Marine-derived anticancer agents

Review

Marine organisms as a source of new anticancer agents

Gilberto Schwartsmann, Adriana Brondani da Rocha, Roberto GS Berlinck and Jose Jimeno

Various active anticancer agents are derived from plants and terrestrial microorganisms. The isolation of C-nucleosides from the Caribbean sponge, Cryptotheca crypta, four decades ago, provided the basis for the synthesis of cytarabine, the first marinederived anticancer agent to be developed for clinical use. Cytarabine is currently used in the routine treatment of patients with leukaemia and lymphoma. Gemcitabine, one of its fluorinated derivatives, has also been approved for use in patients with pancreatic, breast, bladder, and non-small-cell lung cancer. Over the past decade, several new experimental anticancer agents derived from marine sources have entered preclinical and clinical trials. This field has expanded significantly as a result of improvements in the technology of deep-sea collection, extraction, and large-scale production through aquaculture and synthesis. In this paper, examples of marine-derived experimental agents that are currently undergoing preclinical and early clinical evaluation are briefly discussed. A summary of the available information on the results of phase I and II trials of agents such as aplidine, ecteinascidin-734 (ET-734), dolastatin 10 and bryostatin 1 is also presented.
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Figure 1. The Mediterranean tunicate Aplidium albicans.

Over the past few years, about 3000 new compounds from various marine sources (Figure 1) have been described and some have entered clinical trials.6 This activity has been largely due to improvements in the technologies involved in deep-sea sample collection and large-scale drug production through aquaculture and drug synthesis7 which took place in the 1980s. These developments suggest that, in the future, the oceans will become an important source of novel chemical classes not found in the terrestrial environment (Table 2).8,9

Since ancient times, we have relied on nature for our basic needs food, protection, clothing, transport and pharmaceuticals.1,2 The medical armamentarium includes many examples of important agents that were first isolated from plants and microorganisms and that are now in routine clinical use. In the field of anticancer therapy, many active cytotoxic agents were originally developed from natural sources (Table 1).2,3 Until recently, the only major contribution to anticancer therapy from the sea was the synthetic nucleoside analogue cytarabine, which is commonly used in the treatment of leukaemia and lymphoma. The development of cytarabine was initially inspired by a series of C-nucleoside-derived compounds isolated from the Caribbean sponge Cryptotheca crypta. More recently, a fluorinated derivative of cytarabine, gemcitabine, has shown significant activity in patients with solid tumours, such as pancreatic, breast, bladder, and non-small-cell lung cancer.4,5 The oceans cover about 70% of the earths surface, and the marine environment includes tremendous biodiversity; all but two of the 28 major animal phyla are represented.
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New agents undergoing clinical evaluation

Tunicate derivatives

Of the marine-derived compounds that have entered phase I and II trials as antitumour agents, didemnin B, aplidine, and ET-743 are derived from tunicates.9 Didemnin B is a cyclic depsipeptide isolated from the tunicate Trididemnum solidum. It has shown impressive antitumour activity in human tumour models in vitro as well as in tumours growing in athymic mice.10 In initial clinical trials, patients with various solid tumours or non-Hodgkin lymphoma
GS is at the South-American Office for Anticancer Drug Development (SOAD), Comprehensive Cancer Center (CINCAN), The Lutheran University (ULBRA), Brazil; AbdR is doing a Postgraduate Course in Medicine (HCPA-UFRGS), Porto Alegre, Brazil; RGSB is in the Department of Chemistry, University of So Carlos (USP), Brazil; JJ is at PharmaMar SA R&D, Tres Cantos, Madrid, Spain. Correspondence: Professor G Schwartsmann, MD, PhD, Postgraduate Course in Medicine (UFRGS), Porto Alegre, Brazil Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos 2350, 3 Leste Porto Alegre RS Brazil, CEP 90000. Tel: +55 51 3168012. Fax: +55 51 3317143. Email: fsoad@hcpa.ufrgs.br/gschwart.ez@terra.com.br

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Review
Table 1. Cytotoxic agents developed from natural sources Agent Etoposide Oncological use Testicular tumours, small-cell lung cancer Natural source Podophyllum peltatum, Podophyllum Cytarabine Vinblastine Leukaemias and nonHodgkin lymphomas emodi Cryptotheca crypta

Marine-derived anticancer agents

Table 2. Marine-derived experimental anticancer agents Organism Trididemnum soldium Bugula neritina Group Tunicate Bryozoan Metabolite Didemnin B Bryostatin 1 Location Caribbean Gulf of California Okinawa Indian Ocean Phillipines Mediterranean Japan Hawaii Thailand Mozambique Strait Brazil

Ecteinascidia turbinata Tunicate Halichondria okadai Dolabella auricularia Portieria hornemannii Aplidium albicans Aplysia kurodai Elysia rubefescens Mycale sp. Micromonospora marina Ascidian didemnum granulatum Sponge Sea hare Red alga Tunicate Sea hare Mollusc Sponge Actinomycete Tunicate

