Anticancer Drugs from the Coral Reef:
Prospects and Promise


In many instances, a diagnosis of cancer is no longer the death sentence that it once was. Astonishing advances in the three classical modes of treatment (radiation, surgery and chemotherapy), along with more contemporary approaches such as photodynamic therapy, offer new hope to many patients.

Of these distinct forms of medical intervention, perhaps chemotherapy holds the most promise for selectively eradicating cancer cells while at the same time minimizing collateral damage to surrounding tissues. In a typical chemotherapy regime, a patient is treated with one or more chemical agents that either selectively kill cancer cells directly or promote the death of cancer cells by indirect means, such as disrupting solid tumors' blood supply network. Many of these chemical agents owe their origins to natural sources in the environment, whereas other anticancer chemotherapeutics are wholly designed by pharmaceutical scientists based upon current knowledge of cancer onset mechanisms. Selectivity for cancer cell destruction without harming healthy cells is the central focus of these treatment protocols, and chemotherapy's well-known side effects (hair loss, nausea, immunocompromise, etc.) are a continuing reminder that much room for progress remains.

Whether the promise of fully selective anticancer medicines will be realized in our lifetime remains unknown, but exciting developments from the coral reefs and their inhabitants lend credibility to the proposition that the best is yet to come. In fact, coral reef chemistry is coming increasingly to the foreground in the search for new medicines in general, as the long-held dogma that the tropical rain forests were going to be the world's pharmacopoeia has not held up to repeated examination (Cragg, 2005) despite their harboring over half of the world's 250,000 known species of plants. The whole concept of prospecting for pharmaceutical agents in the marine environment was validated by the isolation and identification of some simple nucleic acid analogues, called spongothymidine and spongouridine, from the Caribbean sponge Cryptotethya crypta over 50 years ago (Bergmann and Feeney, 1950, 1951; Bergmann and Burke, 1955). These (at the time) unprecedented structures led chemists to think about and then design structurally related analogues for testing against a range of human diseases, including cancer and AIDS. Several successful drugs have been introduced based upon this sponge isolate-inspired research, including the antileukemic agent ara-C (Upjohn, now Pharmacia), the antiviral compound ara-A (Burrows Wellcome, now Glaxo SmithKline), and the first effective treatment against AIDS, AZT. Interestingly, the wholly synthetic spongothymidine analogue ara-A was subsequently discovered to be a naturally occurring metabolite of the Mediterranean gorgonian Eunicella cavolini (Newman and Craig, 2004).

The discovery of potentially life-saving medicines from reef inhabitants raises profound issues of ecology and economy. Is it ethical to exploit, perhaps to the point of extinction, the producing organisms in order to save human lives? The fragile and deteriorating health of the tropical reefs has long been documented, and it is arguable that the large-scale harvesting of sessile organisms might further exacerbate this decline. Fortunately, the newer technologies of mariculture and, independently, genetic engineering, may provide a sustainable solution. As will be documented below, significant quantities of several anticancer chemotherapeutic lead compounds can be obtained from organisms raised through mariculture. An even more appealing but perhaps more distant solution might stem from the observation that many, and probably most, of the chemotherapeutic agents derived from marine species are actually synthesized by symbiotic microorganisms that live in the host sponge, coral, etc. Culturing these microorganisms in the laboratory, and/or to cloning the genes responsible for the biosynthesis of the compound of interest into well-behaved bacteria, are active and ongoing concerns. These efforts are at the forefront of marine natural products research, and they represent the best hope for satisfying the potentially conflicting goals of saving the reefs and improving human health. In order to set the stage for the role of reef flora and fauna in cancer chemotherapy, a brief and (overly) simplified description of the whole cancer chemotherapeutic enterprise follows.

Drug Discovery

The development of new anticancer medicines is an arduous task that requires the coordinated efforts of teams of scientists from all manner of chemical and biological sciences. The big issue that must be solved is selectivity; because cancer cells are just normal cells whose growth mechanisms have run amok, deliberately and precisely targeting them for destruction without harming the similar healthy cells remains a challenging task. Nevertheless, many exploitable differences distinguish cancer cells from their non-cancerous siblings, and these differences become the focal point of efforts to develop effective anticancer agents. Whereas a detailed discussion of the biochemical basis for this divergence is beyond the scope of this article, it is worth noting that differences in blood supply, oxygen content, DNA access and chemical signaling pathways, among many other factors, have been identified and exploited in this regard. Fortunately, this wide range of different behaviors/characteristics between cancerous and healthy cells ensures that there is more than one way to attack the problem of selective cytotoxicity (= cell killing), so many different types of molecules can be explored for their ability to act as cancer cytotoxins.

