Antiradiation Drugs a Reality? Options

[nprev]

http://medheadlines.com/2008/04/11/new-dru...diation-damage/

Interesting possible applications for a manned Mars flight, to say nothing of the possibilities for eventual human exploration of the Jovian moons...worth watching for future developments.

[Juramike]

http://medheadlines.com/2008/04/11/new-dru...diation-damage/

Interesting possible applications for a manned Mars flight, to say nothing of the possibilities for eventual human exploration of the Jovian moons...worth watching for future developments.

I attended a presentation regarding this compound at last year's AACR meeting.

When normal cells are damaged, normal cells try to take themselves out of the game by activating a suicide pathway. This is called apoptosis or programmed cell death. Radiation damage can cause a cell to detect genetic damage, and initiate the suicide signal.

NF-kB is a nuclear factor that can act as an "override" signal. The nuclear factor NF-kB binds to promoter regions of certain key genes in the DNA that send a survival signal to the cell, telling the cell "don't die."

It is thought that the wrong overactivation of NF-kB may be responsible for some cancers. The mutant cancer cell wants to die, but the override signal due to NF-kB keeps it alive. NF-kB is a rich target in cancer research. It is thought that by blocking expresssion of NF-kB, you can allow bad cells to commit suicide normally. There are many drugs in the pipeline that are targeting control of NF-kB.


The research group was trying to find ways to promote NF-kB. This would help the bad effects due to radiation treatment for cancer. The rapidly dividing cancer cells would get messed up by the radiation, but the normal cells would be protected by increasing up the NF-kB.

They started looking for compounds excreted by microorganisms that coexist in mammalian tissues (icky!). They thought that some of these critters might be able to stay in their host tissues by blocking TLR5 (toll-like receptor) that then revs up NF-kB. There are over a 1000 microorganisms that coexist in our tissues (double yuk!).

They found a protein excreted by the flagella of E. coli and salmonella. Amazingly enough, it turned out salmonella flagella are radioprotective. CBLB502 is a 329 amino acid lipoprotein.

From my scrawly notes taken during the presentation:
"At high radiation doses CBLB502, must be given with 2 h before radiation treatment." (I think it's via intramuscular injection)

"At low doses (8.5 Gy - which would only give 10% survival of non-treated mice), it can be injected after radiation treatment. This worked in primates".

[Now at this point, most of the audience (made up of cancer researchers) was thinking: "But wait, wouldn't the cancer patient know he was going to receive radiation therapy in well in advance of the treatment? Why would they worry about something for unscheduled radiation therapy unless they were thinking... of other applications....like...like...oh my!]

In the talk they also mentioned CBLB612, which is a lipoprotein and acts via TLR2.


While this might protect against relatively short-term exposure, the compound is only preventing the regular apoptotic (cell-suicide) pathway. It is NOT preventing initial DNA damage due to radiation. (There are some cellular DNA-repair mechanisms).

It would be interesting to measure the effects of treatment of this compound over long periods of lower levels of radiation. (And the injectable form would not be optimal). I'd be willing to bet this is being done.

-Mike

[ddeerrff]

Sounds to me like it would promote mutations. Cells with damaged DNA prevented from dying....

[Juramike]

Sounds to me like it would promote mutations. Cells with damaged DNA prevented from dying....

That is the "hotwire" theory of cancer.

Cancer cells are mutated cells that don't die normally AND lose the normal checks and balances that prevent proliferation out of control.

-Mike

[tty]

That is the "hotwire" theory of cancer.

True, and it seems likely that people treated with the drug would subsequently run a higher risk for cancer, since the non-suiciding cells may have damage that make them carcinogenic. However given the choice of dying by radiation sickness next week or by cancer in ten years I certainly know which alternative I would choose.

tty

[nprev]

If it pans out, one immediate application I can see is post-solar flare or strong gamma ray burst prophylaxis for a crew enroute between planets. DNA damage is a given anyhow after such events; makes sense to minimize at least one risk.

It's not enough to permit anyone to walk on Io someday, though. That's gonna take something like a radiation-blocking 'force field', probably combined with some sort of drug therapy just to survive the experience itself. I wouldn't sell the unfortunate person(s) a life insurance policy afterwards.

[Juramike]

It's not enough to permit anyone to walk on Io someday, though. That's gonna take something like a radiation-blocking 'force field', probably combined with some sort of drug therapy just to survive the experience itself.

Take the right drugs, and you can experience walking on Io without leaving the couch.