Review - marine drugs

For personal use only. Reproduce with permission from The Lancet Publishing Group.

THE LANCET Oncology Vol 2 April 2001 221

Various active anticancer agents are derived fromplants and terrestrial microorganisms. The isolationof C-nucleosides from the Caribbean sponge,Cryptotheca crypta, four decades ago, provided thebasis for the synthesis of cytarabine, the first marine-derived anticancer agent to be developed for clinicaluse. Cytarabine is currently used in the routinetreatment of patients with leukaemia and lymphoma.Gemcitabine, one of its fluorinated derivatives, hasalso been approved for use in patients withpancreatic, breast, bladder, and non-small-cell lungcancer. Over the past decade, several newexperimental anticancer agents derived from marinesources have entered preclinical and clinical trials.This field has expanded significantly as a result ofimprovements in the technology of deep-seacollection, extraction, and large-scale productionthrough aquaculture and synthesis. In this paper,examples of marine-derived experimental agents thatare currently undergoing preclinical and early clinicalevaluation are briefly discussed. A summary of theavailable information on the results of phase I and IItrials of agents such as aplidine, ecteinascidin-734(ET-734), dolastatin 10 and bryostatin 1 is alsopresented.Lancet Oncol 2001; 2: 221–25

Since ancient times, we have relied on nature for our basicneeds – food, protection, clothing, transport andpharmaceuticals.1,2 The medical armamentarium includesmany examples of important agents that were first isolatedfrom plants and microorganisms and that are now inroutine clinical use. In the field of anticancer therapy, manyactive cytotoxic agents were originally developed fromnatural sources (Table 1).2,3

Until recently, the only major contribution toanticancer therapy from the sea was the syntheticnucleoside analogue cytarabine, which is commonly used inthe treatment of leukaemia and lymphoma. Thedevelopment of cytarabine was initially inspired by a seriesof C-nucleoside-derived compounds isolated from theCaribbean sponge Cryptotheca crypta. More recently, afluorinated derivative of cytarabine, gemcitabine, hasshown significant activity in patients with solid tumours,such as pancreatic, breast, bladder, and non-small-cell lungcancer.4,5

The oceans cover about 70% of the earth’s surface, andthe marine environment includes tremendous biodiversity;all but two of the 28 major animal phyla are represented.

Over the past few years, about 3000 new compounds fromvarious marine sources (Figure 1) have been described andsome have entered clinical trials.6 This activity has beenlargely due to improvements in the technologies involved indeep-sea sample collection and large-scale drug productionthrough aquaculture and drug synthesis7 which took placein the 1980s. These developments suggest that, in thefuture, the oceans will become an important source of novelchemical classes not found in the terrestrial environment(Table 2).8,9

New agents undergoing clinical evaluationTunicate derivativesOf the marine-derived compounds that have entered phaseI and II trials as antitumour agents, didemnin B, aplidine,and ET-743 are derived from tunicates.9 Didemnin B is acyclic depsipeptide isolated from the tunicate Trididemnumsolidum. It has shown impressive antitumour activity inhuman tumour models in vitro as well as in tumoursgrowing in athymic mice.10 In initial clinical trials, patientswith various solid tumours or non-Hodgkin lymphoma

ReviewMarine-derived anticancer agents

GS is at the South-American Office for Anticancer DrugDevelopment (SOAD), Comprehensive Cancer Center (CINCAN),The Lutheran University (ULBRA), Brazil; AbdR is doing aPostgraduate Course in Medicine (HCPA-UFRGS), Porto Alegre,Brazil; RGSB is in the Department of Chemistry, University of SãoCarlos (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, BrazilHospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos 2350, 3º Leste Porto Alegre – RS – Brazil, CEP 90000. Tel: +55 51 3168012. Fax: +55 51 3317143. Email: [email protected]/[email protected]

Marine organisms as a source of newanticancer agents

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

Figure 1. The Mediterranean tunicate Aplidium albicans.