Ecteinascidin-743 Caribbean Halichondrin B Dolastatin 10 Halomon Aplidine Aplyronine A Kahalalide F Mycaperoxide B Thiocoraline Granulatimide

Hodgkins disease, Catharanthus non-Hodgkin roseus lymphoma, germ-cell tumours, Kaposis sarcoma and breast cancer Acute leukaemia, Hodgkins disease, non-Hodgkin lymphoma, rhabdomyosarcoma, Wilms tumour Catharanthus roseus

Vincristine

Gemcitabine Vinorelbine Paclitaxel Docetaxel

Pancreatic, bladder, breast Cryptotheca and non-small-cell lung cancer crypta Activity in breast and nonsmall-cell lung cancer Ovarian, breast, lung cancer, and others Ovarian, breast, and lung cancers by age 70 Catharanthus roseus Taxus brevifolia Taxus baccata

were given a short intravenous infusion of didemnin B every 3 weeks, and antitumour effects were observed. However, severe neuromuscular and cardiotoxic effects led to the discontinuation of clinical trials.11,12 Another depsipeptide, dehydrodidemnin B, was subsequently isolated from the Mediterranean tunicate, Aplidium albicans (Figure 1) and later called aplidine. The preclinical findings for aplidine suggested potentially high anticancer activity against various different, rapidly proliferating tumour types, as a result of interference with cell-cycle progression at G1.13 Aplidine appears to be more active than didemnin B in preclinical models and so far has not shown evidence of life-threatening neuromuscular toxicity. Because aplidine appears to have higher antitumour activity in preclinical models after longer drug exposure, phase I trials were initiated at various drug schedules, ie 1 h, 3 h, 24 h and 72 h intravenous infusions. Notably, antitumour activity was observed in patients with advanced solid tumours, such as renal-cell carcinoma,

malignant melanoma, tumours of neuroendocrine origin, and medullary carcinoma of the thyroid.1416 The main toxic effects observed so far have been nausea and vomiting, myalgia, transient disturbance of liver function, and local irritation at the injection site. Muscular toxicity was circumvented by the concomitant administration of L-carnitine (E Raymond, unpublished). Aplidine will start phase II trials in various solid tumours in the near future. The ecteinascidins are derived from the Caribbean tunicate Ecteinascidia turbinata (Figure 2) and also show significant antitumour activity in both murine and human tumour cell lines.17 Of the many ecteinascidins that have been isolated, ET-743 was selected for clinical trials (Figure 3). It is a tetrahydroisoquinoline alkaloid that acts by selective alkylation of guanine residues in the DNA minor groove.18 It therefore differs from the other DNAalkylating agents so far introduced in the clinic. It also interacts with nuclear proteins.19 The main drug-induced toxic effects of ET-743 in early clinical trials were pancytopenia, fatigue, emesis and transaminitis. Local toxicity was also observed in patients who received short-term intravenous administration. There were objective and long-lasting tumour responses in patients with advanced resistant mesenchymal tumours, breast cancer, melanoma and ovarian cancer included in phase I clinical trials of ET-743.20,21 Initial results from pilot phase II trials for ET-743 confirm its therapeutic potential in various soft tissue sarcomas and breast cancer. 2226
Dolastatins

Figure 2. The tunicate Ecteinascidia turbinata.

The dolastatins are cytotoxic cyclic and linear peptides derived from the sea hare, Dolabella auricularia (Figure 4), a mollusc found in the Indian Ocean. Dolastatins 10 and 15 are small peptides; dolastatin 10 was selected for clinical trials because of its more favourable preclinical profile.27 It inhibits microtubule assembly, causing cells to accumulate in metaphase28,29 and is extremely potent in vitro. Dolastatin 10 caused bone-marrow toxicity in initial clinical trials, as well as local irritation at the injection site and mild peripheral neuropathy. Phase I and II trials involved
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Review
algae (cyanobacteria).43 Depsipeptide (NSC 630176) is a bicyclic peptide isolated from a strain of Chromobacterium violaceum. It decreases mRNA expression of the c-MYC oncogene and inhibits the growth of Ha-RAS-transformed NIH-3T3 cell line, RAS-1, causing cell-cycle arrest at G0G1.44 It acts as an inhibitor of a histone deacetylase.45 Depsipeptide showed cytotoxic activity in various human solid-tumour cell lines in vitro and also in athymic mice.46 Phase I trials of depsipeptide will begin soon.

MeO HO OAc MeO N O O O O MeO NH HO

Figure 3. Chemical structure of ET-743.

