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Spying on possible polonium therapies

By Mike Nagle , 05-Feb-2007

In the light of the death of former Russian security agent, Alexander Litvinenko, pharma companies developing anti-radiation drugs are increasingly under the spotlight.

A recent article by Steve LeVine in the Wall Street Journal highlighted three drugs that could possibly be used to protect against the effects of radiation poisoning.

The US government had already established Project BioShield in 2004 and set aside $5.6bn to improve medical protection against a biological, chemical, radiological or nuclear attack. However, since Litvinenko was poisoned, companies developing anti-radiation drugs have received a lot more attention.

Polonium is around 5 million times more toxic than hydrogen cyanide (by weight). It is estimated that one gram of polonium 210 (Po-210) could, in theory, lethally poison 50 million. However, the actual toxicity is lower because radiation exposure is spread out over several weeks.

There are two possible approaches when designing a drug against radiation poisoning. The first strategy is to protect the body from the effects of the contaminant. Exposure to radioactive substances can cause bone marrow damage. The immune and blood stem cells are also depleted. In the long-term, effects on cell division can also cause cancer.

LeVine identified two drugs that work on this basis. The first, Protectan (CBLB502), is being developed by Cleveland Biolabs. A derivative of the protein flagellin, it activates NFkB proteins that, in turn, prevent cells from committing suicide, thus giving the immune system more time to respond to the radiation. However, as yet, the drug is only being tested against gamma radiation, rather than the alpha radiation that emanates from polonium.

The second drug is Neumune (HE2100, androstenediol), which is co-developed by Hollis-Eden Pharmaceuticals with the Armed Forces Radiobiology Research Institute (AFRRI) - an agency within the US Department of Defense. The steroid is currently in Phase I/II trials and could ameliorate the effects of bone marrow damage by causing more white blood cells and platelets to be formed.

Also, Drugresearcher.com recently reported that the Minnesota-based pharmaceutical company Humanetics has been cleared to start Phase I clinical trials of Bio 300, a tyrosine kinase inhibitor that could prevent and protect against acute radiation syndrome (ARS). There are no drugs currently approved by the US Food and Drug Administration (FDA) for the prevention and treatment of the bone barrow damage seen in ARS.

Bio 300 is thought to stimulate cell growth and differentiation and prevent radiation-induced cell death, which is triggered by tyrosine kinase. The drug also has potentially significant antioxidant effects that could prevent the cell damage caused by oxidative free radicals during and after exposure to ionising radiation.

In preclinical studies in mice subjected to radiation, survival rates increased from six to 81 per cent with Bio 300 compared with placebo.

RxBio develops RX100, a small molecule drug that can be given orally and promotes cell survival while inhibiting cell suicide. It has been shown, in animal studies, to protect against lethal, whole-body radiation even when administered up to six hours after exposure.

Canadian company Cangene develop Leucotropin (GM-CSF) for the treatment of ARS. GM-CSF is a protein that stimulates the production of infection-fighting white blood cells in the body depleted by radiation.

The second therapeutic approach is to reduce absorption and speed up the excretion of contaminants. It has been suggested that so called chelating agents can do this by binding to and moving heavy metals to the kidney. From here they can do less damage and are eventually excreted from the body.

A study by scientists in Czechoslovakia tested the ability of nine different chelating agents to reduce polonium-210 in rats. The nine compounds included sulphur-based dithiols and dithiocarbamates. The researchers found that the treatments merely caused a redistribution of Po-210 in the body.

However, four compounds were identified as being possibly useful in reducing polonium in the body. These were Dimaval (DMPS), Chemet (succimer or DMSA), phthalamidic acid (DMPA) and dimercaprol, which is also known as British Anti-Lewisite (BAL) - it was developed in Oxford during World War II as a treatment against the now obsolete chemical warfare agent, Lewisite.

The greatest reduction of polonium in the blood came from using BAL and DMPA. However, BAL increased the amount of Po-210 in the brain while DMPA and DMPS increased levels in the kidneys.

The whole-body burden of polonium was significantly reduced when BAL was used in conjunction with other agents. Repeated, prolonged treatment with BAL led to removal of polonium from the bone, spleen and kidneys.

Levels of polonium throughout the body could not be reduced lower than 85% of the untreated controls by any of the chelators tested.

Indeed, the third compound mentioned by LeVine is Chemet from Ovation Pharmaceuticals. It has been approved by the FDA to treat lead poisoning in children. Along with DMPS, the drug has also been used to remove mercury from the body but may also prove useful in cases of polonium exposure.

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