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THE LANCET Oncology Vol 2 April 2001222

were given a short intravenous infusion of didemnin Bevery 3 weeks, and antitumour effects were observed.However, severe neuromuscular and cardiotoxic effects ledto the discontinuation of clinical trials.11,12

Another depsipeptide, dehydrodidemnin B, wassubsequently isolated from the Mediterranean tunicate,Aplidium albicans (Figure 1) and later called aplidine. Thepreclinical findings for aplidine suggested potentially highanticancer activity against various different, rapidlyproliferating tumour types, as a result of interference withcell-cycle progression at G1.13 Aplidine appears to be moreactive than didemnin B in preclinical models and so far hasnot shown evidence of life-threatening neuromusculartoxicity. Because aplidine appears to have higherantitumour activity in preclinical models after longer drugexposure, phase I trials were initiated at various drugschedules, ie 1 h, 3 h, 24 h and 72 h intravenous infusions.Notably, antitumour activity was observed in patients withadvanced solid tumours, such as renal-cell carcinoma,

malignant melanoma, tumours of neuroendocrine origin,and medullary carcinoma of the thyroid.14–16 The main toxiceffects observed so far have been nausea and vomiting,myalgia, transient disturbance of liver function, and localirritation at the injection site. Muscular toxicity wascircumvented by the concomitant administration of L-carnitine (E Raymond, unpublished). Aplidine will startphase II trials in various solid tumours in the near future.

The ecteinascidins are derived from the Caribbeantunicate Ecteinascidia turbinata (Figure 2) and also showsignificant antitumour activity in both murine and humantumour cell lines.17 Of the many ecteinascidins that havebeen isolated, ET-743 was selected for clinical trials (Figure 3). It is a tetrahydroisoquinoline alkaloid that actsby selective alkylation of guanine residues in the DNAminor groove.18 It therefore differs from the other DNA-alkylating agents so far introduced in the clinic. It alsointeracts with nuclear proteins.19

The main drug-induced toxic effects of ET-743 in earlyclinical trials were pancytopenia, fatigue, emesis andtransaminitis. Local toxicity was also observed in patientswho received short-term intravenous administration. Therewere objective and long-lasting tumour responses inpatients with advanced resistant mesenchymal tumours,breast cancer, melanoma and ovarian cancer included inphase I clinical trials of ET-743.20,21 Initial results from pilotphase II trials for ET-743 confirm its therapeutic potentialin various soft tissue sarcomas and breast cancer. 22–26

DolastatinsThe dolastatins are cytotoxic cyclic and linear peptidesderived from the sea hare, Dolabella auricularia (Figure 4), amollusc found in the Indian Ocean. Dolastatins 10 and 15are small peptides; dolastatin 10 was selected for clinicaltrials because of its more favourable preclinical profile.27 Itinhibits microtubule assembly, causing cells to accumulatein metaphase28,29 and is extremely potent in vitro. Dolastatin10 caused bone-marrow toxicity in initial clinical trials, aswell as local irritation at the injection site and mildperipheral neuropathy. Phase I and II trials involved

Review Marine-derived anticancer agents

Table 1. Cytotoxic agents developed from natural sources

Agent Oncological use Natural source

Etoposide Testicular tumours, Podophyllum

small-cell lung cancer peltatum,

Podophyllum

emodiCytarabine Leukaemias and non- Cryptotheca

Hodgkin lymphomas crypta

Vinblastine Hodgkin’s disease, Catharanthusnon-Hodgkin roseuslymphoma, germ-cell tumours, Kaposi’s sarcoma and breast cancer

Vincristine Acute leukaemia, Hodgkin’s Catharanthusdisease, non-Hodgkin roseuslymphoma, rhabdo-myosarcoma, Wilm’s tumour

Gemcitabine Pancreatic, bladder, breast Cryptothecaand non-small-cell lung cancer crypta

Vinorelbine Activity in breast and non- Catharanthussmall-cell lung cancer roseus

Paclitaxel Ovarian, breast, lung cancer, Taxus brevifoliaand others

Docetaxel Ovarian, breast, and Taxus baccatalung cancers by age 70

Figure 2. The tunicate Ecteinascidia turbinata.