OH

Me

OH S

Other compounds in preclinical development

New classes of anticancer drugs isolated from marine organisms in different parts of the world show cytotoxic activity in a variety of preclinical models. Discodermolide, a metabolite of the deep-sea sponge Discodermia dissolute collected in the waters of the Bahamas, induces microtubule stabilisation.47,48 Halichondrin B was initially purified from the sponge Halichondria okadai in Japan and has shown in vivo activity in melanoma and leukaemia models. It can also be obtained from the deep-water sponge Lissodendoryx, which is found in New Zealand. This compound is also active in various human tumour-cell models in vitro and in vivo and appears to interfere with microtubule function.49 The Brazilian tunicate, Ascidian didemnum granulatum, is the source of the aromatic alkaloids granulatimide and isogranulatimide, which appear to act as G2 checkpoint inhibitors.50 These compounds have been synthesised, and several analogues are being developed for further testing. In addition, new bisindole alkaloids of the topsentin and hamacanthin classes have been isolated from the Mediterranean sponge Rhaphisia lacazei, and these compounds also showed significant antiproliferative activity against a series of human cell lines in vitro.51 Five new sesquiterpenes, parahigginols, and parahigginic acid, have been isolated from a Taiwanese marine sponge Parahigginsia sp. Initial studies revealed that these compounds were cytotoxic against murine P-388 and human KB16, A549, and HT-29 tumour cells.52 Another group of marine compounds, the makaluvamines, also show significant antitumour activity in animal models, probably through the induction of dose-dependent DNA cleavage via topoisomerase II.53 Dinoflagellates, unicellular marine protozoons, produce some of the largest and most complex polyketides identified to date. The biological activities of these molecules are quite diverse.54 More recently, the manipulation of the biosynthetic pathways of microbial polyketides through

patients with a range of solid tumours, but so far no significant antitumour activity has been seen.3033
Bryostatins

Bryostatin 1 is a macrocyclic natural lactone isolated from the marine bryozoan, Bugula neritina (Figure 5). It modulates the activity of protein kinase C (PKC), lacks tumour-promoting activity and shows differentiationinducing effects in various in vitro and in vivo models.34,35 It also has immunomodulatory properties, including the induction of cytokine release and expansion of tumourspecific lymphocyte populations.36,37 Bryostatin 1 has shown antitumour activity in phase I trials in patients with malignant melanoma, lymphoma, and ovarian carcinoma and is undergoing broad phase II evaluation. The main toxic effects in initial clinical trials were myalgia, local phlebitis, fatigue, nausea and vomiting, and thrombocytopenia. Bryostatin 1 showed no significant objective antitumour activity in phase I and II trials in patients with advanced solid tumours, including renal-cell and non-small-cell lung cancer, and malignant melanoma.3841 However, it was shown to induce cell differentiation in patients with refractory chronic lymphocytic leukaemia. A phenotype resembling hairy-cell leukaemia was observed following the administration of bryostatin 1 in one patient, who regained sensitivity to 2chlorodeoxyadenoside (2-CdA) treatment.42 A new class of bryostatin analogues, which retain the putative recognition domain of the bryostatins, but are simplified through deletions and modifications in the C1C14 spacer domain, have been designed by use of computer models. All these analogues are bound strongly to a mixture of PKC isozymes, and several show significant growthinhibitory activity against human cancer cell lines in vitro. This work constitutes an important step towards the development and understanding of simplified, synthetically accessible analogues of the bryostatins as potential chemotherapeutic agents.34
Depsipeptide (NSC 630176)

A large number of structurally novel, biologically active cyclic peptides and depsipeptides are found in blue-green
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Figure 4. The sea hare Dolabella auricularia.

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Review

Marine-derived anticancer agents

metabolic diversity, which is ready to be exploited and which will certainly make anticancer drug discovery even more challenging in the next few years.
References

Figure 4. The bryozoan Bugula neritina.

genetic engineering has led to the biosynthesis of a series of interesting bioactive polyketides not identified in nature so far.55 Kahalalide F, another marine-derived agent obtained from the mollusc Elysia rubefescens, which is found in Hawaii, showed substantial antitumour activity in preclinical models and is due to start phase I trials in patients with hormone-refractory prostate cancer.56 Finally, the cryptophycins are a family of antitubulin antitumour agents obtained from cyanobacteria. A synthetic cryptophycin derivative (LY355703, CRYPTO 52) is in the early stages of clinical evaluation.57

Future prospects
Nature has supplied several active anticancer agents (eg the vinca alkaloids, anthracyclines, epipodophyllotoxins, and taxanes), which have significantly improved the management of many types of human cancers.2,4,5,58 These marine-derived compounds are extremely potent in culture, with inhibitory concentrations generally in the nanogram range. The recommended doses of didemnin B, aplidine, and ET-743 for phase II trials were 6.3, 6.0, and 1.5 mg/m2, respectively. One can speculate that these organisms require potency and rapid penetration of cellular membranes for protection against predators, since their aquatic environment will rapidly dilute their poisons.2,4,6 The challenge of identifying new anticancer agents in the oceans has been taken up by a group of scientists who have formed a worldwide collaboration to investigate the organisms found on coral reefs and in deep ocean thermal vents. This field is also expanding thanks to advances in deep-sea collection techniques, aquaculture, and the technology needed to extract nucleic acids from biological materials. The manipulation of microbial biosynthetic pathways through genetic engineering has also led to the production of interesting new molecules. These living organisms represent a rich reservoir of genetic and

Search strategy and selection criteria

Published data for this review were identified by searching MEDLINE, CancerLit, UKCCR Register of Cancer Trials, and references from relevant articles. Relevant researchers and drug companies were also contacted.

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