Radium-223 (²²³Ra, Ra-223) is an

isotope Isotopes are two or more types of atoms that have the same atomic number (number of protons in their nuclei) and position in the periodic table (and hence belong to the same chemical element), and that differ in nucleon numbers ( mass num ...

radium Radium is a chemical element with the symbol Ra and atomic number 88. It is the sixth element in group 2 of the periodic table, also known as the alkaline earth metals. Pure radium is silvery-white, but it readily reacts with nitrogen (rat ...

with an 11.4-day

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ...

. It was discovered in 1905 by T. Godlewski, a Polish chemist from

Kraków Kraków (), or Cracow, is the second-largest and one of the oldest cities in Poland. Situated on the Vistula, Vistula River in Lesser Poland Voivodeship, the city dates back to the seventh century. Kraków was the official capital of Poland un ...

, and was historically known as actinium X (AcX). Radium-223 dichloride is an alpha particle-emitting radiotherapy drug that mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover. The principal use of radium-223, as a

radiopharmaceutical Radiopharmaceuticals, or medicinal radiocompounds, are a group of pharmaceutical drugs containing radioactive isotopes. Radiopharmaceuticals can be used as diagnostic and therapeutic agents. Radiopharmaceuticals emit radiation themselves, which ...

to treat

metastatic Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

cancers in

bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...

, takes advantage of its chemical similarity to

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...

, and the short range of the

alpha radiation Alpha decay or α-decay is a type of radioactive decay in which an atomic nucleus emits an alpha particle (helium nucleus) and thereby transforms or 'decays' into a different atomic nucleus, with a mass number that is reduced by four and an at ...

it emits.

Origin and preparation

Although radium-223 is naturally formed in trace amounts by the decay of uranium-235, it is generally made artificially,Bruland O.S., Larsen R.H. (2003). Radium revisited. In: Bruland O.S., Flgstad T., editors. Targeted cancer therapies: An odyssey. University Library of Tromso, Ravnetrykk No. 29. , pp. 195–202

by exposing natural radium-226 to

neutron The neutron is a subatomic particle, symbol or , which has a neutral (not positive or negative) charge, and a mass slightly greater than that of a proton. Protons and neutrons constitute the atomic nucleus, nuclei of atoms. Since protons and ...

s to produce radium-227, which decays with a 42-minute half-life to

actinium-227 Actinium (89Ac) has no stable isotopes and no characteristic terrestrial isotopic composition, thus a standard atomic weight cannot be given. There are 33 known isotopes, from 204Ac to 236Ac, and 7 isomers. Three isotopes are found in nature, 225 ...

. Actinium-227 (half-life 21.8 years) in turn decays via

thorium-227 Thorium (90Th) has seven naturally occurring isotopes but none are stable. One isotope, 232Th, is ''relatively'' stable, with a half-life of 1.405×1010 years, considerably longer than the age of the Earth, and even slightly longer than the gene ...

(half-life 18.7 days) to radium-223. This decay path makes it convenient to prepare radium-223 by "milking" it from an actinium-227 containing generator or "cow", similar to the moly cows widely used to prepare the medically important isotope

technetium-99m Technetium-99m (99mTc) is a metastable nuclear isomer of technetium-99 (itself an isotope of technetium), symbolized as 99mTc, that is used in tens of millions of medical diagnostic procedures annually, making it the most commonly used medica ...

. ²²³Ra itself decays to ²¹⁹Rn (half-life 3.96 s), a short-lived gaseous

radon Radon is a chemical element with the symbol Rn and atomic number 86. It is a radioactive, colourless, odourless, tasteless noble gas. It occurs naturally in minute quantities as an intermediate step in the normal radioactive decay chains th ...

isotope, by emitting an

alpha particle Alpha particles, also called alpha rays or alpha radiation, consist of two protons and two neutrons bound together into a particle identical to a helium-4 nucleus. They are generally produced in the process of alpha decay, but may also be prod ...

of 5.979 MeV.

Medical use

The pharmaceutical product and medical use of radium-223 against skeletal metastases was invented by Roy H. Larsen, Gjermund Henriksen and Øyvind S. Bruland and has been developed by the former Norwegian company Algeta ASA, in a partnership with

Bayer Bayer AG (, commonly pronounced ; ) is a German multinational pharmaceutical and biotechnology company and one of the largest pharmaceutical companies in the world. Headquartered in Leverkusen, Bayer's areas of business include pharmaceutic ...

, under the trade name Xofigo (formerly Alpharadin), and is distributed as a solution containing radium-223 chloride (1100 kBq/ml), sodium chloride, and other ingredients for intravenous injection. Algeta ASA was later acquired by Bayer who is now the sole owner of Xofigo. The recommended regimen is six treatments of 55 kBq/kg (1.5 μCi/kg), repeated at 4-week intervals.

