Coral Reefs and Chemotherapy
At first glance, the sea sponge appears to be a docile, peaceful creature. As is often the case, however, looks can be deceiving. Some of these creatures, in fact, produce potent toxins to ward off predators and ensure their survival. The compounds generated by these sea sponges - or possibly by one of the many microbes within the sponge - also are proving to have significant potential as anti-tumor agents.
In a study published just last month in Cancer Research, one sea sponge-derived compound, Discodermolide, was shown in laboratory tests to vastly enhance the lung cancer cell-killing ability of paclitaxel (Taxol), perhaps the most well known cancer agent derived from a natural source, the bark of the Pacific Yew tree.
The world leader in searching for land and marine organisms that produce potentially effective anti-tumor agents is the NCI Natural Products Branch (NPB), part of the Developmental Therapeutics Program (DTP) in the Division of Cancer Treatment and Diagnosis. The NPB guides the collection and testing of samples of thousands of terrestrial and marine plants, organisms, and microbes each year; DTP has screened more than 500,000 synthetic and pure natural compounds, and more than 400,000 crude extracts, since its inception as the Cancer Chemotherapy National Service Center in 1955.
"Nature is the ultimate molecular architect," says NPB Director Dr. Gordon Cragg. "I have tremendous respect for synthetic chemists," he continues, "but they couldn't begin to dream up the sort of compounds that nature has been able to produce."
Because they can produce such potent compounds, research into sessile, or anchored, marine organisms like sponges, tunicates, and nudibranchs is especially intense, Dr. Cragg notes. In the ocean, adds Dr. David Newman, an expert on marine collections in the NPB, "What you've got is a system whereby the creature with the best chemistry set wins."
For marine collections, the NPB works with the Coral Reef Research Foundation to collect samples from organisms primarily found in the Indo-Pacific region, which stretches from Southeast Asia across the Indian Ocean to Africa. Terrestrial plant collections have been performed through contracts with four organizations in more than 25 countries, including those in Africa, Madagascar, Central and South America, and Southeast Asia.
"Our collectors are very conscious of aspects of conservation and sustainable harvesting," Dr. Cragg stresses. "An important part of our program is to work with the countries where we are collecting to ensure that conservation measures are carefully followed, and to provide training and technology transfer opportunities for their scientists."
Since 1960, seven terrestrial-source drugs have been approved by the FDA, including irinotecan and etoposide. The most recent, paclitaxel, approved in 1992, is used in the treatment of breast, ovarian, and non-small cell lung cancer, as well as Kaposi's sarcoma.
But while samples from terrestrial sources have been widely collected and screened, the ocean is still a largely untapped resource. "Coral reefs are the rain forests of the marine environment," Dr. Newman says. "In one square meter of reef, there may be more than 100 species of invertebrate."
A number of marine-derived agents are being tested in pre-clinical and clinical investigations (see below). Some, like bryostatin 1 and ET-743, are showing significant promise in phase II cancer clinical trials, often when used in combination with already approved cancer drugs.
Of course, marine-based products can only be talked about, at the moment, in terms of their potential: The Food and Drug Administration (FDA) has yet to approve a marine-derived drug for use in humans. In part, it is the source of these promising compounds that has hindered progress in this area. There is, for example, difficulty getting enough raw material from "wild collections" (as opposed to collecting from organisms that are grown in aquatic "farms"), and the extensive efforts needed to synthesize compounds from wild collections often is not cost effective, though significant advances have been made in recent years.
At the same time, improvements in marine collection technology are turning up some amazing discoveries. Researchers from Scripps Institution of Oceanography reported last year, for instance, on the discovery of microbes from deep ocean sediments that boasted tremendous biological activity. When they tested 100 strains of the organisms, 80 percent produced molecules that inhibit cancer cell growth.
Both Drs. Cragg and Newman expect some marine-based drugs to receive FDA approval for use in cancer patients. But by the same token, Dr. Cragg stresses, an important aspect of both marine and terrestrial natural products research is "to provide what we call a 'good lead,' not necessarily the final drug."
"What we're doing is helping to generate a significant body of knowledge," adds Dr. Newman. "Whether this will produce a compound that will be 'the drug,' I hope that turns out to be the case. But it is definitely producing compounds that have intrinsic biological activity and that can, in turn, be used to produce novel agents that may benefit many cancer patients."