses were performed for tissue evaluation. RESULTS: Significant reductions were found in neointimal proliferation (NIP) (p< 0.0001), media area (MA) (p<0.0001) and percent stenosis (p<0.0001) in the 15-Gy IG, compared to the other groups. The 60-Gy IG had the higher rate of NIP, increase in media and vessel areas (VA) and percent stenosis. The 60-Gy IG also showed the greatest number of xanthomatous cells (60-Gy IG: 86.11% and 15-Gy IG: 14.29%, p<0.0001) and the highest amount of hyaline amorphous tissue (60-Gy IG:58.33% and 15-Gy IG:0%, p=0.0001) and vascular proliferation (60-Gy IG:30.56% and 15-Gy IG:0%, p=0.0221). No statistically significant differences were found among groups concerning other tissue analyses. CONCLUSION: The high-dose irradiation of 60 Gy resulted in intense cell proliferation considered vascular radiolesion, unlike the 15-Gy dose, which was associated with an excellent inhibition of neointimal proliferation.

Animals↗

Long-term tissue tolerance of titanium-encapsulated cobalt-samarium implants.

The tissue reactions of titanium-coated cobalt-samarium magnets were investigated following their full-thickness implantation into the skulls of dogs and pigs (six of each species). The implants, together with the surrounding bone, were removed en bloc 1, 2, 3, 6, 9, and 12 months postoperatively. Following physical and radiological examinations, the excised samples were subjected to histologic investigation. The osseointegration process was observed to follow a normal course around the titanium capsule. The magnetic field did not give rise to any tissue changes that could be demonstrated by means of classical histologic methods.

Alloys↗

Samarium-153 and technetium-99m-labeled monoclonal antibodies in angiogenesis for tumor visualization and inhibition.

BACKGROUND: Angiogenesis is the development of new blood vessels from pre-existing ones. Vascular endothelial growth factor (VEGF) is one of the most important angiogenic activators. Our studies are focused on the detection of VEGF by use of radiolabeled anti-endothelial monoclonal antibodies, which have the ability to localize in newly-formed vasculature of a cancerous origin. MATERIALS AND METHODS: The anti-endothelial monoclonal antibody VG76e was labeled with Samarium-153 and Technetium-99m. Biodistribution of the radiolabeled species was assessed in normal female Swiss mice, while tumor uptake was also evaluated. RESULTS: VG76e was labeled with 99mTc and 153Sm, resulting in a single product with a labeling yield of over 95%. Biodistribution studies showed non-specific uptake in any organ, with elimination via the hepatobiliary system. Finally, satisfactory tumor uptake was observed for both radiolabeled derivatives. CONCLUSION: Monoclonal antibodies raised against epithelial growth factors or their receptors, when labeled with appropriate radionuclides, may be a useful tool for early tumor detection and eventually for therapy.

Animals↗

Radiation absorbed dose calculations for samarium-153-EDTMP localized in bone.

Calculations have been undertaken to estimate the likely radiation dose received by patients undergoing treatment with samarium-153-EDTMP. Previously known bone structure parameters have been employed to partition correctly the energy absorbed in the bone matrix between red bone marrow, yellow marrow, and various types of mineral bone. Both uniform surface and volume distribution of the radioactivity are considered. The key findings of the calculations can be stated in terms of the MIRD "S-factors" for red bone marrow and the endosteal layer of cells on bone surfaces. In particular, the S-factor for red bone marrow is either 0.0276 mGy/MBq.h or 0.0077 mGy/MBq.h for surface and volume distributed radioactivity, respectively. For the endosteal layer of thickness (10 microns) on bone surfaces, the corresponding values are 0.0723 mGy/MBq.h and 0.0213 mGy/MBq.h, respectively.

Beta Particles↗

Human pharmacokinetics of samarium-153 EDTMP in metastatic cancer.

