Gilberto Schwartsmann South-American Office for Anticancer Drug Development (SOAD), Comprehensive Cancer Centre (CINCAN), The Lutheran University (ULBRA) & Postgraduate Course in Medicine (UFRGS), Porto Alegre, Brazil Introduction Man has always relied on nature for survival. Since ancient times, nature has been our main source of food, protection, clothing, transportation and remedies [1,2]. This can be illustrated by the number of natural product derived agents currently in use in routine medical practice (Table 1) [3-5]. In addition o plant-derived compounds, microorganisms constitute a very important source of novel bioactive agents. They have contributed to the medical armamentarium with antibiotics such as penicillins, aminoglycosides and cephalosporins, which represent landmarks in the history of human therapeutics [6,7]. Although marine compounds are yet underrepresented in routine clinical practice, it can be anticipated that aquatic environment may become a potentially valuable source of novel compounds, as the world’s oceans cover about 70% of the earth’s surface and all except 2 of the 28 major animal phyla are represented there [8-11].

Anti-cancer agents derived from natural sources Several new anticancer agents that entered the market in the 1990s were obtained from natural sources (Table 2) [12,13]. There is also a significant number of naturally derived new anticancer candidate compounds that are currently undergoing preclinical and early clinical development (Table 3) [3,14]. Plant-derived compounds, in particular, have . a special place in the anticancer therapy (Table 4) [15,16]. The Vinca alkaloid vincristine (isolated from Catharanthus roseus) is part of various curative regimens in patients with leukaemia and lymphoma [17,18].

Similarly, the epipodophyllotoxin derivative, etoposide (extracted from the mandrake plant Podophyllum peltatum and the wild chervill P. emodi) is included in drug regimens that produce a significant number of cures in patients with germ-cell tumours [19,20]. The taxoids (extracted from the bark of the Taxaceae Taxus brevifolia, T. canadensis, or T. baccata) and the camptothecins (derived from the bark and wood of the Nyssacea Camptotheca acuminata) have also significant anti-solid tumour Table 1 Drugs developed from plant sources Drug Medical use Plant source Aspirin Atropine Benzoin Caffeine Codeine

Digoxin Eugenol Hygoscyamine Morphine Papaverine Pilocarpine Quinine Reserpine Scopolamine Toxiferine Xanthotoxin Analgpsir, antiinflammatnry Pupil dilator Oral disinfectant Stimulant Analgesic, antitussive For atrial fibrillation and CHF For toothache Anticholinergic Analgesic Antispasmodic For glaucoma For malaria prophylaxis Antihypertensive For motion sickness Relaxant in surgery For vitiligo Filipendula ulmaria Atropa belladonna Sty rax tonkinensis Camellia sinensis Papaver somniferum Digitalis purpura Syzigium aromaticum Hyoscyamus niger Papaver somniferum Papaver somniferum Pilocarpus jaborandi

Cinchona pubescens Rauwolfia serpentia Datura stramonium Strychnos guianensis Ammi majus 235 Downloaded from annonc. oxfordjournals. org by guest on December 7, 2010 236 G. Schwartsmann Table 2 Anticancer drugs developed from plant sources Drug Medical use Plant source Etoposide Testicular tumours, small cell lung cancer Teniposide Paediatric acute lymphoblastic leukaemia Vinblastine Hodgkin’s disease, non-Hodgkin’s lymphoma, carcinoma of the testis, Kaposi’s sarcoma, choriocarcinoma, breast cancer Vincristine Acute leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma, rhabdomyosarcoma, Wilm’s tumour

Vindesine Investigational; modest activity in Hodgkin’s disease, non-Hodgkin’s lymphoma, leukaemias, non-small cell lung cancer, and breast cancer Vinorelbine Activity in breast and non-small cell lung cancer Paclitaxel Ovarian, breast, lung cancer and others Docetaxel Ovarian, breast, and lung cancers Topotecan Ovarian cancer Irinotecan Colorectal cancer Podophyllum peltatum and P. emodi Podophyllum pellatum and P. emodi Catharanthus roseus Catharanthus roseus Catharanthus roseus Catharanthus roseus Taxus brevifolia Taxus baccata Camptotheca acuminata Camptotheca acuminata Table 3

