153Sm radiotherapeutic bone agents

Goeckeler, William; Troutner, D.E.; Volkert, WA; Edwards, B.; Simón, Jaime; Wilson, Daniela A.

doi:10.1016/0883-2897(86)90028-0

Cited by 41 publications

(28 citation statements)

References 7 publications

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“…Gemcitabine schedule was initially repetitive daily dosing with daily Â 2, day of rest, then daily Â 2 (patient 1; patient choice not to get dose 3 of 5), then daily Â 5 (patient 2). When this patient developed unexpected grade 4 mucositis, the schedule the single dose schedule 18 to 24 hours after was used (patients [3][4][5][6][7][8][9][10][11][12][13][14].…”

Section: Methodsmentioning

confidence: 99%

Gemcitabine Radiosensitization after High-Dose Samarium for Osteoblastic Osteosarcoma

Anderson

Wiseman

Erlandson

et al. 2005

Clinical Cancer Research

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Osteoblastic metastases and osteosarcoma can avidly concentrate bone-seeking radiopharmaceuticals. We sought to increase effectiveness of high-dose 153 Samarium ethylenediaminetetramethylenephosphonate ( 153 Sm-EDTMP, Quadramet) on osteosarcomas using a radiosensitizer, gemcitabine. Fourteen patients with osteoblastic lesions were treated with 30 mCi/kg 153 Sm-EDTMP. Gemcitabine was administered 1day after samarium infusion. Residual total body radioactivity was within the safe range of <3.6 mCi on day +14 (1.1 F 0.4 mCi; range, 0.67-1.8 mCi).All patients received autologous stem cell reinfusion 2 weeks after 153 Sm to correct expected grade 4 hematopoietic toxicity. Peripheral blood progenitor cells were infused in 11 patients; three patients had marrow infused. Blood count recovery was uneventful after peripheral blood progenitor cells in 11of 11patients. Toxicity from a single infusion of gemcitabine (1,500 mg/m 2 ) in combination with 153 Sm-EDTMP was minimal (pancytopenia). However, toxicity from a daily gemcitabine regimen (250 mg/m 2 /d Â 4-5 days) was excessive (grade 3 mucositis) in one of two patients. There were no reported episodes of hemorrhagic cystitis (hematuria) or nephrotoxicity. At the 6-to 8-week follow-up, there were six partial remissions, two mixed responses, and six patients with progressive disease. In the 12 patients followed >1year, there have been no durable responses. Thus, although high-dose 153 Sm-EDTMP + gemcitabine has moderate palliative activity (improved pain; radiologic responses) in this poor-risk population, additional measures of local and systemic control are required for durable control of relapsed osteosarcoma with osteoblastic lesions. The strategy of radioactive drug binding to a target followed by a radiosensitizer may provide synergy and improved response rate.

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Section: Methodsmentioning

confidence: 99%

Gemcitabine Radiosensitization after High-Dose Samarium for Osteoblastic Osteosarcoma

Anderson

Wiseman

Erlandson

et al. 2005

Clinical Cancer Research

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“…9 153 [Sm] also emits ␥-rays and is therefore amenable to noninvasive photon-based imaging studies to reveal the biodistribution of isotope in the body, facilitating complex dosimetry calculations. 9,10 Besides targeting delivery to sites of tumor growth, another approach to improve the therapeutic index of radiation is to use radiation modifiers that alter the cellular response to radiation. 11 The proteasome inhibitor PS-341 (pyrazylcarbonyl-Phe-Leuboronate, bortezomib, or Velcade; Millennium Pharmaceuticals, Cambridge, MA) has been approved for patients with relapsed or refractory multiple myeloma.…”

Section: Introductionmentioning

confidence: 99%

“…38 The isotope then decays with a half-life of 48.6 hours such that significant delivery of ionizing radiation to the bone marrow space continues for approximately 10 days. 9 Thus, PS-341 administered within 24 hours of the Sm-153-EDTMP would be expected to inhibit proteasome function during the critical period when the rate of ␤-emission in the bone marrow is maximal. However, because this is a complex relationship, further studies will be required to determine whether PS-341 administration at earlier or later times or for longer periods of time might give superior results.…”

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confidence: 99%

Synergistic activity of the proteasome inhibitor PS-341 with non-myeloablative 153-Sm-EDTMP skeletally targeted radiotherapy in an orthotopic model of multiple myeloma