Any potential cancer chemotherapeutic candidate must undergo a rigorous series of tests prior to gaining FDA approval for commercialization. The process typically starts with the basic question of whether the molecule will, in fact, kill cancer cells. These types of assays are commonly performed in vitro against a panel of 60 different types of cancer cells held in a repository at the National Cancer Institute (NCI). In addition, some mechanisms by which molecules might kill cancer cells are indirect, so additional testing in whole animal and/or xenograft models may be conducted as well. Success at this level then leads to further in vitro testing of toxicity against normal cell lines, etc.

The results of preclinical trials with anticancer agents are commonly given as ED50 values, which is the effective dose that kills 50% of the cancer cells. These ED50 values typically are reported in concentration units: fractions of moles/liter (L), where 1 mole = 6 x 1023 molecules. The smaller the ED50, the lower the concentration of compound necessary to cause cancer cell death, and the more likely that the molecule will remain on track for further evaluation. An unofficial threshold below which compounds are considered active, and therefore candidates for further study, is low micromolar (mM, 1 mM = 10-6 moles/L, or about 1 part-per-million for a typical drug-sized molecule). If the ED50 > ~ 10 mM, then it is unlikely that the molecule will be selective enough for its biological target, compared to other possible interaction sites, to remain a viable chemotherapeutic candidate. As detailed further in this article, the anticancer molecules from the reef environment that have been selected for further development all have an ED50 in the nanomolar (nM, 1 nM = 10-9 moles/L, or about 1 part-per-billion for a typical drug-sized molecule) to picomolar (pM, 1 pM = 10-12 moles/L, or about 1 part-per-trillion for a typical drug-sized molecule) range.

A molecule becomes a candidate for testing in humans if it displays both toxicity against cancer cells and is tolerated by healthy cells/whole animals. Human testing is tightly regulated for ethical reasons and follows a three-phase protocol. Initially, Phase I tests are conducted. These tests involve treatment of a small number of healthy (paid) volunteers with the drug candidate in order to ascertain whether humans tolerate the compound. If no adverse effects are detected, then Phase II trials can commence. This part of the drug validation process recruits a small number of patients with different cancers that did not respond to other treatments. Overwhelming success is not expected, because these cancers are typically refractory and beyond conventional treatment. Nevertheless, any sign of improvement is encouraging, even if the cancer is not destroyed. Drug candidates that continue to show therapeutic potential at this point then enter Phase III trials, in which they are administered to a broad range of cancer patients. Dosing schedules, long-term tolerance and therapeutic efficacy are determined during these trials, which can be quite lengthy. Eventually, if the drug candidate survives these experimental challenges, the compiled data are presented to the FDA for evaluation. Approval from the FDA for commercial sale then leads to a new anticancer drug on the market. While these human tests are ongoing, important issues involving pharmacokinetics, drug delivery methods, allergic reactions, etc. are investigated as well. The FDA does not play a passive role in this testing process; rather, it closely monitors progress with the intent of "fast-tracking" to market any promising candidates. Some very thorny issues, such as placebo usage to validate the trials, arise as potentially life-saving drugs are subjected to these lengthy experiments, and many pressures come to bear on the process from medical practitioners, patients and the drug's developer, typically a large pharmaceutical firm.

The statistics of drug discovery are daunting:

  • Failure rate of all preclinical drug candidates: >> 99.9%
  • Failure rate of preclinical anticancer natural product candidates, through 1981: ~ 96% (Bhakuni, 2005) (natural product = a discrete chemical that is extracted from a living organism)
  • Failure rate of all Phase I drug candidates: ~ 30%
  • Failure rate of all Phase II drug candidates: ~ 50%
  • Failure rate of all Phase III drug candidates: ~ 50%
  • Failure after marketing: ~ 10% (Boreman, 2006)
  • It costs about $1.2 billion in current dollars to develop a new drug, from discovery to commercialization (Hileman, 2006).

