Getting a handle on a cure

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http://www.fredericknewspost.com/sectio ... ryid=48273

Published on April 21, 2006

By Alison Walker

News-Post Staff

FREDERICK -- At the National Cancer Institute's Developmental Therapeutics Program at Frederick, a team of researchers uses equipment not out of place in most kitchens, but with a much larger mission than preparing food.

Using a hamburger grinder and a machine similar to a coffeemaker, the Natural Products Branch in DTP creates extracts using Mother Nature, from sea fans to twigs, and tests their ability to fight cancer and other diseases.

Since 1986, NPB has organized the collection of plant, microbial and marine samples from around the world.

Notable discoveries due to DTP's work include the cancer drug Taxol and E7389, an extract that has shown cancer-fighting promise in recent clinical trials.

Extract production

More than 200,000 extracts are sitting in NPB's Natural Products Repository, created through a complicated process of whittling down the original source -- the twig or shell, for example.

The work begins with samples collected by plant and marine biologists from a handful of institutes, including the University of Illinois in Chicago; the Missouri Botanical Gardens in St. Louis; and the Coral Reef Research Foundation in Palau.

To create extracts from marine organisms, researchers smash material containing the organisms with a hammer and use a hamburger mill to grind the pieces.

David Newman, an NPB chemist, said this low-tech equipment works better than other methods to break up frozen material, such as rock and coral.

The team uses a process similar to brewing coffee to create extracts, letting a solvent such as water run through the ground-up, powdered material, creating a liquid extract.

The remaining powder, analogous to wet coffee grounds, is dried and extracted with solvents similar to those used in dry cleaning. Researchers mix the powder and water extracts, forming a paste that, when made from plants, resembles pesto.

The NPR team stores bottles of the paste in 10 two-story, walk-in freezers kept at minus 20 degrees. The bottles are ordered according to a bar-coded number, along with smaller amounts of the paste in vials.

DTP branches test the natural product extracts against tumor cells for disease-fighting abilities. In the repository, the Biological Testing Branch stores tumors from animals, as well as human tumors donated to researchers, in large containers filled with liquid nitrogen.

Mr. Newman declined to say how many of the 1 million-plus tested extracts show promise in fighting cancer. True success is developing a drug that passes clinical trials and is used on patients, he said.

"Promise today is tomorrow's failure," he said. "But the frontiers of science are advancing, not retreating."

From dirt to drugs

Nature has been a source of many of the most effective drugs for the treatment of many diseases. These include antibiotics such as penicillin, statins used

to lower cholesterol and painkillers such as morphine.

More than 60 percent of drugs currently used to treat cancer are derived in some way from nature, according to Gordon Cragg, chief of NPB from 1989 to 2004.

"Nature has been doing this for millennia, eons, at work making molecules," he said. "That's why we're convinced we've got to keep looking at nature."

While many of these drugs are produced synthetically or semisynthetically, Mr. Cragg said, nature provides the initial inspiration.

The drug Paclitaxel, also known as Taxol, is used in hundreds of thousands of patients to treat breast, ovarian and some lung cancers. Its active component was initially produced from the bark of the Pacific yew tree in the Pacific northwest.

The NPB assisted in developing this natural Taxol source -- the yew tree, although the drug is now partially synthesized in labs -- so that enough of the agent became available to do clinical studies.

Two other cancer drugs on the market, vinblastine and vincristine, are produced from Madagascar periwinkles, also known as vincas. Discovered in the 1950s, these agents significantly improved survival rates of children diagnosed with leukemia.

A significant number of the world's 250,000 to 350,000 species of plants have never been studied, Mr. Newman said. At least 10 times as many species inhabit the marine world.

New cancer drug?

Drugs derived from marine sources, including E7389, are showing great promise. DTP played a role in developing the extract, which is currently in clinical trials.

In 1985, marine biologists from the University of Shizuoka in Japan located a sponge in Japanese waters with an extremely potent chemical compound, halichondrin B, that targets cancer cells in a way similar to Taxol.

In 1992, researchers also found the compound in a deepwater sponge off New Zealand. That country worked with NCI-Frederick to collect enough of the sponge to study.

One metric ton of the sponge, at a cost of $500,000, produced one-hundredth of an ounce of the compound.

NPB and BTB researchers presented their findings at a 1995 conference, 10 years after the sponge was discovered. Eisai Research Institute in Andover, Mass., later approached NPB and DTP to help develop a synthetic version of the sponge's active component, E7389.

Eisai made more than 200 modifications to the halichondrin B molecule to make E7389. By 2001, the U.S. Food and Drug Administration approved the drug's use in clinical trials.

In phase II clinical trials with 62 women with resistant breast cancer, about 15 percent responded to E7389 treatment with significant remissions, Mr. Cragg said.

This effectiveness is similar to that of Taxol's in its early phase II trials, and E7389 appears to lack some of Taxol's negative side effects, Mr. Newman said.

"We don't know for sure it'll become a drug," he said. "We hope to hell it will, but we don't know."

E7389's long history -- more than 20 years since the discovery of its original compound in nature -- illustrates how much time and money can be needed to develop new treatments, Dr. Newman said.

"You have to have marine biologists, pharmacologists, chemists, physicians willing to devote their skills and time, but the development of new and more effective drugs makes the efforts very worthwhile," he said.