From: Subject: M. D. Anderson Cancer Center - News Release - Targeted Virus Compels Cancer Cells to Eat Themselves Date: Thu, 4 May 2006 14:15:40 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C66F85.3941E0B0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.2869 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C66F85.3941E0B0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.mdanderson.org/departments/newsroom/print.cfm?displayPrint=1&id=2BFBE8C5-BA5B-421D-96E235C4CF443D07&method=displayFull&pn=00c8a30f-c468-11d4-80fb00508b603a14&PrintPage=1 M. D. Anderson Cancer Center - News Release - = Targeted Virus Compels Cancer Cells to Eat Themselves
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Targeted Virus = Compels Cancer=20 Cells to Eat Themselves
M. = D. Anderson=20 News Release 05/02/06

An engineered virus tracks down and = infects the most=20 common and deadly form of brain cancer and then kills tumor = cells by=20 forcing them to devour themselves, researchers at The = University of=20 Texas M. D. Anderson Cancer Center report this = week in the=20 Journal of the National Cancer Institute.

The modified adenovirus homed in on = malignant glioma=20 cells in mice and induced enough self-cannibalization among = the=20 cancer cells - a process called autophagy - to reduce tumor = size and=20 extend survival, says senior author Seiji=20 Kondo, M.D., Ph.D., associate professor in the = Department=20 of Neurosurgery at M. D. Anderson.

"This virus uses telomerase, an enzyme = found in 80=20 percent of brain tumors, as a target," Kondo says. "Once the = virus=20 enters the cell, it needs telomerase to replicate. Normal = brain=20 tissue does not have telomerase, so this virus replicates = only in=20 cancer cells."

Other cancers are telomerase-positive, and = the=20 researchers showed in lab experiments that the virus kills = human=20 prostate and human cervical cancer cells while sparing = normal=20 tissue. 
 
In addition to demonstrating the = therapeutic potential of the virus, called hTERT-Ad, Kondo = says the=20 international research team also clarified the mechanism by = which=20 such conditionally replicating adenoviruses (CRAs) infect = and kill=20 cancer cells. 

Autophagy is a protective process that = cells employ=20 to consume part of themselves when nutrients are scarce or = to=20 destroy some of their organelles to recycle their = components. A=20 double membrane forms around the material to be consumed, = then=20 everything inside is digested.

Kondo and colleagues showed that hTERT-Ad = (short for=20 human telomerase reverse transcriptase promoter regulated=20 adenovirus) infected the glioma cells and induced autophagy = by=20 inactivating a molecular pathway - the mammalian target of = rapamycin=20 (mTOR) pathway - that is known to prevent cellular=20 self-cannibalization. 

The result was a huge difference in tumor = volume=20 among mice with subcutaneous malignant glioma that got = hTERT-Ad and=20 those that received a different, non-replicating virus. = Average=20 tumor size in the hTERT-Ad group was 39 cubic millimeters, = while=20 those receiving the other virus had an average tumor volume = of 200=20 cubic millimeters. 

Among mice with malignant gliomas in the = brain,=20 those treated with three injections of hTERT-Ad on average = lived 53=20 days. Those receiving the control adenoviruses lived on = average 29=20 days. Two of the hTERT-Ad mice survived 60 days and had no=20 detectable brain tumors.

Analyses of  dead cancer cells showed = telltale=20 signs of autophagy: bits of virus in the cell nucleus and = autophagic=20 vacuoles - cavities with residual digested material. =

The cells showed no sign of having been = killed by=20 apoptosis - a much better known process of programmed cell = death. A=20 normal biological defense mechanism that systematically = kills=20 defective cells, apoptosis is suppressed or dysfunctional in = cancer=20 cells. Many cancer therapies focus on restoring or enhancing = apoptosis to combat the disease.

"We believe that autophagy, but not = apoptosis,=20 mediates the principal anti-tumor effect of conditionally=20 replicating adenoviruses," Kondo says. 

Cells killed by apoptosis show specific = damage to=20 the cell nucleus and DNA, with other cellular organelles = preserved,=20 Kondo explains.  Cells killed by autophagy have little = damage=20 to the nucleus but heavy degradation of the cells'=20 organelles.

Apoptosis and autophagy should be viewed = as type 1=20 and type 2 versions of programmed cell death, Kondo says. In = a=20 Nature Reviews Cancer paper last September, Kondo and = colleagues=20 reviewed therapies and molecules that cause or inhibit the=20 self-cannibalization process and compared autophagy and = apoptosis,=20 which has been more heavily studied.

To improve cancer therapeutics, Kondo and = colleagues=20 concluded that it is vital to identify molecules that = regulate=20 autophagy in cancer cells and to understand how autophagy is = associated with cell death, a relatively new field in cancer = research.

The research group is following up the = malignant=20 glioma findings by studying ways to improve the efficiency = of viral=20 infection of cancer cells.

In addition to Kondo, other co-authors who = contributed to this study include, from M. D. Anderson = Cancer=20 Center: Hideaki Ito, M.D., Ph.D.; Hiroshi Aoki, M.D., Ph.D.; = Yasuko=20 Kondo, M.D., Ph.D.; Eiji Iwado, M.D.;  Arifumi Iwamaru, = M.D.,=20 Ph.D.; Keishi Fujiwara, M.D., Ph.D.; Kenneth R.Hess, Ph.D.;=20 Frederick F. Lang, M.D.; and Raymond Sawaya, M.D.; and from = the=20 Medical School of Hannover in Hannover, Germany: Florian = K=FChnel,=20 Ph.D., Stefan Kubicka, M.D., and Thomas=20 = Wirth.
 

=A92006 The = University of=20 Texas M. D. Anderson Cancer Center
1515 Holcombe Blvd, Houston, = TX=20 77030
1-800-392-1611 (USA) / = 1-713-792-6161   (5.)
Legal = Statements=20  |  Beco= me=20 a Patient  |  Make=20 a Donation  |  Subscribe = to=20 Newsletters =

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