Examples of natural product derived agents approved for marketing (1990-1999) Bisantrene Interferon y-lA Cytarabine ocphosphate Miltefosine Porfimer sodium Pegaspargase Zinostatin stimalamer Gemcitabine Topotecan Irinotecan Fludarabine phosphate Pentostatin Formes tane Paclitaxel Sobuzoxane Bicalutamide Raltitrexed Docetaxel Lyposomal doxorubicin Lyposomal daunomycin Etoposide phosphate The agents are either natural products, semisynthetic analogues or the pharmacophore is from a natural product. From Cragg and Newman, 1999 [3]. activity [21]. Paclitaxel was approved by the FDA for the treatment of ovarian and breast carcinoma, nd has also important activity against other tumours such as non-small cell lung cancer [22]. Irinotecan and topotecan are more water-soluble semi-synthetic camptothecin derivatives which were approved for the treament of advanced colorectal [23,24], and ovarian carcinoma [25-27], respectively. These agents have also shown clinical antitumour activity in other malignancies of the adult and children [27]. Antitumour antibiotics such as doxorubicin, daunomycin, bleomycin, mitomycin, streptozocin and deoxycoformycin are clinically active agents against several types of cancers [28,29]. They were all isolated rom Streptomyces species. Other microbe-derived metabolites under current development are rhizoxin, deoxyspergualin, UCN-01 (7-hydroxystaurosporin), spicamycin (KRN5500), CC-1065 (bizelesin), and the rebeccamycin analogues [3,30,31]. The epithilone derivatives obtained from myxobacteria have gained Table 4 NCI-sponsored experimental agents whose pharmacophores are obtained from natural sources Source Agent Status Animal Animal Animal Marine Marine Microbial Microbial Microbial Microbial Microbial Microbial Microbial Microbial Microbial Microbial Microbial Microbial Microbial Microbial Plant Plant Plant

Pyrimidine base Hydroxydopamine derivative Tributyrin 2-Methoxyestradiol derivative Halichondrin B Dolastatin 10 COL 3 Cordycepin/deoxycoformycin Geldanamycin derivative Iododoxorubicin Rapamycin derivative Vicenistatin Bizelesin Depsipeptide KRN55O0 9-cir-Retinoic acid Quinocarmycin derivative Rebeccamycin derivative Rhizoxin UCN-01 Neriifolin Flavopiridol Perllyl alcohol 5-Ethynyluracyl Preclinical PrecUnical Preclinical Preclinical * Clinical Preclinical Preclinical Preclinical Clinical Preclinical Preclinical Clinical Clinical Clinical Clinical Clinical Clinical Clinical Clinical PrecUnical Clinical

Clinical Clinical From Cragg and Newman, 1999 [3]. also attention in the laboratory, because of the similarity of their mechanism of action to the taxoids [32]. Cytosine arabinoside, a synthetic analogue of the C-nuclesides initially isolated from the Caribbean sponge, Cryptotheca cripta, was the first and, so far, only, marine-derived compound routinely used in cancer therapy. It has significant antitumour activity in leukaemias and lymphomas [33,34]. The systematic exploration of marine organisms as sources of novel bioactive agents initiated in the 1970s and Downloaded from annonc. oxfordjournals. rg by guest on December 7, 2010 Marine organisms and other novel natural sources of new cancer drugs 237 expanded markedly since the mid-1980s. Presently, more than 2500 new metabolites were described from a variety of marine sources, anticipating its future role as a valuable source of novel chemical classes not usually found in the terrestrial environment [35-37]. Several potentially interesting marine compounds are in preclinical development. Discodermolide, a metabolite of the deep-sea sponge Discodermia dissolute, was collected in the waters of the Bahamas, and it was shown to induce microtubule stabilisation [35].

