ILLUMINATING A DEADLY DISEASE
A chemist's groundbreaking cancer detection research has the medical world seeing things in a new light.
Written by Josh Murray
Some would say detecting a disease has never been easier. And much of the progress is due to a better design of the instruments. They are quicker, and they are more accurate. But at Texas Tech University, a chemist is taking detection of colon cancer one step further. In fact, he has, in his own way, illuminated cancerous cells so that they cannot be missed.
Darryl J. Bornhop, Ph.D., associate professor of chemistry at Texas Tech, and his team of researchers from Texas Tech, Texas Tech University Health Sciences Center, the Southwest Cancer Center and the Dow Chemical Company, have worked diligently over the last six years to develop Tb-PCTMB, the chemical highlighter. Each researcher has a unique background. Each brings a certain level of expertise into the lab.
"This is typical of modern biomedical science. You bring in people with a number of different backgrounds because the problem is very complex. So you frequently end up with chemists, engineers, biologists and geneticists all working together," said Barbara C. Pence, Ph.D., associate vice president for research at the Texas Tech University Health Sciences Center. "It is just a modern way of doing things."
But still in this modern world of modern science, colorectal cancer is not easy to detect. In fact, people often do not recognize the symptoms -- a change in bowel habits, unusual rectal bleeding, abdominal pain or fatigue. And even worse, the cancer may go unnoticed for up to 10 years before the lesions become visible to the eye.
"Cancer is considerably treatable if it's found in the early stages," said Bornhop.
Today, medical practitioners use several methods to detect cancerous tissue in the colon. The fecal occult test is a simple procedure to detect traces of blood in the stool. It can be done in doctors' offices or even in private homes and sent to a laboratory for testing. The sigmoidoscopy, a 10-minute procedure, is typically done as an outpatient procedure and screens the lower part of the colon. And the colonoscopy, the most effective method, examines the entire length, almost five feet, of the colon. During this procedure, physicians try to identify potential cancers through changes in the color of the tissue, increased blood vessels and the presence of abnormal growths, known as polyps, in the colon. All of this is seen by physicians under normal white light at the end of the colonoscope.
Colon cancer is such a silent killer that 57,000 Americans will die from colorectal cancer this year, and more than 37,000 of those deaths would be preventable through early detection. And early detection and modern science is what Bornhop is taking one step further.
"When the tissue transforms into cancer cells, its visual properties are slow to change. Once visualization occurs with white light, it gets easier to see, but by that time, it's not just a splash of cells, it's a tumor," said Bornhop.
It is the splash of cells -- in the early stages -- which Tb-PCTMB has shown to detect in laboratory animals.
This chemical marker is similar to those chemicals used for magnetic resonance imaging (MRI). Tb-PCTMB rapidly associates with diseased tissue and unlike some dyes used in other procedures, it cannot be washed off. The researchers have determined that the non-toxic blue fluorescent color is easily detectable. In fact, it has a great deal of tissue specificity when administered topically. The fluorescence of the chemical attaches to cancerous cells to make them clearly visible.
Bornhop said Tb-PCTMB is somewhat like a phorphyn complex. Phorphyns are compounds that occur naturally in the body, and in cancerous tissues, there is a higher concentration. In the past, scientists have developed agents to stimulate the production of phorphyns to selectively kill cancer cells. This state-of-the-art chemical research is not exactly a lifelong project of Bornhop's. It is, however, the blend of two careers.
Before coming to Texas Tech in 1994, Bornhop worked in the medical device industry for three years. He was familiar with visualization technology that allowed physicians to examine almost any part of a patient's body -- knees, the heart, arms, ankles, the colon -- through in-cavity microsurgery.
In his first semester as a faculty member at Texas Tech, he sat in on a lecture given by Garry Kiefer from the Dow Chemical Company. The lecture, Bornhop said, was about the chemical synthesis. At the end of the lecture, Kiefer showed a picture of a piece of bone that was glowing in a blue-green color. Bornhop said a "light" went on for him. The "light" for him was sight-directed chemistry.
"I saw the correlation of early detection and making a chemical associate with or attach to a specific target site," said Bornhop.
In this case, the target site was cancer cells.
After the lecture, he talked to Kiefer and showed him Texas Tech's micro-endoscopy technology. The next day, Bornhop flew to Houston to present his research on fluorescence endoscopy at the Dow Chemical Company.
"Fluorescence is the most recently developed detection application," said Kiefer, who is the research leader in pharmaceutical development at Dow Chemical. "It's our hope to be able to detect cancer lesions before they become visible to the naked eye."
Soon after, Bornhop secured grants from the Whitaker Foundation, the Texas Tech University Research Enhancement Fund and the Dow Chemical Company. Pence offered him laboratory space at the Texas Tech Health Sciences Center.
"I know nothing about the development of chemical compounds. I know how to grow cells, and I know how to study DNA, and I know how to diagnose cancer, but I haven't worked with imaging agents," said Pence. "He's discovered a system to detect the fluorescence from this compound. I had the animal models."
The collaboration began.
The best approach, the researchers decided, was two-pronged. First, they would test cell cultures and then conduct tests in animal models during this pre-clinical development phase.
The cell cultures were used to test the basics of Tb-PCTMB. The researchers were looking to see if the compound would get inside the cell, its lighting capabilities and the appropriate dose ranges. When the researchers were satisfied with the results, they moved on. It was time to experiment with the animal models.
Before animal testing was done, Pence said a health sciences center committee had to weigh the risks and benefits.
"The potential benefits for human medicine is of enough value to support the testing," said Pence. "Many human diseases would not be as treatable today and children would not be immunized without animal testing."
In the laboratory, approved by the Institutional Animal Care and Use Committee, 16 Sprague Dawley rats were injected with a carcinogen, dimethyl hydrozene (DMH) and fed a high-fat, meat-based diet. After 10 weeks, Tb-PCTMB was put to test.
Using a small endoscope, a lighted instrument to view the inside of the colon, Bornhop applied the aqueous solution of the fluorescent compound followed by a saline rinse.
"This is an imaging technique that works best when applied topically," said Bornhop. "In this case, it was a blue-green marker. We then used a fluorescent light source to visualize the chemical on the tissue."
Results from the investigations indicating specificity for detecting colon cancer, particularly the early development of abnormal tissue, was better than 85 percent. Today, the tests continue and include expanded studies for colon cancer and other oral diseases such as oral cancer. A Phase I human clinical trial is expected soon.
Bornhop's discovery could not have come at a better time. In the last 20 to 30 years, only some strides have been made in the treatment of cancer, especially colorectal cancer, said Pence. The big chance for reducing the number of people dying is to prevent cancer or detect cancer in the very early stages, she added.
"It is still too early to know how this testing will fair in humans, but if it is developed safely, it is better than what we have now," said Pence.
And now the testing will move into the next stages of development. Pence said the Food and Drug Administration is always concerned about two things -- safety and efficacy.
Before it reaches humans, Tb-PCTMB will go through three clinical trials to determine if it is safe, if it works, and how it stands up against the current standard methods of testing. Time will tell.
But if all goes as Bornhop has planned, early detection may take on a new look, so to speak. A fluorescent, hard-to-miss look.
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