Fluorescent Compounds Make Tumors Glow

A series of novel imaging agents could light up tumors as they begin to form – before they turn deadly – and signal their transition to aggressive cancers.

The compounds – fluorescent inhibitors of the enzyme cyclooxygenase-2 (COX-2) – could have broad applications for detecting tumors earlier, monitoring a tumor’s transition from pre-malignancy to more aggressive growth, and defining tumor margins during surgical removal.

“We’re very excited about these new agents and are moving forward to develop them for human clinical trials,” said Lawrence Marnett, Ph.D., the leader of the Vanderbilt University team that developed the compounds, which are described in the May 1 issue of Cancer Research.

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.

“COX-2 is expressed at the earliest stages of pre-malignancy – in pre-malignant lesions, but not in surrounding normal tissue – and as a tumor grows and becomes increasingly malignant, COX-2 levels go up,” Marnett said.

Compounds that bind selectively to COX-2 – and carry a fluorescent marker – should act as “beacons” for tumor cells and for inflammation.

Marnett and his colleagues previously demonstrated that fluorescent COX-2 inhibitors – which they have now dubbed “fluorocoxibs” – were useful probes for protein binding, but their early molecules were not appropriate for cellular or in vivo imaging.

“It was a real challenge to make a compound that is COX-2 selective (doesn’t bind to the related COX-1 enzyme), has desirable fluorescence properties, and gets to the tissue in vivo,” Marnett said.

To develop such compounds, Jashim Uddin, Ph.D., research assistant professor of Biochemistry, started with the “core” chemical structure of the anti-inflammatory medicines indomethacin and celecoxib. He then tethered various fluorescent parts to the core structure, ultimately synthesizing more than 200 compounds. The group tested each compound for its interaction with purified COX-2 and COX-1 proteins and then assessed promising compounds for COX-2 selectivity and fluorescence in cultured cells and in animals. Two compounds made the cut. Read more

Cancer Risk The Same For Kidney Transplant Recipients, No Matter The Drug

Drugs taken by kidney transplant recipients to prevent organ rejection carry similar risks of cancer, according to a study appearing in an upcoming issue of the Journal of the American Society Nephrology (JASN). The results suggest that no single medication is to blame for the higher incidence of cancer seen among patients who have undergone transplantation.

Individuals who receive a kidney transplant have an increased risk of developing cancer compared with the general population. Researchers suspected that the increased risk may come from immunosuppressive medications that patients must take long-term to prevent organ rejection. To investigate, Martin Gallagher, MBBS, FRACP (The George Institute for International Health in Australia) and his colleagues studied the incidence of cancer in transplant patients who took part in a randomized clinical trial 20 years ago, looking for any differences in cancer risk associated with different immunosuppressive drugs.

The researchers studied the incidence of cancer among 481 kidney transplant recipients in the Australian Multicentre Trial of Cyclosporine Withdrawal who each received one of three treatment regimens: azathioprine and prednisolone, cyclosporine monotherapy, or cyclosporine monotherapy followed by a switch to azathioprine and prednisolone after three months.

A total of 226 patients in the trial developed at least one cancer. By 20 years post transplant, 27% of patients developed non-skin cancer and 48% of patients developed skin cancer. One type of treatment did not have a greater effect on cancer timing or incidence than another, indicating that the therapies carry similar risks for cancer after kidney transplantation. Read more

Need For Strategies To Address Overdiagnosis In Cancer

Many cancers detected by screening tests are not destined to cause symptoms or death and therefore represent a phenomenon known as overdiagnosis. And because overdiagnosis leads to unnecessary treatment and other harms, it is important to develop clinical and research strategies to quantify, recognize, and manage it, according to a review published online in the Journal of the National Cancer Institute.

H. Gilbert Welch, M.D. and William Black, M.D., of the Dept. of Veterans Affairs Medical Center, White River Junction, Vt. and the Dartmouth-Hitchcock Medical Center used data from large randomized screening trials to estimate the extent of overdiagnosis. They found that about 25% of breast cancers detected on mammograms and about 60% of prostate cancers detected with prostate-specific antigen (PSA) tests could represent overdiagnosis. In a lung cancer screening trial of chest x-rays and sputum tests, they estimate that 50% of the cancers detected represented overdiagnosis. They argue that this estimate will only increase with spiral CT scanning, which, in one observational study, found almost as many lung cancers in non-smokers as smokers.

The authors also point to cancer incidence and mortality statistics as evidence of overdiagnosis in some cancers. For five cancers – thyroid, prostate, kidney and breast cancer, and melanoma – data from the past 30 years show an increasing number of new cases but not an increase in deaths. In each of these cancers, an increase in screening or imaging tests has been associated with an increasing rate of new diagnoses.

In addition to screening, other procedures, such as diagnostic imaging, may contribute to overdiagnosis. CT colonography (virtual colonoscopy) for instance, often detects abnormalities outside the colon that can lead to more tests and possibly overdiagnosis.

The authors suggest several strategies to address the problem. One is to educate patients about the risks and benefits involved with early detection.

“Whereas early detection may well help some, it undoubtedly hurts others,” they write. “Often the decision about whether or not to pursue early cancer detection involves a delicate balance between benefits and harms…different individuals, even in the same situation, might reasonably make different choices.” Read more

Next Page »