Halichondrin B, first isolated from the sponge Halichondria okadai in Japan has shown in vivo activity against melanoma and leukaemia. It is being currently obtained from the New Zealand deep-water sponge Lissodendoryx. Isogranulatimide, an aromatic alkaloid extracted from the Brazilian tunicate, ascidian Didemnum granulation, acts as a G2 checkpoint inhibitor. Its synthesis has been fully accomplished and several analogues are being developed [36]. Experimental anticancer agents in phase I—II trials Tunicate derivatives Of the marine compounds that have entered clinical evaluation, three — didemnin B (DB), aplidine DDB) and ecteinascidin 743 (ET 743) — are derived from tunicates. DB is a cyclic depsipeptide isolated from the tunicate Trididemnum solidum and was the first to enter phase I and II studies. In phase II trials sponsored by the NCI, partial and complete tumour responses were documented in patients with non-Hodgkin’s lymphoma. However, DB caused cardiotoxicity and was stopped in its further development. DB also produced significant nausea and vomiting, and isolated cases of hypersensitivity reactions [36-38]. Aplidine was obtained from a Mediterranean colonial tunicate, Aplidium albicans.

It has a pyruvyl group replacing the lactyl group in DB and its synthesis has been achieved. It appears more active than DB in preclinical models and apparently not cardiotoxic. Aplidine entered clinical trials in 1999 both in Europe and in the US under the sponsorship of the Spanish company Pharma Mar. The ecteinascidins (Ets) are derived from the Caribbean tunicate Ecteinascidia turbinata. Following a period of supply problems, enough amounts of this compound could be obtained from aquaculture and synthesis. The derivative Ecteinascidin 743 (ET 743) showed promising activity in murine and human tur,

II • o ;gt; = 0 «A/V II I I Fig. 1. Chemical structure ET743. mour models, and is currently in early clinical development (Fig. 1) [39,40]. It is a tetrahydroisoquinoline alkaloid that alkylates selectively guanine N2 from the DNA minor groove, and this alkylation is reversed by DNA denaturation. Therefore, it differs from other DNA alkylating agents so far used in the clinic [40]. Dolastatins The dolastatins are cytotoxic peptides, which can be cyclic or linear, derived from the sea hare, Dolabella auricularia, a mollusc from the Indian Ocean. Dolastatin 10 and 15 are small peptides that were shown o interact with tubulin. Dolastatin 10 (NSC 376128) was selected for initial clinical development because of its more favourable preclinical profile (Fig. 2). It is extremely potent in vitro and it was shown to inhibit microtubule assembly, tubulin-dependent guanosine triphosphate (GTP) binding and inhibit vincristine and vinblastine binding to tubulin. It causes cells to accumulate in metaphase arrest and is modulated by the MDR gene product [41,42]. Dolastatin 10 has in vitro activity against several human leukaemia, lymphoma and solid tumour cell lines with IC50S between 0. 1 to 10 nM.

