Saturday, April 12, 2008

New Radioprotective Drug Actually Works

This week in Science:
In summary, CBLB502 reduces radiation toxicity without diminishing the therapeutic antitumor effect of radiation and without promoting radiation-induced carcinogenicity. These properties of a TLR5 agonist acting as an NF-{kappa}B–inducing agent provide further support for our concept of pharmacological imitation of tumor-specific antiapoptotic mechanisms as an approach to radioprotection. This approach was first validated by our demonstration that a chemical inhibitor of the proapoptotic p53 pathway safeguarded mice from lethal acute radiation syndrome. However, we subsequently found that wild-type p53 plays an unexpected role as a survival factor in GI cells exposed to high doses of {gamma}-irradiation, limiting the usefulness of p53 inhibitors to protection against HP, but not GI, acute radiation syndrome. This problem has been resolved by our identification of CBLB502 as a TLR5 agonist that can protect against both major acute radiation syndromes. Our results suggest that TLR5 agonists may be valuable as both adjuvants for cancer radiotherapy and protectants or mitigators for radiation emergencies.
This is pretty spectacular. Animal studies showed a marked increase in survival rates at very high radiation doses- 13 Gy for the mice and 6.5 Gy for the Rhesus monkeys. The most obvious use of the drug is to to protect cancer patients from the effects of radiotherapy- amazingly, it doesn't appear to impact the radiosensitivity of tumors- but it also has potential emergency management applications.

Effective radioprotective drugs were one of the holy grails of civil defense researchers back in the 1950s. The hope was that these drugs could make fallout protection more practical by reducing shelter requirements. Optimists dreamed of drugs that would make fallout shelters unnecessary. High hopes were soon dashed, however. The few radioprotective agents discovered were unable to provide protection against acute radiation poisoning- the circumstance that interested civil defense. Soviet civil defense retained more interest in the idea, and issued an "individual first aid kit" containing drugs for use by individuals in a major war. It contained antibiotics, anti-vomiting medication, nerve gas antidote pills (!), several "anti-radiation drugs" (I have yet to identify exactly what), and a syringe full of morphine.

If CBLB502 can be made into a practical emergency management tool, it could make mass radiation protection much more practical. In particular, it could reduce the immediate needs for sheltering and evacuation following a radiological dispersal event enormously. It's not an absolute panacea- due to the way the drug works it is probably unsafe for children and pregnant women. But it could turn the unsolvable nightmare of protecting the people of a densely populated area from radiation poisoning into a manageable scenario. That's pretty impressive.


DV8 2XL said...

Can this medication be given post exposure or must it be given before? How long before or how long after can it be used to be effective? What is it's shelf-life? How is it administered? How long does the protection last?

While none of these questions would effect it's utility in radiotherapy, they would have implications if it were being contemplated as a CD measure.

Sovietologist said...

The study authors have talked about using it in emergency management, but nothing in the study answers the practical questions, like shelf-life, the length of the protective effect, and so on. The studies so far were not done in a way that can answer these questions. It would apparently be administered as an intramuscular injection. Unless it proves to be unusable in humans for some reason, it should have at least some utility for emergency management; but I admit that it could be a lot less than I hope for.

DV8 2XL said...

I'm not trying to minimize the importance of this discovery. But it seems to me that if it can permit higher fluxes in radiotherapy thus reducing the number of treatments necessary, that would be good news in and of itself.

Any use in emergency management would be gravy.

Stephen said...

It sounds like it can make an impressive difference in acute effects on cells and tissue. Is there any data (or for that matter theory) which would indicate it might have any effects in terms of reducing chronic and after-event issues, especially infertility or cancer?


Oh yeah and I should probably add this so dv82xl doesn't get all angry: Yes, I am aware that a lot of the talk about cancer from radiation from a given event is overblown and that the only decernable increase from Chernobyl was increased thyroid cancer from I-131 and that LNT is not supported by evidence.

However, it's still pretty well established that individuals who have been subjected to unusually large doses of radiation (Not large as in living in Colorado and getting some dental x-rays. Large as in working with a shoe-fitting x-ray machine for ten years) are associated with increased risk of cancer and other genetic issues.

Oh yeah: Also this might be worth keeping a bit on hand on any manned moon or deep space missions in case there happens to be a sunstorm or something.

Sovietologist said...

Oh, dear. I just realized that the link I posted to the fulltext doesn't actually work for anyone else.

Here is an open-access article about it:

I'm not sure if the drug will do much for anything other than acute radiation sickness. Delayed effects like cancer or radiation-induced life shortening seen at high radiation doses may or may not be affected by the drug; the available studies just don't examine them. Given the preliminary results, my guess would be that it wouldn't do that much for cancer, but would be useful for some other radiation-induced effects due to decreased tissue damage. It'll be interesting to see what the impact on these factors is.

DV8 2XL said...

Oh, I'm well aware that excessive radiation can cause cancer, but you are right I do get upset when the risk is overstated at low-level exposures. (as an aside: the department store in the village I live in had one of those shoe-fitting x-ray machines. We used to go in and play with it when we were kids)

It would seem the mechanism of protection is to inhibit cell suicide, and that a shot is only good for a few hours. Looks like it might be effective if given shortly after exposure as well as shortly before.

I have to agree that it doesn't look like it will protect against chromosome damage.

Stephen said...

Actually when I was reading it what occured to me is that it's not impossible that it could worsen the possibility of cancer later on from chromosomal damage.

If the cells which sustained the most chromosomal damage would orginarily also have the highest probability being killed off, then this could possibly preserve some of the cells with damaged genetic material and allow them to pass it on.

The shoe X-ray machine I mention because it had almost no shielding and those who operated them for customers often actually could receive several chest x-rays worth of cumulative exposure on just an average day. When that is multiplied by years at a full time job the exposure could be enormous and is believed to have killed.

Ashutosh said...

I am wondering; if the drug actually prevents apoptosis, it probably would be catastrophic to administer it to pregnant women because in growing foetuses, apopotosis is actually a helpful process that carves out body shape.

DV8 2XL said...

High radiation doses are catastrophic to pregnant women. I would think that this would be a case of trying to save one of the two victims.

I would not want to be the attending physician on that one.

Sovietologist said...

That was the first thing my girlfriend said about it too. This stuff would likely cause horrific birth defects. But then again, how likely is a developing fetus to survive a 700 rem exposure? And if the mother dies of acute radiation poisoning, isn't that a death sentence for the fetus too? Under the circumstances it's meant to be used, it might be the lesser of two evils. Only more animal testing will tell.