Goel

Dispenzieri

Geyer

et al. 2006

Blood

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Multiple myeloma is a highly radiosensitive skeletal malignancy, but bone-seeking radionuclides have not yet found their place in disease management. We previously reported that the proteasome inhibitor PS-341 selectively sensitizes myeloma cells to the lethal effects of ionizing radiation. To extend these observations to an in vivo model, we combined PS-341 with the bone-seeking radionuclide 153-Sm-EDTMP. In vitro clonogenic assays demonstrated synergistic killing of myeloma cells exposed to both PS-341 and 153-Sm-EDTMP. Using the orthotopic, syngeneic 5TGM1 myeloma model, the median survivals of mice treated with saline, 2 doses of PS-341 (0.5 mg/kg), or a single nonmyeloablative dose of 153-Sm-EDTMP (22.5 MBq) were 21, 22, and 28 days, respectively. In contrast, mice treated with combination therapy comprising 2 doses of PS-341 (0.5 mg/kg), 1 day prior to and 1 day following 153-Sm-EDTMP (22.5 MBq) showed a significantly prolonged median survival of 49 days (P < .001). In addition to prolonged survival, this treatment combination yielded reduced clonogenicity of bone marrowresident 5TGM1 cells, reduced serum myeloma-associated paraprotein levels, and IntroductionMultiple myeloma is a neoplasm of antibody-secreting plasma cells that infiltrate the bone marrow and form osteolytic tumors. 1 It is an incurable malignancy causing more than 10 000 deaths each year in the United States. 2 Standard treatment is with corticosteroids, thalidomide, alkylating agents, and stem-cell transplantation, but median survival remains only 4 years. 1 Multiple myeloma is highly radiosensitive and is locally radiocurable. 3,4 Novel systemic radionuclide-based therapies may therefore provide a significant advance in clinical therapy of myeloma.Both samarium-153 ethylenediaminetetramethylene phosphonate (Sm-153-EDTMP) [5][6][7] and Holmium-166 phosphonate chelate, 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetra-methylene phosphonic acid 8 have been used as a basis for skeletal-targeted radiotherapy in multiple myeloma. 153-Sm-EDTMP emits ␤-particles with a range of 0.5 mm to 1.01 mm and has a half-life of 48.6 hours. It can therefore deliver effective doses of radiation to neoplastic plasma cells in bone marrow with limited toxicity to normal nonhematopoietic tissues. 9 153 [Sm] also emits ␥-rays and is therefore amenable to noninvasive photon-based imaging studies to reveal the biodistribution of isotope in the body, facilitating complex dosimetry calculations. 9,10 Besides targeting delivery to sites of tumor growth, another approach to improve the therapeutic index of radiation is to use radiation modifiers that alter the cellular response to radiation. 11 The proteasome inhibitor PS-341 (pyrazylcarbonyl-Phe-Leuboronate, bortezomib, or Velcade; Millennium Pharmaceuticals, Cambridge, MA) has been approved for patients with relapsed or refractory multiple myeloma. 12 This drug has pleiotropic antimyeloma effects leading to tumor-cell killing in the bone marrow microenvironment. We recently demonstrated that PS-341 synergistically e...

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“…153 Sm-lexidronam avidly targets bone, with skeletal uptake ranging between 55% and 75% (20). Emission of h-particles with a range of f3 mm allows targeting of effective doses of radiation while essentially sparing nonhematopoietic tissue (16,26). Although 153 Sm-lexidronam has been viewed as a palliative therapy for metastatic bone disease, emerging evidence suggests that this radiopharmaceutical also has antimyeloma activity.…”

Section: Discussionmentioning

confidence: 99%

A Phase I Study of Samarium Lexidronam/Bortezomib Combination Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma

Berenson

Yellin

Patel

et al. 2009

Clinical Cancer Research

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Sm-lexidronam/bortezomib regimen. Results: Twenty-four patients were enrolled. Median values for age, time since diagnosis, and number of prior treatments were 63 years, 29 months, and three regimens, respectively. The most common toxicities were hematologic; during the first cycle, median neutrophil and platelet nadirs were 1,000/mm 3 and 98,500/mm 3 , respectively, and observed generally 3 to 4 weeks post-treatment. The incidences of grade 4 neutropenia and thrombocytopenia were 12.5% and 8.3%, respectively, during treatment cycle 1. Dose-limiting toxicity, reached in cohort 6 as a result of hematologic toxicity, defined the maximum tolerated dose as 0.5 mCi/kg Sm-lexidronam appears to be a well-tolerated regimen, which showed clinical activity in this phase I trial for patients with relapsed or refractory multiple myeloma.

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153Sm radiotherapeutic bone agents

Cited by 41 publications

References 7 publications

Gemcitabine Radiosensitization after High-Dose Samarium for Osteoblastic Osteosarcoma

Gemcitabine Radiosensitization after High-Dose Samarium for Osteoblastic Osteosarcoma

Synergistic activity of the proteasome inhibitor PS-341 with non-myeloablative 153-Sm-EDTMP skeletally targeted radiotherapy in an orthotopic model of multiple myeloma

A Phase I Study of Samarium Lexidronam/Bortezomib Combination Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma

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