[ RadSafe ] RE: Comment to "hormesis"

Dan W McCarn hotgreenchile at gmail.com
Sun Dec 16 02:31:52 CST 2007

Comment on Hormesis, superficiality, and risk:

There was a very interesting letter in the magazine "Nature" last October
(on line) and December 2006 (in print) on the causative issues of why some
types of glioma stem cells (glioblastoma, a form of brain cancer) are quite
radiation resistant compared to normal brain cells.  In the joint work of
Duke University and at M.D. Anderson, a glycoprotein was identified that
seemed to trigger radiation resistance. Their study (so far unpublished)
involved development of a vaccine that "blocked" this glycoprotein
preventing the glioma stem cells from developing radiation resistance.  A
patient trial is underway.  I am familiar with the trial at M.D. Anderson
because my roommate at Shell Oil was part of that study.  Unfortunately,
"Uncle Bernie" recently succumbed to the disease at the age of 86.

Apparently there are some quite specific mechanisms that are activated by
radiation allowing preferential repair of DNA.  In the words of the
researchers, this glycoprotein causes "preferential activation of the DNA
damage checkpoint response and an increase in DNA repair capacity".  They
state further that "In both cell culture and the brains of immunocompromised
mice, CD133-expressing glioma cells survive ionizing radiation in increased
proportions relative to most tumour cells, which lack CD133."


I find it to be quite unfortunate that while cancer researchers seem to
embrace causative mechanisms for radiation resistance, there still appears
to be quite mixed and jaded response to the rather blunted word "Hormesis";
perhaps the word "radioresistance" might be more palliative.

While I am but a "mere" geologist, this article helped focus my
understanding that very specific cellular mechanisms account for what others
might call "Hormesis"; which appears to be too vague a term for many to be
able to "digest".  In this way, I agree with Bjorn.

But to dismiss radioresistance out of hand, especially with specific models
being actively researched, seems perfectly absurd.

The abstract follows.

Dan ii

Dan W. McCarn, Geologist; 3118 Pebble Lake Drive; Sugar Land, TX 77479; USA
Cell: +1-505-710-3600; Home: +1-281-903-7667; Fax: +1-713-241-1012; Office:
HotGreenChile at gmail.com, Dan.McCarn at shell.com 

Nature 444, 756-760 (7 December 2006) | doi:10.1038/nature05236; Received 1
June 2006; Accepted 7 September 2006; Published online 18 October 2006

Glioma stem cells promote radioresistance by preferential activation of the
DNA damage response
Shideng Bao1,2, Qiulian Wu1,2, Roger E. McLendon2,3, Yueling Hao1,2, Qing
Shi1,2, Anita B. Hjelmeland1,2, Mark W. Dewhirst4, Darell D. Bigner2,3 and
Jeremy N. Rich1,2,5,6

Department of Surgery,
Preston Robert Tisch Brain Tumor Center,
Department of Pathology,
Department of Radiation Oncology,
Department of Medicine, and,
Department of Neurobiology, Duke University Medical Center, Durham, North
Carolina 27710, USA 
Correspondence to: Jeremy N. Rich1,2,5,6 Correspondence and requests for
materials should be addressed to J.N.R. (Email: rich0001 at mc.duke.edu).

Top of pageIonizing radiation represents the most effective therapy for
glioblastoma (World Health Organization grade IV glioma), one of the most
lethal human malignancies1, but radiotherapy remains only palliative2
because of radioresistance. The mechanisms underlying tumour radioresistance
have remained elusive. Here we show that cancer stem cells contribute to
glioma radioresistance through preferential activation of the DNA damage
checkpoint response and an increase in DNA repair capacity. The fraction of
tumour cells expressing CD133 (Prominin-1), a marker for both neural stem
cells and brain cancer stem cells3, 4, 5, 6, is enriched after radiation in
gliomas. In both cell culture and the brains of immunocompromised mice,
CD133-expressing glioma cells survive ionizing radiation in increased
proportions relative to most tumour cells, which lack CD133.
CD133-expressing tumour cells isolated from both human glioma xenografts and
primary patient glioblastoma specimens preferentially activate the DNA
damage checkpoint in response to radiation, and repair radiation-induced DNA
damage more effectively than CD133-negative tumour cells. In addition, the
radioresistance of CD133-positive glioma stem cells can be reversed with a
specific inhibitor of the Chk1 and Chk2 checkpoint kinases. Our results
suggest that CD133-positive tumour cells represent the cellular population
that confers glioma radioresistance and could be the source of tumour
recurrence after radiation. Targeting DNA damage checkpoint response in
cancer stem cells may overcome this radioresistance and provide a
therapeutic model for malignant brain cancers.

-----Original Message-----
From: radsafe-bounces at radlab.nl [mailto:radsafe-bounces at radlab.nl] On Behalf
Of Bjorn Cedervall
Sent: Saturday, December 15, 2007 10:31 PM
To: radsafe at radlab.nl
Subject: [ RadSafe ] RE: Comment to "hormesis"

Hormesis is a mix of many different phenomena. Therefore the concept causes
confusion unless each phenomenon is analyzed and interpreted separately:
adaptive response (priming, by-stander effects, genomic instability,
induction of radical scavengers & repair enzymes etc), stress mechanisms,
evolution of evolvability (including tuning of mutation rates), natural
(statistical) selection against those least fit, the individual vs. the gene
pool of the same species etc, interpretation of what is good/bad for an
individual vs. the corresponding population and so on. This boils down to:
The concept "hormesis" gives no help in the understanding of radiation
biology and all its subtopics can be discussed under headings such as those
just mentioned (part of evolutionary biology). It was perhaps OK to lump all
the different biological phenomena ("radiation is beneficial"...) 30 to 70
years ago but today when we know so much more about radiobiological
mechanisms we do not have any use for that word.
Hormesis is often referred to in a superficial way like "radiation is good
for you" which basically only can hurt the nuclear industry because the
business may be perceived as being driven by narrow minded cynical risk
takers which, as most of us know, is far from the dominating attitude.
My personal ideas only,
Bjorn Cedervall   bcradsafers at hotmail.com
PhD, Associate Professor (Medical Radiation Biology, Karolinska Institutet)
MSc (Theoretical Chemistry: Nuclear chemistry & biochemistry, Royal
Institute of Technology)
Radiology specialist (Nuclear power safety) - have now been in this field
for 24 years.

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