These compelling numbers make it clear that a high premium is placed on discovering good lead compounds. During the period from 1981 - 2002, 79 new anticancer drugs were brought to market (Newman, 2003). Of these molecules, 30 were extracted from natural sources (or were derived from molecules extracted from natural sources), often guided by folklore medicine. In fact, the NCI maintains an ever-expanding repository of over 60,000 plant and marine organism samples available for testing, and about 700 new marine samples are added each year. None of the source organisms for these 79 drugs was of marine origin, reflecting an early bias toward exploring the more readily accessible terrestrial flora, as marine collection was, until recently, not very practical. One of the real success stories that has emerged from these efforts is the anticancer drug taxol (1 trade name: paclitaxel), originally isolated from the bark of Pacific yew trees, Figure 1. It took over 20 years to shepherd this compound through all of the isolation, structural/chemical work and biological testing necessary to gain FDA approval, but in 1993 it became available to cancer patients. Taxol is approved for use against ovarian, lung and breast cancers, and Kaposi's sarcoma. Since its release to the public, it remains the top-selling anticancer drug, with maximum annual sales of ~ $1.6 billion in 2000 and $0.9 billion in 2004.

Figure 1. Taxol (1) and its source, the pacific yew tree.

Throughout this article the chemical structures of the anticancer compounds under discussion will be provided in a pictorial representation that typically is used by organic chemists. The "language" of organic chemistry, like any language, has its own self-consistent rules of grammar, sentence structure, shortcuts and iconography. It is beyond the scope of this article to delve any more deeply into these details, but the take-home messages from these molecule depictions are (1) they all are complex with many atoms, and many connections (bonds) between atoms, and (2) they all are very different from one another. They are but a glimpse into the whole portfolio of potentially active drug candidates, and elucidating the relationship between the intimate details of their molecular structure and their observed anticancer activity occupies a good deal of pharmaceutical research. The premise behind that research is that if a set of "rules" that relate structure to function for any given compound can be identified, then that information might aid in the de novo design of new drugs for that disease, but perhaps with advantages not available to naturally derived compounds. It is this goal that drives much of the pharmaceutical industry.

Where will the next taxol come from? That is the pivotal question which commands the attention of thousands of pharmaceutical scientists, oncologists and medical researchers. The attractiveness of natural sources for anticancer medicines remains high for a variety of reasons, but the bottom line is a statistical argument: if all of the matter in the universe were converted to random, different and unique drug-like molecules, there still would not be enough molecules to guarantee that an active drug (for any disease) would be in hand -too many structural variables are involved. This sobering conclusion comes from a comparison of the estimated mass of the universe (~3 x 1055 gm) to the most commonly cited calculated number of conceivable drug-like molecular entities (>1060 different and discrete chemical structures that have the characteristics commonly found in drug molecules). So, the question arises, how can these infinitesimal odds for finding a drug be improved? If screening random molecules is futile, might any sources of molecules be inherently biased toward desirable biological activity? Many researchers in this area feel that the best bet lies with molecules derived from natural sources ("natural products"), because natural products' structures and chemistries have evolved over geological time to serve as effective partners for protein receptors, the key molecular-level event that determines a molecule's potential to act as a drug (Williams, 1989).

One starting point is simply observing organisms in their natural habitats in order to discern behaviors that might signal the production of (cyto)toxic materials. Immobile organisms (e.g., plants, sessile marine invertebrates) communicate via chemicals, and the messages that they send and receive involve all forms of behavior, from mating calls to defense against predation to attacking/subduing prey or competitors. Chemists screening for potential anticancer agents take special note of messages that are lethal to their recipients. If an organism has evolved an effective cytotoxin, presumably to use against another organism in its environment, could that molecule be co-opted to serve as a selectively lethal agent against cancer cells? These observations provide an enormous head start on the road to drug discovery.

The marine environment offers drug hunters some attractive features not shared by terrestrial locations. First and foremost is its species diversity. It has been estimated that between one million and two million different species of (mostly microbial) organisms live in the marine environment. Almost all of these species are concentrated in either the ~ 1% of fringe territory between sea and land where reefs abound, or near deep sea thermal vents (Simmons, 2005). Proximity fosters spatial competition, especially for living space among sessile invertebrates. That inevitability apparently has led to the development of sophisticated chemical arsenals in many of these organisms. The second feature of marine organisms that recommends them for drug prospecting is the generally high potency of their chemical agents. Unlike their terrestrial counterparts, marine organisms must overcome the enormous dilution factors involved when dispersing chemicals into the sea. These chemical agents must be effective at the very low concentrations that dilution by seawater imposes. Consequently, some of the most potent cytotoxins known have been found in extracts from marine organisms. Through 2004, approximately 16,000 discrete chemical compounds had been isolated and characterized from marine sources (Bhakuni, 2005), although only a fraction of these species have been subjected to detailed biological evaluation as chemotherapeutic agents for any disease.