Table 2. Marine-derived experimental anticancer agents

Organism Group Metabolite Location

Trididemnum soldium Tunicate Didemnin B Caribbean

Bugula neritina Bryozoan Bryostatin 1 Gulf of California

Ecteinascidia turbinata Tunicate Ecteinascidin-743 Caribbean

Halichondria okadai Sponge Halichondrin B Okinawa

Dolabella auricularia Sea hare Dolastatin 10 Indian Ocean

Portieria hornemannii Red alga Halomon Phillipines

Aplidium albicans Tunicate Aplidine Mediterranean

Aplysia kurodai Sea hare Aplyronine A Japan

Elysia rubefescens Mollusc Kahalalide F Hawaii

Mycale sp. Sponge Mycaperoxide B Thailand

Micromonospora Actinomycete Thiocoraline Mozambiquemarina Strait

Ascidian didemnum Tunicate Granulatimide Brazilgranulatum

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patients with a range of solid tumours, but so far nosignificant antitumour activity has been seen.30–33

BryostatinsBryostatin 1 is a macrocyclic natural lactone isolated fromthe marine bryozoan, Bugula neritina (Figure 5). Itmodulates the activity of protein kinase C (PKC), lackstumour-promoting activity and shows differentiation-inducing effects in various in vitro and in vivo models.34,35 Italso has immunomodulatory properties, including theinduction of cytokine release and expansion of tumour-specific lymphocyte populations.36,37

Bryostatin 1 has shown antitumour activity in phase Itrials in patients with malignant melanoma, lymphoma,and ovarian carcinoma and is undergoing broad phase IIevaluation. The main toxic effects in initial clinical trialswere myalgia, local phlebitis, fatigue, nausea and vomiting,and thrombocytopenia. Bryostatin 1 showed no significantobjective antitumour activity in phase I and II trials inpatients with advanced solid tumours, including renal-celland non-small-cell lung cancer, and malignantmelanoma.38–41 However, it was shown to induce celldifferentiation in patients with refractory chroniclymphocytic leukaemia. A phenotype resembling hairy-cellleukaemia was observed following the administration ofbryostatin 1 in one patient, who regained sensitivity to 2-chlorodeoxyadenoside (2-CdA) treatment.42

A new class of bryostatin analogues, which retain theputative recognition domain of the bryostatins, but aresimplified through deletions and modifications in the C1-C14 spacer domain, have been designed by use of computermodels. All these analogues are bound strongly to a mixtureof PKC isozymes, and several show significant growth-inhibitory activity against human cancer cell lines in vitro.This work constitutes an important step towards thedevelopment and understanding of simplified, syntheticallyaccessible analogues of the bryostatins as potentialchemotherapeutic agents.34

Depsipeptide (NSC 630176)A large number of structurally novel, biologically activecyclic peptides and depsipeptides are found in blue-green

algae (cyanobacteria).43 Depsipeptide (NSC 630176) is abicyclic peptide isolated from a strain of Chromobacteriumviolaceum. It decreases mRNA expression of the c-MYConcogene and inhibits the growth of Ha-RAS-transformedNIH-3T3 cell line, RAS-1, causing cell-cycle arrest atG0–G1.44 It acts as an inhibitor of a histonedeacetylase.45 Depsipeptide showed cytotoxic activity invarious human solid-tumour cell lines in vitro and also inathymic mice.46 Phase I trials of depsipeptide will beginsoon.

