Oceans: Medicine Chests of the Future?

As disease resistance to antibiotics and other drugs continues to build, even new methods of discovery such as combinatorial chemistry may not be able to meet the ever-increasing need for more efficient and more effective compounds. According to a core group of researchers, however, an untapped reservoir of powerful new medicines is in the oceans. In fact, so rich is life in the oceans that some seafaring scientists go so far as to say the greatest bounty in the medicine chest of the new millennium will be found there.1 In recent years a small community of biological and chemical oceanographers has discovered a significant number of novel metabolites with potent pharmacological properties in marine organisms. Although the pharmaceutical industry at large has been reluctant to catch the new wave, the National Cancer Institute (NCI) and a few smaller drug and biotech companies have, and several robust new compounds derived from marine natural products are now in the clinical pipeline, with more in preclinical development. For those in the oceanographic community who have explored the depths of this watery medium that covers approximately 70 percent of Earth's surface, the potential is obvious, but current knowledge is limited. "Of the 27 diverse phyla of life, only 17 occur on land, yet 27 of the 27 occur in the ocean ..., and so the largest proportion of biodiversity is in the ocean," says marine chemist Bill Fenical, director of the Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography. "There are one million cells in one milliliter of seawater and they're all different, yet we know something about only one or two percent of those. The oceans are a huge resource for drugs and other products in agrichemicals and skin care ..., and we are discovering new things all the time." The sessile nature of many marine organisms has evolved a unique repertoire of chemicals used for defense, as well as communication and reproduction. "It is a jungle down there, and there's heavy competition between phyla and between species; this has produced some quite remarkable compounds," says Ken Rinehart, professor of organic chemistry at the University of Illinois, Urbana, who discovered two of the marine compounds now in clinical trials. Marine chemist Ray Andersen, professor of chemistry and oceanography, University of British Columbia, agrees: "We find unique molecular structure types not duplicated anywhere and that's what you need for drug discovery, new chemical structural types that are biologically active." Actually, there was a first, albeit very small, wave of marine-derived drugs that resulted in several products currently on drugstore shelves. Back in the 1950s, chemists extracted compounds from a sponge found in the waters off the coast of Florida that wound up as antiviral drugs Acyclovir (Zovirax®), to treat herpes, and Cytarabine (Cytosar®), to treat non-Hodgkin's lymphoma. Later Cephalasporins (antibiotics) were discovered in a sample from the Mediterranean Sea. Since then, "the marine natural products have provided a number of very important biochemical reagents that are used in cell biology, neurosciences, and absolutely almost every facet of modern biology, but none have gotten through yet as drugs," comments veteran marine chemist John Faulkner of Scripps Institution. There is a host of reasons for that. For starters, the field of biomedical research in the oceans is relatively young, really only starting in earnest in the late 1960s. "For the first 10, 12 years, people were looking for novel structures, fascinated by the novel chemistry, and there wasn't so much emphasis on looking for drug leads," recalls Andersen. "It's only been since 1980 that people have gotten really serious about looking for new drugs from the sea." In addition, it took a while for technology to catch up. "The physical techniques to isolate these compounds--the special kind of chromatography, which is very gentle, and magnetic resonance, which correlates protons with carbons, and a special type of mass spectrometry, which is very gentle as well--those things didn't come around until 1982 or so," notes Rinehart. "Basically, these last 15 years have been the formative years, developing our techniques and figuring out what works and what doesn't work," assesses Shirley Pomponi, director of biomedical marine research at Harbor Branch Oceanographic Institution. Photo: Patrick