Imaging agents offer new view of inflammation, cancer

 by Biomechanism 

“Study describes first COX-2-targeted PET imaging agent”

A series of novel imaging agents could make it possible to “see” tumors in their earliest stages, before they turn deadly.

The compounds, derived from inhibitors of the enzyme cyclooxygenase-2 (COX-2) and detectable by positron emission tomography (PET) imaging, may have broad applications for cancer detection, diagnosis and treatment.

Positron emission tomography (PET) is a test that uses a special type of camera and a tracer (radioactive chemical) to look at organs in the body, and is often used to find cancer, to check blood flow, or to see how organs are working.

Vanderbilt University investigators describe the new imaging agents in a paper featured on the cover of the October issue of Cancer Prevention Research.

“This is the first COX-2-targeted PET imaging agent validated for use in animal models of inflammation and cancer,” said Lawrence Marnett, Ph.D., director of the Vanderbilt Institute of Chemical Biology and leader of the team that developed the compounds.

COX-2 is an attractive target for molecular imaging. It’s not found in most normal tissues, and then it is “turned on” in inflammatory lesions and tumors, Marnett explained.

“As a tumor grows and becomes increasingly malignant, COX-2 levels go up,” Marnett said.

To develop compounds that target COX-2 and can be detected by PET imaging, Jashim Uddin, Ph.D., research assistant professor of Biochemistry, started with the “core” chemical structures of the anti-inflammatory medicines indomethacin and celecoxib and modified them to add the element fluorine in various chemical configurations.

After demonstrating that the fluorinated compounds were selective inhibitors of COX-2, the investigators incorporated radioactive fluorine (18-F) into the most promising compound. Intravenous injection of this 18-F compound into animal models provided sufficient signal for PET imaging.

The researchers demonstrated the potential of this 18-F compound for in vivo PET imaging in two animal models: irritant-induced inflammation in the rat footpad and human tumors grafted into mice.

They showed that the 18-F compound accumulated in the inflamed foot, but not the non-inflamed foot, and that pre-treatment of the animals with celecoxib blocked the signal. In mice bearing both COX-2-positive and COX-2-negative human tumors, the 18-F compound accumulated only in the COX-2-positive tumor.

The studies support further development of these agents as probes for early detection of cancer and for evaluation of the COX-2 status of pre-malignant and malignant tumors.

“Because COX-2 levels increase during cancer progression in virtually all solid tumors, we think these imaging tools will have many, many different applications,” Marnett said.

Bone marrow cells migrate to tumors and can slow their growth

 by Biomechanism 

Bone marrow cancer is called multiple myeloma. Frequently the first sign of multiple myeloma is bone pain due to the presence of many malignant cells in the bone marrow.

Bone marrow-derived cells (BMDCs) participate in the growth and spread of tumors of the breast, brain, lung, and stomach. To examine the role of BMDCs, researchers developed a mouse model that could be used to track the migration of these cells while tumors formed and expanded. Their results, published in the November issue of The American Journal of Pathology, strongly suggest that more effective cancer treatments may be developed by exploiting the mechanism by which bone marrow cells migrate to tumors and retard their proliferation.

“Our results provide an excellent in vivo experimental model where the temporal dynamics of tumor-infiltrating BMDCs may be monitored in an immunocompetent host and novel therapies targeting BMDCs for the inhibition of tumor progression may be investigated,” commented lead investigator Wafik S. El-Deiry, MD, PhD, Professor and Chief, Hematology/Oncology Division at the Penn State Hershey Medical Center and Associate Director for Translational Research at the Penn State Hershey Cancer Institute. “In the future, it may be possible to use specific identified tumor-infiltrating BMDCs to deliver therapeutic cargo.”

A first group of mice expressing a fluorescence gene served as donors of the bone marrow cells. A second group of mice, whose marrow had been destroyed by radiation, were injected with the donated fluorescent bone marrow. The transplanted bone marrow cells were allowed to proliferate for 8 weeks. Then, colon cancer cells were injected into the same mice and tumors formed over the next 3 weeks.

Monitoring tumor growth by optical imaging, researchers found that the tumors contained numerous types of BMDCs. Notably they also found that tumor growth is reduced in animals that received the bone marrow transplants, compared with untransplanted host mice.

According to the authors, cancer has long been viewed as a disease in which transformed cells grow and invade tissues. However, they believe that it is becoming clear that cancer is a more complex disease in a heterogeneous microenvironment where many cellular interactions are occurring in the malignant tissue.

“This type of mouse model allows scientists to actually see in living color the complicated relationships and interplay between the…tumor’s own cells and the immune system cells within the host…” said El-Deiry, who is also an American Cancer Society Research Professor. He added: “this ongoing war on cancer within this tumor microenvironment has surprising twists and turns.” El-Deiry and his colleagues hope to steer patient outcomes “with additional treatments that can help [them] overcome the cancer.”

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The article is “High-Resolution Imaging and Antitumor Effects of GFP+ Bone Marrow-Derived Cells Homing to Syngeneic Mouse Colon Tumors” by Niklas K. Finnberg, Lori S. Hart, Nathan G. Dolloff, Zachary B. Rodgers, David T. Dicker and Wafik S. El-Deiry (doi: 10.1016/j.ajpath.2011.07.028). It will appear in The American Journal of Pathology, Volume 179, Issue 5 (November 2011) published b

y Elsevier.

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New study confirms genetic link to suicidal behavior

 by Biomechanism 

A new study from the Centre for Addiction and Mental Health has found evidence that a specific gene is linked to suicidal behaviour, adding to our knowledge of the many complex causes of suicide. This research may help doctors one day target the gene in prevention efforts.

In the past, studies have implicated the gene for brain-derived neurotrophic factor (BDNF) in suicidal behaviour. BDNF is involved in the development of the nervous system.

After pooling results from 11 previous studies and adding their own study data involving people with schizophrenia, CAMH scientists confirmed that among people with a psychiatric diagnosis, those with the methionine (“met”) variation of the gene had a higher risk of suicidal behaviour compared to those with the valine variation.

The review, published in the International Journal of Neuropsychopharmacology, included data from 3,352 people, of whom 1,202 had a history of suicidal behaviour.

The news coincides with Mental Illness Awareness Week, October 2-8, and World Mental Health Day, October 10.

“Our findings may lead to the testing and development of treatments that target this gene in order to help prevent suicide,” says Dr. James Kennedy, director of CAMH’s Neuroscience Research Department. “In the future, if other researchers can replicate and extend our findings, then genetic testing may be possible to help identify people at increased risk for suicide.”

As the low-functioning BDNF met variation is a risk factor for suicidal behaviour, it may also be possible to develop a compound to increase BDNF functioning, Dr. Kennedy says.

About 90 per cent of people who have died by suicide have at least one mental health disorder, the researchers note. Within the studies they reviewed, participants had schizophrenia, depression, bipolar disorder or general mood disorders. In each case, the researchers compared the genotypes of people who had attempted or completed suicide with those who were non-suicidal.

“Our findings provide a small piece of the puzzle on what causes suicidal behaviour,” says Dr. Kennedy.

“When assessing a person’s suicide risk, it’s also important to consider environmental risk factors, such as early childhood or recent trauma, the use of addictive drugs or medications and other factors.”