1 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; 2 Pharmamar, SA, Madrid; 3 Hospital Universitario Doce de Octubre, Medical Oncology Department, Madrid, Spain
Received 3 April 2003; revised 30 April 2003; accepted 3 June 2003
Key words: aplidine, bryostatin, cancer, dolastatin, ET-743, marine
Introduction
Since ancient times, nature has been an important source of medicines: a fact illustrated by the large number of natural products currently in use in medical practice. These products have been identified and developed through folklore knowledge of the medicinal properties of plants, animal extracts and minerals. Microorganisms are also a prolific source of novel agents. They have yielded some of the most important pharmaceutical products, such as the antibiotics, penicillin and aminoglycosides, which represent landmarks in the history of medicine.
Almost 60% of drugs approved for cancer treatment are of natural origin. Vincristine, irinotecan, etoposide, taxanes and camptothecines are all examples of plant-derived compounds. Dactinomicine, anthracyclines, mitomycin and bleomycin are anticancer agents derived from microbial sources [1].
Although marine compounds are under-represented in current pharmacopoeia, it is anticipated that the aquatic environment will become an invaluable source of novel compounds in the future. The marine ecosystem represents 95% of the biosphere, and all except one of the 33 animal phyla are represented in aquatic environments [2]. Most sessile marine invertebrates contain a primitive immune system and produce toxic chemicals as a form of defense. Many of these products act as regulators of specific biological functions. Some of them have pharmacological activity due to their specific interactions with receptors and enzymes. Because these substances become immediately diluted by large volumes of seawater, they need to be highly potent on a molar basis, and also have to retain a relatively low solubility [3].
The development of marine compounds as therapeutic agents is still in its infancy due to the lack of an analogous ethno-medical history as compared with terrestrial habitats, together with the relative technical difficulties in collecting marine organisms. Over the last few decades significant efforts have been made, by both pharmaceutical companies and academic institutions, to isolate and identify new marine-derived, natural products. These initiatives have been accompanied by funding support from governmental agencies. Specific programs directed towards the collection and characterization of marine natural products and evaluation of their biological activity have been established [4]. This systematic investigation of marine environments is reflected in the large number of novel compounds reported in the literature over the past decade [5]. Some of these agents have entered preclinical and clinical trials, and it may be expected that this number will increase in the future. This article will review some of the technical strategies that are being employed to collect and identify novel marine products with potential antitumoral properties, and will also provide a summary of the available clinical trial information of agents with promising activity.
Sources, collection, screening and supply of marine anticancer agents
The isolation of new anticancer agents derived from marine sources has been based on the collection of marine macroorganisms, such as algae, sponges, tunicates and bryozoans (Table 1). The progress in scuba-diving techniques and deep-water collection instruments has been pivotal in the collection programs implemented by academic and pharmaceutical groups. While 40 years ago, the collection of marine organisms was limited to those found in intertidal and shallow subtidal environments, the advent of scuba diving has enabled investigators to explore shallow subtidal environments to a depth of 40 m for 15 min with no decompression stops. Depths of up to 200 m are now accessible using closed-circuit computerized mixed gas rebreathers [6]. Deep-water collections can be made by dredging or trawling, and by the use of manned and unmanned submersibles, or remotely operated vehicles (ROVs). Although dredging and trawling are cost-effective methods, they suffer from several disadvantages such as: the limitations on taking photographs; the inability to collect organisms that grow in niches difficult to access; the environmental damage; and the non-selective nature of the sampling. On the other hand, the high cost of ROVs precludes their extensive use in routine collection operations.
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The expected limitations in the supply of marine macroorganisms, as well as the realization that there is a tremendous biological reserve of marine microorganisms, has resulted in increasing interest in the exploitation of the latter in the search for new chemical entities. Several features make marine microorganisms an attractive source when searching for pharmaceutical compounds. The complex microbiological adaptations needed to grow in the ocean are completely different from those of land-based organisms. Nutrients are scarce and microbial symbiosis is common. Furthermore, competition for resources at the microscopic level is intense. This has resulted in a variety of chemical substances produced by microorganisms for their own defense, a range of compounds that has the potential to be a major source of new drugs [9].
Although largely still unexplored, the complexities of marine microbial growth and cultivation can be solved. It has been demonstrated that marine bacteria are uniquely adapted to the saline environment. They can be selectively isolated and mass cultured in media that uses natural nutrients and growth factors derived from marine sources. In culture, marine microbes have the potential to provide large quantities of natural products. This approach, however, also has its own caveats, which include the difficulties in isolating and culturing marine microbes, the lack of stable production and the fact that the majority of marine microbes are still unknown [10]. New programs are emerging to exploit marine microorganisms and the results are promising. These studies have demonstrated the capability of marine bacteria to produce compounds not available from terrestrial sources. They also have led to an increase in knowledge of the many bioactive compounds produced by these microorganisms [11, 12].
