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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."
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