Samarium-153 ethylenediaminetetramethylene phosphonic acid ([153Sm]EDTMP) has been proposed to palliate pain resulting from osteoblastic metastatic bone cancer. Encouraging results in dogs with primary malignant bone cancer provided the catalysis for human biodistribution studies in five patients with metastatic skeletal carcinoma. The objective was to assess the preferential localization of [153Sm]EDTMP in bony lesions and compare it to the 99mTc-labeled phosphonates. Blood clearance of [153Sm]EDTMP was rapid with minimal accumulation in nonosseous tissues. Both radiopharmaceuticals showed identical lesion uptake in 23 paired lesions (p greater than 0.05). This indicates that the two radiopharmaceuticals concentrate in metastatic skeletal lesions by the same mechanism and since [153Sm]EDTMP emits beta radiation it may be therapeutically useful in ameliorating metastatic bony cancer pain.

Aged↗

High specific activity [samarium-153] EDTA for imaging of experimental tumor models.

Enriched samarium oxide (98.2% 152Sm2O3) was irradiated in low neutron flux and high neutron flux reactors to produce 153Sm with specific activities of 14.3 GBq and 22.1 TBq mmol-1 Sm, respectively, at the time of use. Formulation of 153Sm as [153Sm]EDTA, with a 1:10 molar ratio of SM:EDTA, provided a stable radiotracer in vitro and in vivo. High specific activity [153Sm]EDTA showed superior uptake in cell culture (20.8 +/- 0.9% vs. 5.5 +/- 0.1% for 6 and 600 pmol Sm per 10(6) cells, respectively) and better tumor index values (51 vs. 37 at 10.9 nmol and 1.09 mumol Sm kg-1, respectively) in the BDF1 mouse/Lewis lung tumor model. High specific activity [153Sm]EDTA scintigrams of Copenhagen x Fisher rats bearing transplanted Dunning R3327 tumors clearly delineated the tumors within 6 hr, with moderate liver and bone uptake and low soft-tissue background. The injected radiotracer underwent rapid central compartment clearance and whole-body elimination. The absence of observed adverse histopathological toxicity combines with high image quality within 6 hr, to support the clinical tumor-imaging potential of this agent. Comparative studies with [67Ga]citrate at molar-equivalent doses indicated that high specific activity [153Sm]EDTA was a superior radiotracer in these in vitro and in vivo models.

Animals↗

Europium and samarium as labels in time-resolved immunofluorometric assay of follitropin.

This time-resolved immunofluorometric assay for human follitropin involves use of europium- or samarium-labeled monoclonal antibodies, with an average incorporation ratio of 3 mol of Eu3+ or Sm3+ per mole of antibody. These lanthanide ions are bound to the antibody molecules by means of the anhydride of diethylenetriaminepentaacetic acid. The solid-phase antibody is immobilized inside polystyrene tubes in which plasma samples were assayed in a one-step procedure. After incubation, the fluorescence intensity of Eu3+ or Sm3+ label is measured by time-resolved fluorometry, with a nitrogen laser as the pulsed excitation source. The sensitivity of the assay is largely better with Eu3+ than with Sm3+ because of the difference in their intrinsic luminescence properties. Results obtained with the proposed methods correlated well with those by an immunoradiometric method.

Adolescent↗

Radiation dose calculations in persons receiving injection of samarium-153 EDTMP.

Samarium-153 EDTMP has been proposed as a radionuclide therapeutic agent to treat malignant bone tissue disorders. Data obtained from laboratory rats has been used to calculate the radiation dose for humans following the administration of [153Sm]EDTMP. The data reveals that the highest doses are present in the skeleton and the urinary bladder wall (bladder dose varies with frequency of voiding). Skeletal activity was used to estimate the bone marrow dose from the [153Sm]EDTMP beta radiation. Although this estimate indicates high marrow irradiation it is only an approximation since the beta radiation from inhomogeneously deposited bone activity surrounding the marrow produces variable radiation dose distributions.

Animals↗