Other compounds in preclinical developmentNew classes of anticancer drugs isolated from marineorganisms in different parts of the world show cytotoxicactivity in a variety of preclinical models. Discodermolide, ametabolite of the deep-sea sponge Discodermia dissolutecollected in the waters of the Bahamas, induces microtubulestabilisation.47,48

Halichondrin B was initially purified from the spongeHalichondria okadai in Japan and has shown in vivo activityin melanoma and leukaemia models. It can also be obtainedfrom the deep-water sponge Lissodendoryx, which is foundin New Zealand. This compound is also active in varioushuman tumour-cell models in vitro and in vivo and appearsto interfere with microtubule function.49

The Brazilian tunicate, Ascidian didemnum granulatum,is the source of the aromatic alkaloids granulatimide andisogranulatimide, which appear to act as G2 checkpointinhibitors.50 These compounds have been synthesised, andseveral analogues are being developed for further testing. Inaddition, new bisindole alkaloids of the topsentin andhamacanthin classes have been isolated from theMediterranean sponge Rhaphisia lacazei, and thesecompounds also showed significant antiproliferativeactivity against a series of human cell lines in vitro.51

Five new sesquiterpenes, parahigginols, andparahigginic acid, have been isolated from a Taiwanesemarine sponge Parahigginsia sp. Initial studies revealed thatthese compounds were cytotoxic against murine P-388 andhuman KB16, A549, and HT-29 tumour cells.52 Anothergroup of marine compounds, the makaluvamines, alsoshow significant antitumour activity in animal models,probably through the induction of dose-dependent DNAcleavage via topoisomerase II.53

Dinoflagellates, unicellular marine protozoons, producesome of the largest and most complex polyketides identifiedto date. The biological activities of these molecules are quitediverse.54 More recently, the manipulation of thebiosynthetic pathways of microbial polyketides through


N

N

OO

NH

HO

MeO

OH

OAc

MeO

MeO

HO

OH

SO

O

Me

Figure 3. Chemical structure of ET-743.

Figure 4. The sea hare Dolabella auricularia.


THE LANCET Oncology Vol 2 April 2001224

genetic engineering has led to the biosynthesis of a series ofinteresting bioactive polyketides not identified in nature sofar.55

Kahalalide F, another marine-derived agent obtainedfrom the mollusc Elysia rubefescens, which is found inHawaii, showed substantial antitumour activity inpreclinical models and is due to start phase I trials inpatients with hormone-refractory prostate cancer.56 Finally,the cryptophycins are a family of antitubulin antitumouragents obtained from cyanobacteria. A syntheticcryptophycin derivative (LY355703, CRYPTO 52) is in theearly stages of clinical evaluation.57

Future prospectsNature has supplied several active anticancer agents (eg thevinca alkaloids, anthracyclines, epipodophyllotoxins, andtaxanes), which have significantly improved themanagement of many types of human cancers.2,4,5,58 Thesemarine-derived compounds are extremely potent inculture, with inhibitory concentrations generally in thenanogram range. The recommended doses of didemnin B,aplidine, and ET-743 for phase II trials were 6.3, 6.0, and1.5 mg/m2, respectively. One can speculate that theseorganisms require potency and rapid penetration of cellularmembranes for protection against predators, since theiraquatic environment will rapidly dilute their poisons.2,4,6

The challenge of identifying new anticancer agents inthe oceans has been taken up by a group of scientists whohave formed a worldwide collaboration to investigate theorganisms found on coral reefs and in deep ocean thermalvents. This field is also expanding thanks to advances indeep-sea collection techniques, aquaculture, and thetechnology needed to extract nucleic acids from biologicalmaterials. The manipulation of microbial biosyntheticpathways through genetic engineering has also led to theproduction of interesting new molecules. These livingorganisms represent a rich reservoir of genetic and

metabolic diversity, which is ready to be exploited andwhich will certainly make anticancer drug discovery evenmore challenging in the next few years.

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Review Marine-derived anticancer agents

Search strategy and selection criteriaPublished data for this review were identified by searchingMEDLINE, CancerLit, UKCCR Register of Cancer Trials,and references from relevant articles. Relevant researchersand drug companies were also contacted.

Figure 4. The bryozoan Bugula neritina.



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Review - marine drugs