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Induced viral gene expression used to image tumors

BioPhotonics
Apr 2007
Michael J. Lander

Studies have shown that certain cancers may be caused by viruses that infect and alter cells. Recently, scientists from Johns Hopkins Medical Institutions developed a technique for imaging the expression of viral genes in those cancers. In contrast to other techniques for molecular-genetic imaging, their method does not require transfection of the target cells.

In developing the method, Dr. Martin G. Pomper, Dr. Richard F. Ambinder and colleagues concentrated on the thymidine kinase gene found in tumor-associated gamma herpes viruses such as Epstein-Barr. They knew that, when in the reproductive (lytic) stage, the viruses express these genes at a detectable level, although the latent stage — and, thus, low expression — generally prevails.

To get around this, the researchers induced viral replication with the anticancer agent bortezomib, whose replication-inducing activity they discovered after screening a large library of compounds. They then targeted the cells with 2'-fluoro-2'-deoxy-b-D-5-iodouracil-arabinofuranoside labeled with iodine-125, which selectively associated with the viral kinase, collecting in cells where it was produced.

The scientists created the technique as a way to select patients for viral lytic induction therapy and to determine why certain patients do not respond to this type of therapy. Unlike the current clinical standard — PET with [18F]fluorodeoxyglucose — their method not only images the metabolism of cancer cells but also enables measurement of the activity of an enzyme that is expressed in tumors when the associated virus is replicating. The compound used does not enable imaging of quiescent tumors, as does the glucose derivative; rather, it allows imaging of only virus-associated tumors once viral reproduction is induced by an agent such as bortezomib.

To study the effectiveness of their technique, the scientists introduced cancer cells into mice, allowed lymphoma to form and administered bortezomib. Twenty-four hours later, they injected the labeled compound into the tail vein of each mouse.

With a dedicated small-animal SPECT-CT device from Gamma Medica Inc., they took high-resolution scans of the lymphoma-bearing mice and analyzed the images with software from the National Institutes of Health and SourceForge.

BNVirus.jpg
Researchers used SPECT-CT to image tumor metabolism in mice. The number of hours elapsed between administration of a radioactively labeled compound and the imaging procedure is shown. Reprinted with permission of Clinical Cancer Research.

Only one day after injection of the radiopharmaceutical, the images revealed the tumors of mice treated with the agent and labeled compound. The latter’s absorption into the bladder caused this organ to appear as well — a disadvantage that resulted from the expected metabolism of the agent. Four days after injection, malignancies appeared most clearly, and radioactivity in nontarget sites significantly decreased.

In all experiments, tumors did not appear in images where bortezomib had not been administered. The researchers also were unable to image tumors that did not harbor the viruses. Together, the results demonstrated the ability of the technique to image metabolism effectively in specific cancer cells and to reveal specifically viral rather than human thymidine kinase activity. The technique is also highly sensitive because induction of viral reproduction must occur in only 5 percent of tumor cells to allow effective imaging. It also can be adapted for use with PET.

Pomper noted that other nucleoside analogs, functionalized with various labels, could be used to image an assortment of viral-induced tumors in humans as well — work for which the group has received approval for clinical testing.

“We hope that techniques like this will integrate molecular imaging more deeply into cancer therapy trials,” Pomper said. The current compounds also might help reveal infection by bacteria that produce thymidine kinase. Stronger radioactive isotopes such as iodine-131, when used as labels, could even allow targeted destruction of cancer cells.

Clinical Cancer Research, March 1, 2007, pp. 1453-1458.


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