At present, about 22 marine-derived natural products are in either Phase I, Phase II or Phase III clinical trials for anticancer efficacy (Newman, 2006). A description of four promising candidates follows, and in addition, mention is made of an interesting soft coral-derived preclinical candidate whose study has directly benefited from the marine ornamental (i.e., reef hobbyist) trade.

Ecteinascidin 743

Ecteinascidin 743 (2) was isolated from the tunicate, Ecteinascidia turbinata (often called a "sea squirt"), a species of soft-bodied filter feeder found in the Caribbean and Mediterranean Seas, Figure 2 (Cragg, 2005; see also Newman, 2006a). In what is to become a common theme in the discussion of producing organisms, further scrutiny of the tunicate revealed that, in fact, a symbiotic microorganism, Endoecteinascidia frumentensis, appeared to be the actual source of ecteinascidin 743.

Preliminary ecteinascidin 743 in vitro screening experiments against ovarian, breast and non-small cell lung cancer cell lines revealed an astonishing potency, down to the picomolar range, or about 0.7 parts-per-trillion! Follow-up Phase I trials identified tolerable dose regimens for application to human cancers, and both Phase II and Phase III trails currently are being pursued. In total, approximately 2000 cancer patients have been treated with ecteinascidin 743, and the most promising results have emerged from both ovarian cancer and soft tissue sarcoma (STS) studies. In one trial of ovarian cancer patients (overall five-year survival rate ~ 20%), 10 of 29 patients (35%) exhibited tumor shrinkage with no recurrence at the six-month mark. Soft tissue sarcomas are aggressive cancers with bleak long-term prognoses (overall five-year survival rate ~ 8%). Treating a group of 183 STS patients with ecteinascidin 743 led to the following promising responses: 14 experienced tumor shrinkage greater than 50%, 14 achieved tumor shrinkage of 25 - 50 %, and 66 exhibited tumor stabilization (neither growth nor shrinkage). These encouraging results place ecteinascidin 743 at the forefront of anticancer agents derived from marine organisms, and approval for commercialization by Ortho Biotech (Johnson & Johnson) is expected sometime in 2006. However, it would not be practical to harvest the producing organism for the drug, given the quantities necessary for broad treatment, as one ton of tunicates (about the weight of an American bison ("buffalo")) would yield only 1 gram of compound (about the weight of a packet of artificial sweetener). As an alternative, chemists have devised an industrial-scale synthesis of this complex molecular architecture starting from a readily available and structurally-related bacterial fermentation product called saframycin.

Figure 2. Ecteinascidin 743 (2) and its nominal source, the tunicate Ecteinascidia turbinata.

The biochemical mechanism by which ecteinascidin 743 selectively kills tumor cells is a subject of much active research, and that story is far from complete. It appears to react chemically with certain DNA segments, and through these interactions, disrupts the normal biochemical machinery of DNA reading and repair. The specific genes that ecteinascidin 743 attacks code for proteins that regulate several aspects of cell division, but the remaining cellular DNA does not appear to be otherwise affected. In addition, ecteinascidin 743 interferes with DNA repair mechanisms, another potentially lethal action. The basis for this fortuitous DNA preference remains unclear, but it can be exploited to terminate cancer cells with sufficient selectivity to qualify ecteinascidin 743 as a useful drug.


Auristatin (3), a wholly synthetic analogue of the naturally occurring marine isolate dolastatin 10 (4), differs from the natural material only by deletion of the green thiazole unit in 4 (Figure 3) (Cragg, 2005). Dolastatin 10 was originally isolated from the Indian Ocean sea hare, Dolabella auricularia, a common algae eater that is broadly available in the marine aquarium trade (Figure 3). Subsequent studies revealed that the sea hare does not actually make the dolastatins (over a dozen related species have been identified to date), but rather simply sequesters them from its diet, presumably to act as part of its defensive arsenal. The actual source of the dolastatins appears to be the cyanobacteria upon which Dolabella grazes (i.e., Symploca sp. VP642, Symploca hynoides and Lyngbya majuscule), and several of the dolastatins have been isolated from these primary sources. The amount of dolastatins recoverable from the sea hares is minuscule: about 10 milligrams (~ the weight of an uncooked grain of rice) of dolastatin 10 from 10,000 sea hares, and so total chemical synthesis, both of the natural products and of the more promising analogues such as auristatin, is employed to provide drugs for testing.