It has documented ntitumour activity in various human solid tumour models, such as LOX#IMVI melanoma, OVCAR- 3 ovarian carcinoma and NCI-H522 NSCLC O CH3 OCH3O H3CO Fig. 2. Structure of dolastatin 10 (NSC 376128). Downloaded from annonc. oxfordjournals. org by guest on December 7, 2010 238 G. Schwartsmann Fig. 3. Structure of bryostatin-1 (NSC 339555). cell lines. In animal toxicology studies, myelosuppression was the dose-limiting toxicity. This agent is highly bound to plasma proteins and pharmacokinetic studies in animals showed a rapid degradation probably by hepatic metabolism [43,44]. This agent entered phase I trials as an i. v. olus injection every 3 weeks. The maximum tolerated dose (MTD) was 300 mg/m2 for heavily preteated patients, while 400 mg/m2 appears to be the MTD for minimally pre-treated patients. The dose-limiting toxicity (DLT) was myelosuppression, and local irritation and phlebitis, and mild peripheral neuropathy were also observed. Phase II trials are being initiated in breast, colon, lung, ovarian and prostate cancer, as well as lymphomas and leukaemias [45,46]. Bryostatins Bryostatin-1 (NSC 339555) is a macrocyclic natural lactone isolated from the marine Bryozoan, Bugula neritina (Fig. 3). It has shown both antitumour as ell as immunomodulatory effects [47,48]. It is a potent activator of the protein kinase C (PKC) family, lacking tumour-promoting activity and with antagonistic effects on tumour-promoting phorbol esters. This effect is probably related to down-regulation of PKC or by specific isoform activation. It also stimulates cytokine production, bone marrow progenitor cells and neutrophils [49-51]. In vitro, bryostatin-1 has cytotoxic activity against various leukaemia and solid tumour cell lines [50]. It has also in vivo antitumour activity in various murine models, including leukemia, lymphoma, ovarian cancer and melanoma.

It was shown to enhance the antitumour effects of various anticancer agents, such as vincristine, cytosine arabinoside, cisplatin, melphalan, paclitaxel and others. These effects may be schedule-dependent [47,48,52]. This agent was studied in phase I trials at different infusion schedules. The recommended doses for phase II trials were 25-35 M-g/m2 when administered over one hour for three of every four weeks; 25 u. g/m2 given as a weekly 24 hour infusion. Myalgia was the DLT in all trials. Other toxicities were joint aches and a transient decrease in platelet counts [53,54]. Notably, partial responses were reported in atients with melanoma, ovarian cancer and NHL. Phase II trials of bryostatin-1 are being conducted at various infusion regimens in a large number of tumour types in both solid and haematological malignancies. In addition, phase I trials of brystatin-1 in combination with other agents, such as cisplatin, paclitaxel, fludarabine, vincristine, cytosine arabinoside and 2-CDA are also being conducted under the sponsorship of the US NCI [51,53,54]. MGI-114 MGI-114 (6-hydroxymethylacylfulvene; HMAF; NSC 683863) is a semisynthetic derivative of illudin S, a naturally occurring sesquiterpene obtained from he mushroom Omphalotus olearius, which exerts its cytotoxic effect following its rapid intracellular uptake, covalent binding to DNA, inhibition of DNA synthesis and induction of apoptosis (Fig. 4). Binding to non-DNA cellular components appears also important for cytotoxicity [55,56]. In preclinical models, this form of DNA damage is more difficult to be repaired and requires functional DNA helicase activity. MGI-114 has shown in vitro cytotoxic activity in various human tumours and also in paediatric tumours. In vivo studies in animals bearing human tumour xenografts have shown antitumour ctivity in MX-1 breast carcinoma, MV522 lung CHjOH HO” Fig. 4. Structure of MGI-114 (NSC 683863). Downloaded from annonc. oxfordjournals. org by guest on December 7, 2010 Marine organisms and other novel natural sources of new cancer drugs 239 adenocarcinoma, DU145 and PC-3 prostate, HT-29 colon carcinoma and HL60/MRI myeloid leukaemia. It is also active in mdrl/gpl70 and other chemotherapy- resistant tumours. In preclinical models, including paediatric tumour cell lines, its antitumour effects were shown to be synergistic with paclitaxel, topotecan, irinotecan and 5-fluorouracil [55,56].