Another major advance in the study of marine compounds has been the change in the nature of the studies performed with the isolated products. Nowadays, the compounds are systematically tested for relevant biomedical properties including antiproliferative effects. The major screening system is carried out by the National Cancer Institute of the USA. This system looks for selective activity in a panel of 60 human tumor cell lines [4]. Alternative strategies employ a more mechanistic-based approach, with systems designed to screen for substances with inhibitory properties towards specific enzymatic reactions. This type of assay offers specificity and can focus on a number of discrete drug targets. The potentially confounding effects of toxic components are also avoided, permitting the screening of crude extracts from marine organisms [13]. This type of screening can also be adapted to high-throughput screening, which offers the potential to readily screen hundreds of thousands of extracts in parallel against numerous therapeutic targets. Taken together these data show that the study of marine anticancer compounds is yielding not only the discovery and development of new drugs, but also the identification of new molecular targets for therapeutic intervention.
Marine-derived compounds in clinical development
Bryostatin-1
Bryostatin-1 is a macrocyclic lactone isolated from the marine invertebrate Bugula neritine [14]. Bryostatin-1 is a potent activator of protein kinase C (PKC), and has antagonistic effects on tumor-promoting phorbol esters. Bryostatin-1 also has immunomodulatory functions, induces the differentiation of myeloid and lymphoid cell lines, platelet aggregation and promotes hematopoiesis [15]. Furthermore, bryostatin-1 inhibits the production of components of the matrix metalloproteinases family, down-regulates multidrug-resistance 1 (MDR1) gene expression, modulates bcl-2 and p53 gene expression and induces apoptosis [16, 17]. It has demonstrated significant antitumor activity in preclinical models against a wide spectrum of cell lines [18] and, in addition, has been shown to enhance the antitumor effects of various chemotherapeutic agents, such as cytosine arabinoside, gemcitabine, vincristine, cisplatin and paclitaxel [19].
Based on its novel mechanism of action and its potency, bryostatin-1 entered phase I trials using different infusion schedules [2025]. None of these studies has thus far characterized the human pharmacokinetics of the agent due to the lack of a sensitive and reliable assay to determine plasma levels of bryostatin-1. Data regarding PKC modulation, a potential biological surrogate, have not been consistent. Thus, the optimal dose and schedule of administration has not yet been determined. The dose-limiting toxicity (DLT) of bryostatin-1 has consistently been severe myalgias, which were dose-related, cumulative and independent of the schedule of administration [2025]. The pathogenesis of this phenomenon is uncertain and there are not consistent data to support an inflammatory or myolitic origin [21, 24]. The agent also produced hematological toxicity. Patients treated at doses over the maximum tolerated dose (MTD) had significant decrement in platelets, leukocytes and, particularly, hemoglobin in the immediate post-treatment period. They typically recovered to baseline shortly after treatment, with the exception of hemoglobina decrement which persisted 12 weeks after dosing [22, 23]. Biological studies did not observe any effects of the agent on bone marrow progenitors. This observation suggests that the hematological effects were due to peripheral blood cells pooling, rather than a decrease in production.
Objective responses were observed in phase I studies of bryostatin-1 in some solid tumors [24]. Based on these results, a large number of phase II studies of bryostatin-1 using various infusion regimens were conducted in both solid and hematological malignancies [20, 2628]. To date, phase II studies on bryostatin-1 have failed to demonstrate any clinical meaningful activity. The toxicity profile was quite favorable with myalgias being the most common side-effect reported. These data, together with the synergy observed between bryostatin-1 and traditional cytotoxic drugs in vitro, suggested a potential role of bryostatin-1 as a modifier to traditional chemotherapy. Several phase I studies of bryostatin-1 in combination with cytotoxic agents have been conducted [2935]. Myalgias have been the most frequent side-effect in combination regimens. Other reported toxicities appeared to be related to the cytotoxic drugs rather than bryostatin-1. The initial reports of phase II studies of bryostatin-1 in combination regimens are disappointing. One study reported some activity suggesting synergy [36], while others have failed to find activity [3739].
In summary, despite the promising results in preclinical and early clinical studies with bryostatin-1, phase II studies have failed to show a significant benefit as a single agent. The reasons for this lack of efficacy are unclear, but might be related to pharmacological factors. Additional studies to improve the understanding of bryostatin-1 pharmacokinetics and pharmacodynamic effects in tumor tissues will aid in the further development of this agent.