Colin The oceans contain the largest proportion of biodiversity on Earth. During those formative years, marine researchers have homed in on where to look for exotic compounds, discovering "the best sources of pharmacologically active compounds [to be] bacteria, cyanobacteria, fungi, certain groups of algae, sponges, soft corals and gorgonians, sea hares, nudibranchs, bryozoans, and tunicates," according to Faulkner. Now the science is accelerating. "There's been a quantum leap in two areas. One is in the assays, which can now be completed very rapidly, and the second is you can also do structural chemistry fairly rapidly," says David Newman, project officer for marine collections at NCI's Natural Products Branch. In fact, the list of novel anticancer drug candidates at that NCI branch includes more compounds from the ocean these days than terrestrial sources. "I'm a zealot when it comes to the marine environment, because what you find is some absolutely fascinating chemistry," Newman offers. "And what we have found, over the last five to seven years, when we compare the initial hit rates in our in vitro screens with source, is that the most potent agents and the ones that have the odd test results are coming from the marine environment. They're still hydrogen-carbon-oxygen based, but the shapes we are finding are quite different. There are, for example, three quite different molecules [discodermolide, eleutherobin, and laulimalide] that show biological activity on the tubulin system, which is the one Taxol® works on, although these molecules are entirely different from Taxol® in terms of their molecular shape." Currently, the NCI is sponsoring a host of Phase I and Phase II trials on the following compounds: Bryostatin 1--a compound isolated from the bryozoan Bugula neritina, an organism that attaches itself to the bottoms of boats off the coast of California, primarily for use as a treatment of melanoma, non-Hodgkin's lymphoma, and renal cancer; Dolostatin 10--a linear peptide derivative isolated from the sea hare Dolabella auricularia from the Indian Ocean, for use in the treatment of breast and liver cancers, solid tumors, and leukemia; AE941--a shark cartilage preparation, developed by Aeterna in Quebec, for use in treatment of various tumors, is about to go into Phase III trials. In the private sector, a small pharmaceutical company, PharmaMar, based in Spain, holds the licenses and is conducting clinical trials on Ecteinascidin-743 (ET743) and Dehydrodidemnin B, both found in organisms discovered by Rinehart back in the 1970s.2 ET743, a compound isolated from a Caribbean tunicate, has shown activity against ovarian3 and other tumors, and is currently in Phase II trials in Europe, Canada, and the United States, being tested against 14 different tumor types. Dehydrodidemnin B, isolated from Mediterranean tunicate Aplidium albicans, is currently in Phase II studies in the United States and Europe, being tested for its anticancer properties. Allergan Pharmaceuticals licensed an anti-inflammatory, manoalide, isolated from the Palauan sponge Luffariella variabilis and patented by the University of California. Allergan took the compound through Phase I trials for the treatment of psoriasis, then launched a medicinal chemistry program with it. While it is commercially available as a standard probe for PLA2 inhibition, no pharmaceutical based on manoalide has yet reached drugstores. A number of other compounds are in preclinical development, including: Discodermolide, a metabolite of the deep-sea sponge Discodermia dissolute discovered by Pomponi in the waters off the Bahamas, was first described by Ross Longley and Sarath Gunasekera, also of Harbor Branch, as an immunosuppressive and cytotoxic agent.4 Its potent antiproliferative activity, however, was recently shown to be the result of its ability to stabilize microtubules,5 and in 1998 Novartis Pharma AG licensed the compound for development as a candidate agent for treatment of cancers; Halichondrin B, first isolated from the Japanese sponge Halichondria okadai, has shown promise in vivo as a treatment for melanoma and leukemia and is currently in preclinical trials at the NCI with material obtained from the New Zealand deep-water sponge Lissodendoryx; Isogranulatimide, derived from a Brazilian tunicate, is "the first G2 checkpoint inhibitor discovered by rational means," says Andersen. "In vitro, it shows selective or enhanced killing of