Figure 3. Auristatin (3), dolastatin 10 (4), and dolastatin 10's nominal source, the sea hare Dolabella auricularia.

Preliminary in vitro screens against various cancer cell lines revealed remarkably potent cytotoxicity for dolastatin 10, much like ecteinascidin 743, down at the picomolar level (~1 part-per-trillion), against ovarian cancer, non-small cell lung cancer and myeloid leukemia, among others. Followup toxicology and Phase II studies provided only disappointment, as it appeared that problems with the agent's overall toxicity and, as a consequence, its insignificant anti-tumor effects at tolerable doses, rendered it unsuitable for further development. However, the dolastatins' modular structure (a linear sequence of amino acids) facilitated the exploration of structural modifications that might preserve anticancer activity but suppress systemic cytotoxicity. One such analogue is auristatin. It displayed less in vitro potency than dolastatin 10, acting at about the 1 part-per-billion level against non-small cell lung cancer, but it did not carry the burden of systemic cytotoxicity that derailed the dolastatin 10 drug development effort. Phase I trials for auristatin have been completed, and this anticancer agent is currently in Phase II, with Phase III trials to start soon. Data in the public literature for auristatin are limited, but one report does indicate that 4 of 44 patients with non-small cell lung cancer experienced complete or partial responses upon exposure to this drug candidate.

The biochemical mechanism-of-action for auristatin and the dolastatins is quite different from that of ecteinascidin 743, as these Dolabella-derived agents do not act on a cell's DNA. Rather, they appear to interact with components of the cellular scaffolding that is required for successful cell division. This interaction disrupts the normal processes of cell division, and ultimately the cell dies. The details of these interactions are still under active investigation. The basis for cancer cell-over-healthy cell selectivity is not known, but it may be no more complex than the fact that cancer cells are continuously dividing and are therefore susceptible to interference with their division mechanism, whereas normal cells are mostly quiescent.


E7389 (5) is the common name given to a synthesized derivative of the sponge isolate halichondrin B (6) (Figure 4) (Cragg, 2005, and Newman, 2006b). E7389 exhibits an anticancer profile similar to that of the parent 6, but E7389's greatly simplified structure (the green half of halichondrin B has been deleted) renders it a far more attractive candidate for drug development. Halichondrin B and structurally related congeners were isolated from several species of sponges, including Halichondria okadai from the waters of Japan, an Axinella sp. from the western Pacific, Phakellia carteri from the eastern Indian Ocean and Lisodendoryx sp. from deep water off New Zealand's coast. The results of initial cytotoxicity screens generated enough excitement about halichondrin B's potential as an anticancer agent that a massive collection program was conducted. This effort yielded about 300 milligrams of 6 (about the weight of an aspirin tablet) from 2200 lbs. of Lissodendoryx (about the weight of a Toyota Spyder sports car) harvested around New Zealand. Later in these studies, it was discovered that this sponge could be aquacultured in less than 30 feet of water with good success, and with comparable amounts of halichondrin B present.

    Figure 4. E7389 (5), halichondrin B (6), and halichondrin B's nominal source, a sponge of the genus Lissodendoryx.

