June 10, 1999
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Probes Detect Early Growth Of Cancer Tumors

By William J. Cromie

Gazette Staff

Picture this: doctors inject an invisibly small probe into your blood, and it swims directly to cells where cancer has just begun to grow. The device signals back the exact location and the stage of the disease. Doctors then use the information to determine the best treatment for destroying a tumor in its earliest stages of existence.

What's more, the same type of probe can later revisit the tumor site to see if the treatment is successful.

Such a system belonged in the realm of science fiction only a year ago. Today, it appears to be on its way to reality.

Researchers at Harvard University and Massachusetts General Hospital in Boston used such a probe to detect the presence in mice of breast cancer cells too small to feel.

"This is a fundamental new imaging system that allows us to home in on and look at specific enzymes that characterize many different disease processes," says Ralph Weissleder, associate professor of radiology at Harvard Medical School, who heads the research effort. "The diseases include breast, prostate, and colon cancers, as well as inflammatory ailments like rheumatoid arthritis."

The probes, small enough to work their way through chinks in the membranes surrounding human cells, consist of a biological raft holding 10 to 20 protein-like stalks. Atop each stalk is a tiny sack containing fluorescent dye. When enzymes common in tumor cells wash over the raft, the stalks break and the dye emits fluorescence which is recorded by a new type of camera system.

"It is the first time anyone has detected the presence of specific enzymes in a living creature," notes Weissleder, who directs the Center for Molecular Imaging Research at Harvard-affiliated Massachusetts General Hospital. The feat opens the door to recognizing the tremendous variety of enzymes that catalyze biological reactions involved in maintaining good health as well as contributing to disease.

A Raft of Possibilities

Weissleder's laboratory also developed probes to detect metastases, the spreading of cancer from its original site, and angiogenesis, the growth of new blood vessels that nourish tumor cells. Still in the research stage, these probes have not yet been used in humans.

The raft by itself, however, proved to be safe when it was injected into humans during an experimental trial. In these experiments, the raft carried a harmless radioactive cargo which allowed it to be tracked as it rode through the blood stream.

The stalks and dyes present no safety problems, so the next step will be to inject complete probes into the cells of people with known tumors. "We want to determine if the probes will identify the types of tumors, their location, and their stage of development," Weissleder explained. He and his colleagues plan to prepare an application to the U.S. Food and Drug Administration to permit such studies.

"In the meantime, we continue to do basic research to demonstrate the breadth of different applications of this technique," Weissleder says.

His team wants to identify enzymes that are more plentiful in cancer cells than in normal cells, and enzymes that occur predominantly in tumors. Weissleder refers to the latter as "enzymes that make a tumor a tumor." Once such compounds have been identified, probes can be customized to carry different stalks with different dyes. A combination of dyes could be used to detect several types of tumors.

When a treatment is successful, follow-up probes will show less or no fluorescence, a signal that tumor-associated enzymes are less active or inactive. Fluorescence occurs at near-infrared frequencies which cannot be seen and must be detected by a special camera system. Unlike x-ray and nuclear techniques, no radioactivity is involved and near-infrared rays don't damage healthy cells.

In addition to cancer markers, Weissleder's group plans experiments with enzymes involved in other diseases. For example, it might be possible to recognize enzymes that destroy the cartilage of people with rheumatoid arthritis. "There is also a potential for early diagnosis and treatment evaluation in AIDS and heart disease patients," Weissleder says. AIDS involves enzymes similar to those in tumor cells, and enzymes are active in processes that block blood vessels in the heart.

Watching Genes

Many types of future treatments for cancer and other diseases will involve attempts to replace missing or malfunctioning genes. One obstacle to success is determining if the replacements have reached the right place and have been turned on, or activated. Genes produce certain enzymes that can be spotted by the probes, so the rafts might provide crucial information about the location and activity of genes used for therapy.

Weissleder works with researchers Alexei Bogdanov, Ching-Hsuan Tung, and Umar Mahmood. They comprise one of only a few teams working in this exciting area. "There's an explosion out there as researchers explore what actually can be done," Weissleder points out. The National Institutes of Health, the world's largest supporter of medical research, has acknowledged this explosion by making more than $40 million available for further experiments over the next five years.


Copyright 1999 President and Fellows of Harvard College