Didemnins
The didemnins are a family of cyclic depsipeptides obtained from the Caribbean tunicate Trididemnun solidum [40]. Didemnin B (DB) was the most potent didemnin in the antitumor screening system that was selected for clinical development. DB inhibits the synthesis of RNA, DNA and proteins [40]. The agent demonstrated antitumoral activity against a variety of tumor models. The substantial evidence of activity in preclinical models with dose-dependent and tolerable toxicity profiles provided the impetus for phase I clinical trials, making DB the first marine natural product to be evaluated in clinical trials. The initial phase I trials of DB evaluated different schedules of administration [4144]. The toxicity profile of DB was quite similar across the trials, with dose-dependent nausea and vomiting being the most commonly reported side-effects. Phase II trials using DB at the recommended doses were associated with poor efficacy, while trials using more aggressive regimens resulted in higher levels of toxicity, including cardiotoxicity [4547]. These findings brought about the cessation of DBs clinical development.
Aplidine (dehydrodidemnin B) is a second-generation didemnin that was isolated from the Mediterranean tunicate, Aplidium albicans [48]. Aplidine interferes with the synthesis of DNA and proteins and induces G1G2 cell cycle arrest [49]. Furthermore, aplidine possesses a unique and differential mechanism of cytotoxicity which involves the inhibition of ornithine descarboxylase, an enzyme that is critical in the process of tumor formation and growth [49]. Recent data also indicate that aplidine inhibits the expression of the vascular endothelial growth factor gene, having antiangiogenic effects [50].
In preclinical studies, aplidine was more active than DB and displayed substantial activity against a variety of solid tumor models, including tumors noted to be resistant to DB [51]. On the basis of its preclinical activity, aplidine entered phase I clinical trials, in patients with solid tumors and lymphomas, utilizing different schedules of administration (Table 2) [5256]. Treatment with aplidine has generally been well tolerated, with the most common adverse events being asthenia, nausea, vomiting and transient transaminitis. Hypersensitivity reactions have also been reported. The agent does not induce hematological toxicity, mucositis or alopecia. The occurrence of neuromuscular toxicity with the elevation of creatine kinase levels has been dose-limiting in three of these studies [5456]. Selected biopsies of affected muscles revealed muscular atrophy and loss of thick myosin filaments. Interestingly, the use of L-carnitine appears to prevent and ameliorate muscular toxicity [55]. Aplidine has shown some antitumor activity in phase I trials [54, 55], and is currently under active phase II development in solid tumors. Recent translational studies also indicate in vitro activity in acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) [57].
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The complexity and low yield of chemical synthesis of dolastatins, together with their poor water solubility, have been significant obstacles to broad clinical evaluation. These facts also have motivated the development of analog compounds. LU103793 is a stable and water soluble analog of dolastatin 15 that has shown prominent activity against a broad range of tumors [67]. LU103793 has been evaluated in five phase I clinical trials with different schedules of administration (Table 3) [6872]. The side-effects of LU103793 depend on the schedule of administration. Cardiac toxicity consisting of hypertension and acute myocardial infarction in the pretreatment period was the DLT in studies in which the drug was given either as a rapid intravenous infusion every 3 weeks or on a weekly administration schedule. However, myelosuppression, particularly neutropenia, was the most frequent dose-limiting effect on schedules that involved 24-h infusion weekly and short infusion daily schemes.
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Ectenaisdin 743 (ET-743)
Ectenaisdins (Ets) are tetrahydroisoquinolone alkaloids isolated from Ectenaiscidia turbinata, a tunicate that grows on mangrove roots throughout the Caribbean sea. ET-743 was selected for clinical development because of its cytotoxic activity and its relative abundance within the tunicate compared with others Ets [77]. ET-743 alters the interaction of DNA with transcription factors and other proteins [78]. It also produces a delay in cell progression from G1 to G2 phase, inhibition of DNA synthesis and cell cycle arrest in G2 phase, that eventually results in p53-independent apoptosis [79]. ET-743 inhibits translational activation of the MDR1 gene. ET-743 also interacts with other molecular targets such as the microtubule network [79]. In the NCI human cell line screen, ET-743 was particularly active against cancer cell lines derived from melanoma and carcinomas of the colon, breast, lung, brain and ovary [80]. Cures were observed in a wide variety of solid tumor models [81].
