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      Targeted α Therapies for the Treatment of Bone Metastases

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          Abstract

          The skeleton is the target tissue for many types of tumors, and, recently, the survival of patients with prostate cancer metastasis has been increased using α-emitting drugs known as targeted α therapies. The use of α-radiopharmaceuticals in medicine was hypothesized at the beginning of the nineteenth century after the observation that α-radionuclides were associated with high cell-killing energy and low tissue penetration in healthy tissues. In the prostate cancer (PC) scenario, current research suggests that this class of radiopharmaceuticals has limited toxicity, and that the mechanism of action does not overlap with pre-existing drugs, allowing us to extend therapeutic armaments and address medical oncology towards personalized and precision medicine. Ongoing studies may extend these benefits also to bone metastases deriving from other neoplasms. The aim of this review is to summarize the current research on targeted α therapies and try to identify the right patient to be treated in the right time in order to integrate in these medications in the every-day clinical practice.

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          Most cited references42

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          Lutetium 177 PSMA radionuclide therapy for men with prostate cancer: a review of the current literature and discussion of practical aspects of therapy

          Abstract Prostate‐specific membrane antigen (PSMA) is a receptor on the surface of prostate cancer cells that is revolutionising the way we image and treat men with prostate cancer. New small molecule peptides with high‐binding affinity for the PSMA receptor have allowed high quality, highly specific PET imaging, in addition to the development of targeted radionuclide therapy for men with prostate cancer. This targeted therapy for prostate cancer has, to date, predominately used Lutetium 177 (Lu) labelled PSMA peptides. Early clinical studies evaluating the safety and efficacy of Lu PSMA therapy have demonstrated promising results with a significant proportion of men with metastatic prostate cancer, who have already failed other therapies, responding clinically to Lu PSMA. This review discusses the practical issues of administering Lu PSMA, and gives an overview of the findings from currently published trials in regards to treatment response rates, expected toxicities and safety.
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            Significant antitumor effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental skeletal metastases model.

            The therapeutic efficacy of the alpha-particle-emitting radionuclide (223)Ra (t(1/2) = 11.4 days) in the treatment against experimental skeletal metastases in rats was addressed. Biodistribution studies, involving measurement of (223)Ra in bone marrow samples, were performed in rats after i.v. injection. To study the therapeutic effect of (223)Ra, an experimental skeletal metastases model in nude rats was used. Animals that had received 10(6) MT-1 human breast cancer cells were treated with (223)Ra doses in the range of 6-30 kBq after 7 days. The biodistribution experiment demonstrated that (223)Ra was selectively concentrated in bone as compared with soft tissues. The femur content of (223)Ra was 800 +/- 56% of injected dose per gram tissue times gram body weight (b.w.; mean +/- SD) 1 day after the injection and 413 +/- 23% of injected dose per gram tissue times gram b.w. at 14 days. The femur:kidney ratio increased from (5.9 +/- 2.0).10(2) at 1 day to (7.2 +/- 3.0).10(2) at 14 days, whereas the femur:liver ratio increased from (6.2 +/- 0.2).10(2) to (9.1 +/- 6.6).10(2). Femur:spleen ratio increased from (8.1 +/- 0.3).10(2) at 1 day to (6.4 2.2).10(3) at 14 days. The femoral bone:marrow ratio was 6.5 +/- 2.1 after day 1 and larger than 15 at day 14. All of the tumor-bearing control animals had to be sacrificed because of tumor-induced paralysis 20-30 days after injection with tumor cells, whereas the rats treated with > or =10 kBq of (223)Ra had a significantly increased symptom-free survival (P < 0.05). Also 36% (5 of 14) of rats treated with 11 kBq and 40% (2 of 5) of rats treated with 10 kBq were alive beyond the 67-day follow-up period. No signs of bone marrow toxicity or b.w. loss were observed in the groups of treated animals. The significant antitumor effect of (223)Ra at doses that are tolerated by the bone marrow is most likely linked to the intense and highly localized radiation dose from alpha-particles at the bone surfaces. The results of this study indicate that (223)Ra should be additionally studied as a potential bone marrow-sparing treatment of cancers involving the skeleton.
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              Radium-226 and radon-222: concentration in atlantic and pacific oceans.

              Measurements of radon-222 in seawater suggest the following. The radium-226 content of surface water in both the Atlantic and Pacific oceans is uniformly close to about 4 x 10(-14) gram per liter. The deep Pacific has a concentration of radium-226 that is four times higher and the deep Atlantic a concentration twice as high as that of the surface. These distribution profiles can be explained by the same particle-settling rate for radium-226 from surface to depth for the two oceans and by a threefold longer residence time of water in the deep Pacific than in the deep Atlantic. The vertical distribution of the deficiency of radon-222 in the surface water of the northwest Pacific Ocean suggests a coefficient of vertical eddy diffusion as high as 120 square centimeters per second and a gas-exchange rate for carbon dioxide in surface water between 14 and 60 moles per square meter per year. Vertical profiles of the excess of radon-222 in near-bottom water of the South Atlantic give coefficients of vertical eddy diffusion ranging from 1.5 to more than 50 square centimeters per second.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                28 December 2017
                January 2018
                : 19
                : 1
                : 74
                Affiliations
                [1 ]UOC Oncologia, ULSS 1 Dolomiti, Belluno Medical Hospital “San Martino”, Viale Europa 22, 32100 Belluno, Italy
                [2 ]Bayer Spa, Viale Certosa 210, 201156 Milan, Italy; roberto.barsanti@ 123456bayer.com
                Author notes
                [* ]Correspondence: fable.zustovich@ 123456aulss1.veneto.it ; Tel.: +39-0437-516512
                Article
                ijms-19-00074
                10.3390/ijms19010074
                5796024
                29283383
                a929dded-c282-4d32-8180-60e110b3a947
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 November 2017
                : 06 December 2017
                Categories
                Review

                Molecular biology
                radium 223,bone metastases,breast cancer,prostate cancer,tumour cell dormancy
                Molecular biology
                radium 223, bone metastases, breast cancer, prostate cancer, tumour cell dormancy

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