In a phase I study of MGI-114 given as a 5-minute infusion daily for 5 days every 28 days, grade 3 thrombocytopenia and neutropenia, and reversible renal damage were documented at a dose of 14 mg/m2/day. Other toxicities were nausea and vomiting, fatigue, asthenia, local phlebitis, facial flushing, alopecia and mucositis. Maximum plasma concentrations of MGI-114 in the range of levels required for in vitro cytotoxicity were obtained in the patients [57]. Therefore, the recommended dose for phase II trials was 10. 6 mg/m2/day for 5 consecutive days every 4 weeks. The US NCI is currently sponsoring rials in various solid rumours. A phase I trial widi the above mentioned schedule is also being performed in solid paediatric malignancies. Flavopiridol Havopiridol (NSC 649890) is the first cytotoxic agent in clinical trials that targets cell cycle progression at either Gl or G2 via the inhibition of cyclindependent kinases (CDKs). It is a synthetic flavone derived from the plant alkaloid rohitukine isolated from Amoora rohituka, and later from Dysoxylum binectariferum (Fig. 5) [58]. It blocks cell growth and causes apoptosis in various rumour cell lines. It binds ATP competitively at the nucleotide-binding ite of CDKs. The G2 arrest is caused by both direct inhibition of CDK1 and changes in the regulatory phosphorylation of CDK1. The Gl arrest appears to depend on the inhibition of CDK2 and CDK4. At higher doses, flavopiridol also inhibits protein kinase A and C [58,59]. It has in vitro antiproliferative activity with IC50s between 50-200 nmol/1, and has been shown to be synergistic with various anticancer drugs, such as cisplatin, paclitaxel, 5-fluorouracil, cytosine arabinoside and topotecan. For some agents, this effect was schedule dependent (paclitaxel and 5-fluorouracil) while not for others (cisplatin).

In vivo antitumour activity was demonstrated in colon, prostate, lung, breast, ovary, gastric and renal carcinomas as well as glioma, melanoma and lymphoma [58,59]. Phase I trials of flavopiridol given as a 3-day continuous i. v. infusion every 14 days have been performed [60]. The DLT was a secretory-type diarrhoea, and fatigue, asthenia, anorexia, local tumour pain, and transient rise in bilirubin was also observed. Objective responses were documented in patients with renal, gastric and colon cancer, and with NHL. The recommended dose for phase II trials was 50 mg/m2/day x 3. The initial phase II trials will e conducted in patients with colorectal, prostate, NSCLC, and renal cell carcinoma, and in patients with non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia. Combination studies with cisplatin or paclitaxel are also being initiated in patients with advanced solid tumours. CCI-779 CCI-779 [sirolimus 42-{3-hydroxy-2-(hydroxymethyl)- 2-methylpropanoate}; NSC 683864] is a soluble structural analogue of rapamycin (sirolimus), a macrolide antibiotic isolated from Streptomyces hygroscopicus. It causes cell cycle arrest at Gl through the inhibition of signalling pathways that produce inhibition of RNA translation.

It has marked immunosuppressive effects by interacting with signal transduction pathways that are critical for normal T cell function as well as for tumour cells. CCI-779 binds to immunophilins, inhibiting their function [61,62]. Being more water soluble and more stable than rapamycin, CCI-779 was selected for preclinical and potential future clinical development. It inhibits key signal transduction pathways, such as those regulated by p70s6 kinase and phosphorylated heat- and acid-stable protein (PHAS-I). The above mentioned inhibitory effect interferes with cell-cycle progression through Gl [63]. Preclinical studies suggested hat tumours with deletion of the pl5/pl6 family of CDK inhibitors, such as melanoma, may be especially susceptible to CCI-779 [62,63]. Two schedules of CCI-779 administration are being evaluated in phase I trials, weekly and daily times five every 2 weeks. Phase II trials are being planned for breast, pancreas, colon, glioma, lymphoma, small-cell lung cancer and melanoma [64]. Fig. 5. Structure of flavopiridol (NSC 649890). Downloaded from annonc. oxfordjournals. org by guest on December 7, 2010 240 G. Schwartsmann H3CN D-V4I J ^CH-C1 NH •Cv .. CHa 1 LAM O CH3 Fig. 6. Structure of depsipeptide (NSC 630176).

