Making Drugs from Plants : Part 2

by Food and Drug Administration (FDA)

(Page 2 of 2)

Cell Lines

The screening tests are all in vitro — in test tubes and petri dishes — a key element to the potential success of this program, says Boyd.

One plant or animal can produce several extracts, and each extract may be made up of thousands of elements. Since the aim of this program is to test thousands of plants and animals, traditional in vivo screening (in living animals such as rats and mice) "rapidly becomes unmanageable and prohibitively expensive," says Boyd. In addition, animal testing isn't as sensitive, so many promising compounds could be missed.

"The in vitro cell line screen is at least 100 times more sensitive than a primary in vivo screen," says Boyd. "The enhanced sensitivity of the screens will allow discovery of less "potent" substances and substances present at low concentrations."

Boyd adds that the new screen also increases the chances of discovering novel agents that work against specific cancers. "That may be even more important than sensitivity," Boyd says.

The new NCI anti-tumor screen uses 60 different human cancer cell lines, including ones for leukemia, melanoma, colon cancer, lung cancer, ovarian cancer, brain cancer, and kidney cancer. The cell lines, originally developed from tumors taken from cancer patients, are kept frozen in liquid nitrogen, where they remain alive but dormant.

Samples for screening are then revived (thawed) and cultured as needed. Substances found active against certain of the cancer lines in the in vitro screen are then tested in vivo against the same kind of lines implanted in laboratory mice.

Although the process sounds simple, it's been a "five-year ordeal to get [the screen] up and running," says Boyd. "The [anti-tumor] screen is truly unprecedented in its scope and complexity."

During 1989, the screen was run primarily on known compounds to develop a basis for comparing test substances. Starting in 1990, the screening shifted to the thousands of samples stored at NCI's natural products repository. NCI researchers are also using the screen on new compounds submitted to NCI by cancer researchers worldwide.

One boost to the development of the anti-tumor screen has been the concurrent development of an anti-HIV screen. Because the genetic makeup of the AIDS virus is much simpler than that of the myriad of cancer cells, the anti-HIV screen is already being used to screen 1,000 samples a week.

"The [anti-HIV screen] is working beautifully," says Boyd. Already some entirely new structural classes of very potent, very novel anti-HIV compounds have been identified, he says.

When the time comes to test an extract for anti-cancer activity, the cancer cells in the screen are stained pink. If the extract is effective — that is, toxic to the cells — the color will fade as the cancer cells die. The less color, the more promise.

The opposite result signals success with the anti-HIV screen. Healthy cells that have been inoculated with the AIDS virus are stained — orange in this case. If the color doesn't fade, it indicates that the extract got to the virus before the virus killed the normal cells.

For example, an extract from the bark of Homalanthus acuminatus, the Samoan tree mentioned in the beginning of this article, has shown potent activity against the AIDS virus in the anti-HIV screen.

NCI researchers have also screened extracts from blue-green algae and have already found some to be very active against the AIDS virus.

"Most people think of blue-green algae as just simple pond scum," says Boyd. "That's just as false an assumption as you can imagine because there are thousands and thousands of different kinds of so-called blue-green algae."

Once an extract shows promise, the natural products chemistry lab separates the extract into basic components. For example, a chemical process called high performance liquid chromatography turns the black, tarry-looking sludge into white powders and gold liquids. "It's amazing what you can fish out of these black goos," says chemist Kirk Gustafson. Then the screening process starts all over again on the various components isolated by the chemists.

Finally, with the isolated active ingredient detected by the screen, special instruments such as a nuclear magnetic resonance spectrometer and a mass spectrometer "fingerprint" the structure to determine its chemical identity.

Even with the discovery of a promising extract, there is still a long way to go before reaching the goal — a drug to treat cancer or AIDS. Tests on animals and finally clinical human trials require several years to obtain proof of safety and effectiveness.

Drug Farms

The success of any of these natural products against disease could prove bittersweet if the plant can't be collected or grown in sufficient quantity or the extract can't be reproduced synthetically.

Usually it is a problem to make these natural product compounds in the lab, explains Boyd. "Often [these extracts] are very inapproachable by known chemistry," says Boyd. "They have very complex structures."

For example, taxol, an extract from the bark of the Pacific yew tree, is currently being tested in people as a treatment for ovarian cancer. But taxol "can't be made chemically," says Boyd, "so the challenge is to get enough of the trees." One solution, explains Boyd, may be to grow seedlings of the yew tree and "harvest" the taxol by pruning the branches.

Meanwhile, collecting plants and marine organisms — both those with proven success and those with only promise and folklore to back them up — continues around the world.

"You can't do natural products drug discovery research by testing a few samples here and there," Boyd says. "You have to look at a wide diversity of things to have any hope of ... defeating the probability of not finding the things."

Original Research at FDA

While approval decisions are FDA's main responsibility in connection with drugs derived from natural products, one FDA lab is also conducting some original research.

Researchers with FDA's Laboratory of Molecular Pharmacology, part of the agency's Center for Biologics Evaluation and Research, are studying an extract of Coleus forskohlii, a cousin of the common coleus grown in shady gardens throughout the United States. A plant native to India and Nepal, the roots of Coleus forskohlii have been used for centuries, as part of a traditional Hindu system of medicine known as ayurveda, to treat skin infections and to rid the body of parasitic worms.

The extract from those roots, forskolin, is a potential agent for monitoring the activity of many enzymes in the human body, and may some day be used to make tumors more susceptible to the actions of anti-cancer drugs, according to Ken Seamon, chief of the lab. Seamon and other members of his staff are currently working on isolating derivatives of forskolin that would be specific for different enzymes.

About the Author

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FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.