Based on its novel mechanism of action, high potency and positive therapeutic index in preclinical studies, ET-743 entered phase I clinical trials (Table 4) [8284]. In these trials, ET-743 was generally well tolerated with non-cumulative hematological and hepatic toxicities being the most commonly reported adverse events. The DLTs in all the phase I studies, except in the 72-h infusion schedule, were hematological toxicity and fatigue. Dose-related asymptomatic and reversible transaminitis was prevalent in phase I trials, but it was not a treatment-limiting toxicity. Grade 12 elevation of alkaline phosphatase (ALP) level has been reported in almost 50% of patients receiving treatment. Nausea, vomiting and asthenia were also reported but seldom severe. The most severe adverse events associated with ET-743 at the recommended phase II dose included long-lasting pancytopenia, renal and hepatic failure, and rhabdomyolysis. Across the different phase I trials evidence of antitumor activity was noted in patients with advanced and heavily pretreated ovarian, breast, and mesenchimal tumors. In some cases, the responses were long lasting in heavily pretreated patients.
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Selected new natural marine products with promising applications in oncology
Over the last few years, a large number of novel compounds have been identified and characterized. Several of these agents are in the process of entering clinical trials (Table 5). Some of the newest and more interesting agents derived from marine sources have a common mechanism of action, which involves the disruption of microtubular function. The most relevant examples within this category include the halichondrins, spongistatin, curacin, laulimalide and discodermolide [93]. The majority of these compounds bind the vica alkaloids (halicondrins, spongistatin) or the colchicine-binding domain (curacin) inhibiting the polymerization of microtubules. Halichondrin B, a macrocyclic polyether isolated from the sponge Halichondria okadai, was selected for preclinical development by the NCI. Analogs derived from the total synthesis of halichondrin B have shown activity superior to the natural product. One of these, NSC707389, is now being tested in the clinical setting [94].
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Other compounds of marine origin with promising activity include thiocoraline and kahalalide F. Thiocoraline is a novel bioactive depsipeptide isolated from Micromonospora marine, a marine microorganism located in the Mozambique Strait that inhibits RNA synthesis. Thiocoraline demonstrated potent and selective cytotoxic effects against lung and colon cancer cell lines as well as melanoma. Interestingly, this drug exerted preferential antiproliferative effects in colon cancer cell lines with defective p53 systems [95].
Thiocoraline represents a model of an anticancer agent acquired from marine microorganism and illustrates how the problems of drug supply can be overcome by artificial culture. Kahalalide F (KF) is a dessipeptide isolated from the mollusk Elysia rubefescens from Hawaii. KF induces cytotoxicity and blocks the cell cycle in G1 phase in a p53-independent manner. In vitro, KF displayed activity against solid tumors with an interesting pattern of selectivity in prostate cancer cell lines. In addition, extensive in vivo work demonstrated that the agent had activity in breast and colon cancer. The intracellular target of kahalalide seems to be the lysosomas where the agent interferes with the organization of the organella. These results suggest that cells containing high lysosomal activity, such as prostate cancer cells, would be a suitable tumor type to explore the activity of this agent [96]. In phase I clinical trials of KF evaluating a continuous weekly infusion schedule in patients with advanced solid tumors, the DLT has been early-onset transaminitis. Other reported toxicities have been fatigue, headache, vomiting and pruritus limited to the hands [97, 98]. Hematological toxicities have not been observed. Additional studies of this agent are planned.
Conclusions
The marine ecosystem is an enormously rich source of natural products with potential therapeutic usefulness in oncology. Over the past few years, >2000 new compounds from various marine sources have been described and characterized. The significant expansion of this field is due to improvements in the technologies involved in sample collection, the closer collaboration among scientists from a variety of disciplines worldwide and the support of governmental institutions as well as pharmaceutical companies. Some of these compounds have been tested in clinical trials and are in advanced stages of development, while others are still in preclinical stages. These agents are characterized as having unique mechanisms of action and pharmacological properties. They represent potential candidates for the treatment of malignant disease, either to be used as single agents, or as part of a combination regimen. More recently, the focus of attention has shifted towards microscopic organisms. Microorganisms are abundant in the marine ecosystem and biologically rich. In fact, it is believed that a number of metabolites obtained from some macroorganisms may be produced by their associated microorganisms. In addition, microorganisms can be adapted to artificial culture conditions thus avoiding problems of collection and supply.
In summary, the marine world has become an important source of anticancer agents with novel mechanisms of action. The continuation of preclinical and clinical studies is required in order to assess the exact role of this new class of compound in the treatment of patients with cancer. It is anticipated that marine-derived anticancer drugs will represent valuable tools in the oncological armamentarium.
Footnotes
+ Correspondence to: Dr Maria L. Amador, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Room 162A, 1650 Orleans Street, Baltimore, MD 21231, USA. Tel: +1-410-502-5835; Fax: +1-410-614-9006; E-mail mamador2{at}jhmi.edu
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