Fig. 7. Structure of rebeccamycin analog (NSC 655649). Depsipeptide Depsipeptide (NSC 630176) is a biclyclic peptide isolated from a strain of Chromobacterium violaceum by Fujisawa Pharmaceutical Co. (Fig. 6). It decreases mRNA expression of the c-myc oncogene and inhibits the growth of Hd-ras-transformed NIH3T3 clonal cell line, Ras-1. It did not affect DNA synthesis but causes cell cycle arrest at G0/G1. More recently, it was demonstrated that it acts as an inhibitor of a histone deacetylase [65,66]. It possesses potent preclinical antitumour activity both in vitro and in vivo. In vitro, depsipeptide howed cytotoxic activity in various human solid tumour cell lines, such as NSCLC, stomach, breast and colon adenocarcinomas, with IC5Os of 0. 3-3. 2 ng/ml, and was less potent against cultured normal cells. This agent appears to be also a substrate for MDR P-glycoprotein. In vivo, it showed antitumour activity against various murine and human solid tumours (such as stomach, colon, breast and melanoma models) [65-67]. Two phase I trials of depsipeptide are being conducted using a 4 hour i. v. infusion weekly and twice-weekly, respectively, every 21 days. NSC D655649 (rebeccamycin analogue) The rebeccamycin analogue (l,ll-dichloro-6-[2-A’- iethylamino]-12,13-dihydro-12-(4-0-methyl-D-glucopyranosyl)- 5H-indolo[pyrrolo[3,4-c]carbazole-5,7- (6H)-dione; NSC D655649) is a synthetic antibiotic with the antitumour properties of its less water-soluble parent compound, rebeccamycin, which was isolated from the actinomycete strain Saccharothrix aewcolingenes found in the soil in Panama (Fig. 7). It causes an unwinding of supercoiled DNA without inducing single-strand or double-strand breaks and also inhibits topoisomerase II by limiting strandpassing ability. This compound showed in vivo antitumour activity against various murine models as ell as in human tumour xenografts, such as ESC LOX melanomas and in the ESC RXK-393 renal tumour models [68].

Currently, three phase I studies of NSC D655649 in adults and one phase I trial in children are being conducted. Two adult and one paediatric trial use a single i. v. infusion every 21 days. The MTD is 572 mg/m2 and the recommended dose for phase II is 500 mg/m2 in adults. In children, the recommended dose for phase II is 585 mg/m2. The DLT was local irritation and phlebitis at the injection site, but it became nausea and vomiting, myelosuppression (mainly neutropenia) after the use of a central i. v. ine. Hyponatremia and elevations of liver enzymes were also documented (ALT/AST). Phase I trials of a 5-daily i. v. dose every 21 days revealed similar toxicity profile and produced partial responses in ovarian, gastric and cholangiocarcinoma [69]. Conclusion Nature has given a major contribution to cancer therapy. It contributed with the introduction of several active agents that dramatically changed the natural history of many types of human cancers. This new wave of natural product derived experimental agents is offering us the opportunity to evaluate not only totally new chemical classes of anticancer agents, ut also novel and potentially relevant mechanisms of action [73-75]. Marine compounds, for instance, can interfere with very relevant intracellular targets such as signal transduction, microtubule stabilisation or new forms of interaction with DNA. They can be extremely potent in culture, with IC50S in tumour cell lines in the nanogram range [76,77]. Probably they need potency and rapid penetration in cellular membranes to protect themselves efficiently in an aquatic environment that rapidly dilute their poisons. However, these compounds can be very toxic to normal tissues as well. We are witnessing that Downloaded from annonc. xfordjournals. org by guest on December 7, 2010 Marine organisms and other novel natural sources of new cancer drugs 241 phenomenon with marine compounds that entered clinical evaluation. The same holds true for other plant- and microbial-derived experimental agents. Therefore, the challenge of finding more selective anticancer agents with a more favourable therapeutic index still remains. The search for new natural product derived compounds for cancer treatment will continue through an active international collaboration among researchers in investigating rainforests, coral reefs and deep subsurface thermal vents [70-72].

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