p53-tumor cells relative to normal cells or p53+ cells, and ... it's a compound we've been able to synthesize quite easily. So we've got a short, efficient synthesis of it, and we're making analogues." The compound has been licensed to a small Vancouver company, Kinetek, which is gearing up to test this hypothesis in vivo; Debromohymenialdisine (DBH), one of several constituents of the common Palauan shallow-water sponge Stylotella aurantium,6 "is the most interesting druglike molecule we've encountered," says Faulkner. Licensed to Genzyme Tissue Repair, it is one of the few marine compounds that is easily synthesized and is being developed for treatment of osteoarthritis. In the meantime, an anti-inflammatory compound, Pseudopterogorgia elisabethae, extracted from the sea fan by Fenical, has found its way to the marketplace, in an Estée Lauder skin care product, Resilience. "This proves unequivocally that biologically active agents are in the ocean and can be used and developed," Fenical asserts. Shirley Pomponi The potency of compounds derived from marine organisms has also proven to be the downfall of some drug candidates. Didemnin B, a substance extracted from a tunicate found in the western Caribbean Sea, for example, went through NCI-sponsored Phase II trials and then was pulled. "We returned it to Davy Jones' Locker, because it was just too toxic," says Newman. "We find this quite a bit with marine organisms. "They are exquisitely potent, and occasionally they are just too toxic." Toxicity is not the only problem. Bristol-Myers Squibb, one of the few major pharmaceutical companies to look into marine-derived compounds, recently returned licenses for eleutherobin--a compound isolated from a small Australian soft coral of the genus Eleutherobia, discovered by Fenical, because, he says, "we couldn't get any of it"--and bryostatin 1. "Right now, people are willing to do anything to discover drugs, but still it remains that the pharmaceutical industry has not invested in the most diverse component of the Earth," Fenical sighs. "The only real hero here is the NCI. They have not been myopic in their views." It appears, not too surprisingly, to be a dollars and cents issue as much as anything. "The fact that it takes a little longer to do everything in the marine environment is real, and the economic pressures of drug development are real, and the politics are real," says Faulkner. A.J.S. Rayl (ajsrayl@loop.com) is a freelance writer in Malibu, Calif. Next Issue: Addressing Economics, Politics, and New Approaches S.A. Pomponi, "The bioprocess-technological potential of the sea," Journal of Biotechnology, 70[1-3]:5-13, April 30, 1999. K.L. Rinehart et al., "Marine natural products as sources of anti-viral, anti-microbial, and anti-neoplastic agents," Pure and Applied Chemistry, 53:795-817, 1981. G. Valoti et al., "Ecteinascidin-743, a new marine natural product with potent antitumor activity on human ovarian carcinoma xenografts," Clinical Cancer Research, 4:1977-83, August 1998. R.E. Longley et al., "Discodermolide--a new marine-derived immunosuppressive compound. In vitro studies," Transplantation, 52:650-6, 1991; and R.E. Longley et al., "Discodermolide--a new marine-derived immunosuppressive compound. In vivo studies," Transplantation, 52:656-61, 1991. E. ter Haar et al., "Discodermolide, a cytotoxic marine agent that stabilizes microtubules more potently than taxol," Biochemistry, 35:243-50, 1996; and R.J. Kowalski et al., "The microtubule-stabilizing agent discodermolide competitively inhibits the binding of paclitaxel (Taxol) to tubulin polymers, enhances tubulin nucleation reactions more potently than paclitaxel, and inhibits the growth of paclitaxel-resistant cells," Molecular Pharmacology, 52:613-22, 1997. M. Roberge et al., "High throughput assay for G2 checkpoint inhibitors and identification of the structurally novel compound isogranulatimide," Cancer Research, 58:5701-6, 1998; and R.G.S. Berlinck et al., "Granulatimide, isogranulatimide and didemnimide E, aromatic alkaloids isolated from the Brazilian ascidian didemnum granulatum: structure elucidation, synthesis, and G2 checkpoint inhibition activity," Journal of Organic Chemistry, 63:9850-6, 1998. D.H. Williams, D.J. Faulkner, "Isomers and tautomers of hymenialdisine and debromohymenialdisine," Natural Product Letters, 9[1]:57-64, 1996.

Oceans: Medicine Chests of the Future?

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