The whole relationship between marine sponges, potential pharmaceutical agents and the reefkeeping hobby deserves more comment. Sponges appear to be the real natural product factories of the marine environment in terms of the sheer volume and structural diversity of the natural products obtained. In reality, many recent studies have revealed that the sponges themselves likely contribute little chemistry to the assembly of these compounds; rather, the sponges are basically repositories for many species of symbiotic bacteria and other microflora that actually perform the biosynthesis of the isolated chemical species. In fact, the microfloral content of many sponges constitutes more than half the sponge's dry weight (Piel, 2004)! The observation that halichondrin B can be found in sponges from so many geographically disparate locations is consistent with the speculation that a microorganism living within the different sponges, and shared among them, is responsible for its biosynthesis. No tests of this hypothesis have appeared yet. In terms of the current state and future directions of marine natural products chemistry, sponges, or, more precisely, the microorganisms that cohabitate within sponges, appear to be the clear center of attention. Sponge collection can be a chancy endeavor, with issues of sustainability, identification and access (a political problem) looming large. As an alternative, the aquaculturing of sponges as a deliberate means to harvest their natural products' bounty is still in its infancy. It is in this area that reefkeeping hobbyists are poised to have a major impact. The argument can be made that the field of sponge husbandry resides currently where small-polyp stony coral husbandry stood 20 or so years ago. Some sponges are as colorful and articulated as the most coveted stony corals, but knowledge of their care and survivability in reef tanks remains underdeveloped (Shimek, 2005). If members of the reefkeeping hobby who are seeking a challenge turn their attention to identifying conditions under which various sponges can survive importation, propagation and life in a reef tank in general, then perhaps the major importers and marine ornamental sellers will start stocking and selling them in large numbers. In turn, the lessons gained in sponge husbandry could have a significant impact on their availability, especially of those that have been raised under controlled environments. These types of advances in sponge husbandry can only accelerate the search for sponge-derived natural products that may provide pharmaceutical leads. If you cultivate sponges, then the next blockbuster drug may be residing in your tank even as you read this!

Back to halichondrin: Sub-nanomolar (~ parts-per-billion) in vitro potency against a variety of cancer cell lines, including non-small cell lung cancer, marked halichondrin B as a candidate for clinical testing (Newman, 2004). However, a lack of sufficient material thwarted plans to pursue these studies further. Fortunately, at about the same time that the preliminary biological activity was documented, chemical synthesis efforts by Yoshito Kishi at Harvard University led to the introduction of several halichondrin B analogues, one of which, labeled E7389, showed very promising activity. Sub-picomolar (~ parts-per-trillion) in vitro cytotoxicity against non-small cell lung cancer and low-nanomolar efficacy against a colon cancer cell line suggested that truncating the halichondrin B molecule (cf. 5 vs. 6) did not attenuate its anticancer properties. Sufficient quantities of 5 were available through chemical synthesis to continue into clinical trials, and Phase I results demonstrated good tolerance for this species. Phase II trials are currently ongoing as a joint venture between the National Cancer Institute and Eisai Co., Ltd. for both breast and lung cancer (Newman, 2006a), but results have not yet been reported in the open literature.

The biochemical mechanism by which halichondrin B and, presumably, E7389 contributes to cancer cell death has been studied in detail (Cragg, 2005). The evidence accumulated so far points to a scenario related to that described for auristatin whereby 6 (or 5) selectively binds to the components that make up the intracellular scaffolding erected during cell division, and this binding disrupts the scaffold's assembly process and hence the normal course of cell division. The (rapidly dividing) cells so challenged cannot cope with the disruption and die.


Bryostatin 1 (7) is representative of a family of 20 structurally related isolates from the bryozoan (Shimek, 2003) Bugula neritina (Figure 5) (Cragg, 2005). Bryostatins were among the first marine isolates to demonstrate significant anticancer activity, and this family of compounds has been under active study for over 30 years. Their promising initial responses in early anticancer screens led to large-scale collections to compensate for the exceedingly low amount of material that could be culled from each organism (< 10 milligrams, at best, from a kilogram of B. neritina). For example, 28,600 pounds (~ the weight of the M113 armored personnel carrier) of Bugula neritina were collected and processed to yield a total of 18 grams (~ one rounded tablespoon of sugar) of bryostatin 1 - enough for clinical trials to commence. This level of collection was not sustainable, so the NCI sponsored aquaculturing efforts that led to successes for both in-sea (mariculture) and on-land (aquaculture) cultivation of this bryozoan. As with the previously described cases, the wide geographical spread of bryostatin-producing B. neritina and the common observation that many colonies yield no bryostatin led researchers to speculate that a commensal microorganism, and not the bryozoan itself, was responsible for the production of the bryostatins. Subsequent direct probing of this question led to the discovery that a symbiotic organism, named Candidatus Endobugula neritina, actually biosynthesizes the bryostatins. This observation bears some significance to the question of large-scale bryostatin manufacture should it become a widely used anticancer drug. At present, it is quite difficult to identify conditions that would permit cultivation and harvesting of whole marine invertebrates such as Bugula neritina on a scale commensurate with commercial needs. However, using microorganisms as chemical factories has had a long and successful history in the pharmaceutical industry. Therefore, either culturing the producing microbe Candidatus Endobugula neritina itself, or transferring its bryostatin-producing gene cluster into a well-behaved surrogate microbe, may become viable options for the commercial manufacture of bryostatin 1.