Mechanism of action

The use of radium-223 to treat metastatic bone cancer relies on the ability of

from radium-223 and its short-lived decay products to kill cancer cells. Radium is preferentially absorbed by bone by virtue of its chemical similarity to calcium, with most radium-223 that is not taken up by the bone being cleared, primarily via the gut, and excreted. Although radium-223 and its decay products also emit

beta Beta (, ; uppercase , lowercase , or cursive ; grc, βῆτα, bē̂ta or ell, βήτα, víta) is the second letter of the Greek alphabet. In the system of Greek numerals, it has a value of 2. In Modern Greek, it represents the voiced labiod ...

and

gamma radiation A gamma ray, also known as gamma radiation (symbol γ or \gamma), is a penetrating form of electromagnetic radiation arising from the radioactive decay of atomic nuclei. It consists of the shortest wavelength electromagnetic waves, typically s ...

, over 95% of the decay energy is in the form of alpha radiation. Alpha radiation has a very short range in tissues compared to beta or gamma radiation: around 2-10 cells. This reduces damage to surrounding healthy tissues, producing an even more localized effect than the beta-emitter strontium-89, also used to treat bone cancer. Taking account of its preferential uptake by bone and the alpha particles' short range, radium-223 is estimated to give targeted osteogenic cells a radiation dose at least eight times higher than other non-targeted tissues.FDA Access Data on Xofigo (Radium-223 dichloride)
/ref>

Clinical trials and FDA and EMA approval

The phase II study of radium-223 in

castration-resistant prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that surr ...

(CRPC) patients with

bone metastases Bone metastasis, or osseous metastatic disease, is a category of cancer metastases that results from primary tumor invasion to bone. Bone-originating primary tumors such as osteosarcoma, chondrosarcoma, and Ewing's sarcoma are rare; the most co ...

showed minimum

myelotoxicity Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (t ...

and good tolerance for the treatment. ²²³Ra successfully met the primary endpoint of overall survival in the phase III ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer patients) study for bone metastases resulting from CRPC in 922 patients. The ALSYMPCA study was stopped early after a pre-planned efficacy interim analysis, following a recommendation from an Independent Data Monitoring Committee, on the basis of achieving a statistically significant improvement in overall survival (two-sided p-value = 0.0022, HR = 0.699, the median overall survival was 14.0 months for ²²³Ra and 11.2 months for placebo).Full data report from the ALSYMPCA trial of radium-223 presented
/ref> Earlier phase II of the trial showed a median increased survival of 18.9 weeks (around 4.4 months). The lower figure of 2.8 months increased survival in interim phase III results is a probable result of stopping the trial; median survival time for patients still alive could not be calculated. A 2014 update indicates a median increased survival of 3.6 months. In May 2013, ²²³Ra received marketing approval from the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) as a treatment for CRPC with bone metastases in patients with symptomatic bone metastases and without known visceral disease. ²²³Ra received priority review as a treatment for an unmet medical need, based on its ability to extend overall survival as shown its Phase III trial. This study also led to approval in the

European Union The European Union (EU) is a supranational union, supranational political union, political and economic union of Member state of the European Union, member states that are located primarily in Europe, Europe. The union has a total area of ...

on 19 September 2013 The

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Eur ...

subsequently recommended restricting its use to patients who have had two previous treatments for metastatic prostate cancer or who cannot receive other treatments. The medicine must also not be used with

abiraterone acetate Abiraterone acetate, sold under the brand name Zytiga among others, is a medication used to treat prostate cancer. Specifically it is used together with a corticosteroid for metastasis, metastatic Prostate cancer#Castration-resistant cancer, ca ...

, prednisone or prednisolone and its use is not recommended in patients with a low number of osteoblastic bone metastases. ²²³Ra also showed promising preliminary results in a phase IIa trial enrolling 23 women with bone metastases resulting from

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

that no longer responds to endocrine therapy. ²²³Ra treatment reduced the levels of bone

alkaline phosphatase The enzyme alkaline phosphatase (EC 3.1.3.1, alkaline phosphomonoesterase; phosphomonoesterase; glycerophosphatase; alkaline phosphohydrolase; alkaline phenyl phosphatase; orthophosphoric-monoester phosphohydrolase (alkaline optimum), systematic ...

(bALP) and urine N-telopeptide (uNTX), key markers of bone turnover associated with bone metastases in breast cancer, diminished bone pain slightly though consistently, and was well tolerated. Another single-arm, open-label Phase II trial reported possible efficacy of ²²³Ra combined with endocrine therapy in hormone-receptor-positive, bone-dominant breast cancer metastasis.

Side effects

The most common side effects reported during clinical trials in men receiving ²²³Ra were nausea, diarrhea, vomiting and swelling of the leg, ankle or foot. The most common abnormalities detected during blood testing were

anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...

lymphocytopenia Lymphocytopenia is the condition of having an abnormally low level of lymphocytes in the blood. Lymphocytes are a white blood cell with important functions in the immune system. It is also called lymphopenia. The opposite is lymphocytosis, which r ...

leukopenia Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of ...

thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients a ...

and

neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteri ...

Other radium-223-based compounds

Although radium does not easily form stable molecular complexes, data has been presented on methods to increase and customize its specificity for particular cancers by linking it to

monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ...

, by enclosing the ²²³Ra in

liposome A liposome is a small artificial Vesicle (biology and chemistry), vesicle, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, lipo ...

s bearing the antibodies on their surface.

References

External links

* * {{Portal bar , Medicine Bayer brands Drugs acting on the musculoskeletal system Experimental cancer drugs Isotopes of radium Radiation therapy Radiopharmaceuticals