Sometimes an antibiotic is much more

For years, tetracyclines have proved invaluable as a family of everyday antibiotics. Now, a therapeutic alter ego for these drugs is emerging–one unrelated to their germ-fighting prowess.

At the American Association for the Advancement of Science (AAAS) annual meeting in San Francisco last week, scientists reported using tetracyclines to thwart a variety of diseases including periodontal bone loss and cancer.

The new applications tap the drugs’ ability to rein in certain destructive enzymes in the body, explains Lorne M. Golub of the School of Dental Medicine at the State University of New York (SUNY) at Stony Brook. His team first identified this role of tetracyclines some 20 years ago.

At that time, Golub’s group was studying rats to investigate why people with poorly controlled diabetes face a high risk of periodontal disease. The team learned that diabetes fosters a breakdown of collagen, the major structural protein in bone and other connective tissues. Behind collagen’s breakdown were enzymes, such as collagenases.

Because bacteria in the mouth produce toxins that can trigger production of these enzymes, Golub decided to apply a tetracycline antibiotic to the problem. To his surprise, the drug protected collagen even in animals with no periodontal germs–indicating that the tetracycline hadn’t been acting as an antibiotic in its defense of collagen.

Follow-up tests showed that the tetracycline disarmed the collagenase made by certain immune system cells that contribute to inflammation, but other antibiotics had no effect. Moreover, the tetracycline was effective well below the dose that killed germs.

“The medical implications were immediately obvious,” Golub recalls. They suggested that tetracyclines might fight a host of debilitating chronic diseases.

Studies in his lab and elsewhere are now beginning to validate that initial hunch. For instance, at the AAAS meeting, Golub reported that his team has confirmed the capability of tetracyclines to defuse collagen-degrading enzymes extracted from inflammatory cells, bone, cartilage, and joints of people with arthritis. He also cited preliminary data from studies on animals and postmenopausal women indicating that these drugs can slow the age-related bone loss that contributes to osteoporosis.

Sometimes the scientists gave low doses of one of two tetracyclines, doxycycline and minocycline. Other times, they used analogs that have no antibiotic action. Such drugs would permit long-term use, even at high doses, without killing beneficial bacteria in the body or selecting for microbes resistant to antibiotics.

Stony Brook periodontologist Maria E. Ryan has focused on the use of tetracyclines to prevent diabetes complications that can occur when high concentrations of sugar in blood spur the body to produce collagen-digesting enzymes.

At the AAAS meeting, she reported success with diabetic patients who were genetically predisposed to periodontal disease. Her team used low-dose doxycycline, which both fostered reattachment of the gums around the base of the teeth and slowed the erosion of adjacent bone. In addition to disarming enzymes, she notes, the drug reduced the overproduction of cytokines such as interleukin-1 beta. These inflammatory compounds not only activate cells that break down bone, Ryan notes, but also decrease insulin’s action and so aggravate diabetes.

Her team has patented a modified tetracycline to treat adult-onset diabetes. In animal experiments, this drug prevented a number of complications, including cataracts, wasting, and impaired wound healing.

“There hasn’t been much research addressing complications of diabetes,” notes James Mulvihill of Kennebunkport, Maine, who is a past president of the Juvenile Diabetes Foundation in New York City. He says that’s why “I’ve had my eye on what they [at SUNY] have been doing.” Their animal data leave him “hopefully optimistic that these medications will prove efficacious in humans,” he says.

New tetracyclines are generating comparable excitement for their ability to thwart angiogenesis, the enzyme-driven process by which a tumor brings in new blood vessels to feed itself.

Last week, Golub reported unpublished data from experiments with prostate cancer cells. With colleagues at the University of Miami School of Medicine, he showed that both doxycycline and COL-3, a nonantibiotic analog, could disarm a collagen-degrading enzyme made by those cells. Tumors use this particular enzyme, gelatinase, to initiate angiogenesis.

Also at the meeting, Bruce J. Dezube of Beth Israel Deaconess Medical Center in Boston reported preliminary data from a trial of COL-3 in 18 people with Kaposi’s sarcoma, the most common AIDS-related cancer. All had advanced disease that was resistant to other drugs.

Though the study had been designed to establish only the dose of COL-3 that patients could tolerate, the antiangiogenesis drug cleared up all signs of tumors in one patient and shrank tumors by 50 percent or more in seven other patients. In another two, the drug arrested the growth of tumors. That’s an overall response rate of more than 50 percent, Dezube notes–well above the 3 to 5 percent typical of such early studies of cancer drugs.

The findings were sufficiently promising, notes James Pluda of the National Cancer Institute in Bethesda, Md., that his agency has agreed to fund a follow-up trial of the drug in Kaposi’s sarcoma. The institute is also funding several preliminary studies of such nonantibiotic tetracyclines in cancers of the brain and other sites.

Acknowledging that the new data are exciting, Stuart B. Levy of the Tufts University School of Medicine in Boston nevertheless expresses concern that physicians will continue to prescribe low doses of conventional tetracyclines for these new functions even after new analogs are available. “Use of antibacterial tetracyclines for any purpose other than an antibiotic would be wasting a good product,” he maintains. Such use, he says, risks antibiotic resistance (SN: 6/5/99, p. 356) in the user and the environment.