Figure 5. Bryostatin 1 (7), and its nominal source, the bryozoan Bugula neritina.

The preliminary preclinical in vitro data for bryostatin 1 were very promising, and the availability of the material as described above paved the way for clinical trials. Over 80 human clinical trials have been conducted to date, and the upshot of these studies is that bryostatin 1 is not a very effective anticancer agent when used on its own. However, Phase 1 and Phase II trials that tested bryostatin 1 in conjunction with another established anticancer agent such as taxol (1) yielded much more promising findings. For example, 7 of 11 non-small cell lung cancer patients responded favorably to this combination therapy, whereas in another independent trial, treatment of chronic lymphocytic leukemia and non-Hodgkin's lymphoma patients with bryostatin 1 and the anticancer drug fludarabine resulted in 23 objective responses from a 53-patient cohort. Currently, Phase II trials for bryostatin 1, in combination with other established anticancer drugs, are ongoing.

Bryostatin's biological mechanism-of-action is yet again different from those discussed with the other anticancer compounds. It selectively binds to, and thereby inhibits the function of, a critical cell growth enzyme called Protein Kinase C-alpha (PKC-a). The precise mechanism by which the down-regulation of PKC-a activity leads to cancer cell death remains to be unraveled.


Corals, especially soft-bodied corals, are legitimate sources of many secondary metabolites that display intriguing biological activities. Unfortunately, the subset of coral metabolites that exhibit significant anticancer activity on the order of the compounds described above is minimal at present. Eleutherobin (8) (Figure 6) is one of the more promising candidates from this small pool. It was originally isolated from the octocoral Eleutherobia sp. in Australian waters, and its preliminary anticancer screens were encouraging. Further collection was disallowed for political reasons, so the problem languished until the encrusting Caribbean gorgonian Erythropodium caribaeorum was found to provide eleutherobin at the 10 milligram-per-kilogram level. Subsequently, material was also made available through total chemical synthesis. This story took an interesting turn when it was recognized that E. caribaeorum was "a staple of the decorative seawater aquarium industry" (Taglialatela-Scafati, 2002). The E. caribaeorum cultured in reef tanks did, in fact, produce eleutherobin at levels commensurate with those from the wild coral. In this instance, aquarists really did have a potential anticancer drug within their domain! Whether eleutherobin is produced by the coral itself or by a symbiotic microorganism has not yet been addressed.

Figure 6. Eleutherobin (8) and its producing organism, the encrusting gorgonian Erythropodium caribaeorum.

The initial preclinical screens revealed in vitro activity at the 10 nM (~15 parts-per-billion) level against several cancer cell lines (Lindel, 1997). However, no further in vivo studies have been described in the open literature. One of the reasons this compound in particular has generated, and continues to generate, much interest is that it appears to exert its cytotoxicity through the same molecular mechanism used by the clinically successful anticancer agent taxol (1). Eleutherobin binds (competitively with taxol) at the cellular scaffolding that is assembled during division and disrupts the whole cell division process, leading to cellular death. A related mechanism was described earlier for E7389, although in the case of taxol and eleutherobin, drug binding prevents the scaffold from disassembling at the appropriate point in the cell division sequence. With E7389, on the other hand, the assembly process itself is interrupted.


In summary, very promising anticancer activity has been documented for several naturally occurring compounds (or their chemically synthesized analogues) derived from organisms that inhabit the tropical reefs. Several of these compounds have advanced to human trials, and the results remain encouraging. Should any of these compounds move to commercialization, it is unclear whether large-scale production hurdles can be overcome. Further expansion of the knowledge base for aquaculturing the nominal producing organisms can only help this effort, and it is in this area that reef hobbyists can conceivably have a favorable impact. In addition, the near universal conclusion that the natural products of chemotherapeutic interest are actually biosynthesized by microbial symbionts raises intriguing questions about the relationship between the "container" organism and its environment. How/why does it recruit its microflora, and how/why are the symbionts stimulated to produce the compounds of interest? Growing these sessile invertebrates under varying, but controlled, conditions might be one avenue by which some insight can be gained on these points. Again, these are questions that could benefit from the input of the reef aquarium hobby.

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