Mar.Drugs 2014,12 1076 Table 1 highlights the evolution of this pipeline from 2004 until now.This pipeline is quite dynamic with a significant and growing number of marine-derived molecules entering in clinical trials, and some others being discontinued for several causes.The main reasons for the withdrawals of development in clinical phases I-III are mainly due to lack of efficacy (43%)and drug toxicity (33%)[68].In 2004 cytarabine,vidarabine,ziconotide and omega-3-acid ethyl esters were the only FDA/EMEA approved drugs.Just nine years later,the approved drugs in the marine drug pipeline doubled.This is a amazing improvement since during the first 30 years of MNP research,cytarabine and vidarabine were the only ones entering the market.Just three compounds in clinical trials in 2004 remain in the pipeline:pliditepsin,DMXBA(GTS-21)and bryostatin I. 4.1.1.Cytosar-U and Vira-A by Bedford Laboratories(Bedford,OH,USA)and King Pharmaceuticals(Tenafly,NJ,USA),Respectively The presence of an arabinose unit instead of ribose in the nucleosides spongouridine and spongothyminide was the pitfall that inspired the synthesis of several ara-nucleosides that steered the development of the marketed drugs cytarabine(FDA approved in 1969 for cancer)and vidarabine (FDA approved in 1976 as antiviral).The key feature of this discovery was the understanding of the role of those compounds in the sponge.Actually,unlike their analogous found in DNA and RNA,they can be found in a free-state,a fact that led scientists to hypothesize that they were used as a defence mechanism for Cryptotethia crypta.The investigations of these compounds led,ultimately,to the antimetabolite concept in pharmacology (molecules structurally similar to the human metabolites that inhibit the use of a metabolite)[69]. Cytarabine was chemically synthesized in 1959 and later produced by fermentation of Streptomyces griseus.Curiously,the natural analogue of cytarabine was later isolated from the gorgonian Eunicella cavolini [70]but obviously the extraction yield of 0.04%has turned this source economically impractible.Cytarabine continues to be the election drug for the treatment of myeloid leukaemia,non-Hodgkin's lymphoma and meningeal leukaemia.It may be used alone or in combination with other anticancer agents.Forty years after its entry into the market there is still no better approach to treat these diseases,despite the research efforts to improve therapeutics [69] However,cytarabine has a short plasma half-life,low stability and limited bioavailability [71],reasons why therapeutic regimens consist in continuous intravenous infusion for seven days,the three first ones in combination with other drugs.This overdosing of patients may lead to side effects,and thus, various prodrug strategies and delivery systems have been exploited extensively to enhance the performance of cytarabine.The first step to improve the bioavailability and stability of cytarabine was the understanding of its mechanism of action and metabolism.Cytarabine has low rates of passive diffusion across membranes and enters into the cells acting as mimetic substrates (antimetabolic agents)for specialized nucleoside transporter proteins.Although the mechanism of action is not completely understood,it appears that cytarabine is converted intracellularly by deoxycytidine kinase, to active cytarabine triphosphate.Activity occurs as the result of inhibition of DNA polymerase via competition with deoxycytidine triphosphate,resulting in the inhibition of DNA synthesis.A limited, but significant,incorporation of cytarabine into both DNA and RNA has also been reported and may contribute to cytotoxic effects [71]
Mar. Drugs 2014, 12 1076 Table 1 highlights the evolution of this pipeline from 2004 until now. This pipeline is quite dynamic with a significant and growing number of marine-derived molecules entering in clinical trials, and some others being discontinued for several causes. The main reasons for the withdrawals of development in clinical phases I–III are mainly due to lack of efficacy (43%) and drug toxicity (33%) [68]. In 2004 cytarabine, vidarabine, ziconotide and omega-3-acid ethyl esters were the only FDA/EMEA approved drugs. Just nine years later, the approved drugs in the marine drug pipeline doubled. This is a amazing improvement since during the first 30 years of MNP research, cytarabine and vidarabine were the only ones entering the market. Just three compounds in clinical trials in 2004 remain in the pipeline: pliditepsin, DMXBA (GTS-21) and bryostatin I. 4.1.1. Cytosar-U ® and Vira-A ® by Bedford Laboratories (Bedford, OH, USA) and King Pharmaceuticals (Tenafly, NJ, USA), Respectively The presence of an arabinose unit instead of ribose in the nucleosides spongouridine and spongothyminide was the pitfall that inspired the synthesis of several ara-nucleosides that steered the development of the marketed drugs cytarabine (FDA approved in 1969 for cancer) and vidarabine (FDA approved in 1976 as antiviral). The key feature of this discovery was the understanding of the role of those compounds in the sponge. Actually, unlike their analogous found in DNA and RNA, they can be found in a free-state, a fact that led scientists to hypothesize that they were used as a defence mechanism for Cryptotethia crypta. The investigations of these compounds led, ultimately, to the antimetabolite concept in pharmacology (molecules structurally similar to the human metabolites that inhibit the use of a metabolite) [69]. Cytarabine was chemically synthesized in 1959 and later produced by fermentation of Streptomyces griseus. Curiously, the natural analogue of cytarabine was later isolated from the gorgonian Eunicella cavolini [70] but obviously the extraction yield of 0.04% has turned this source economically impractible. Cytarabine continues to be the election drug for the treatment of myeloid leukaemia, non-Hodgkin‘s lymphoma and meningeal leukaemia. It may be used alone or in combination with other anticancer agents. Forty years after its entry into the market there is still no better approach to treat these diseases, despite the research efforts to improve therapeutics [69]. However, cytarabine has a short plasma half-life, low stability and limited bioavailability [71], reasons why therapeutic regimens consist in continuous intravenous infusion for seven days, the three first ones in combination with other drugs. This overdosing of patients may lead to side effects, and thus, various prodrug strategies and delivery systems have been exploited extensively to enhance the performance of cytarabine. The first step to improve the bioavailability and stability of cytarabine was the understanding of its mechanism of action and metabolism. Cytarabine has low rates of passive diffusion across membranes and enters into the cells acting as mimetic substrates (antimetabolic agents) for specialized nucleoside transporter proteins. Although the mechanism of action is not completely understood, it appears that cytarabine is converted intracellularly by deoxycytidine kinase, to active cytarabine triphosphate. Activity occurs as the result of inhibition of DNA polymerase via competition with deoxycytidine triphosphate, resulting in the inhibition of DNA synthesis. A limited, but significant, incorporation of cytarabine into both DNA and RNA has also been reported and may contribute to cytotoxic effects [71]
Mar.Drugs 2014,12 1077 Table 1.The marine pharmaceutical clinical pipeline:2004-2013 evolution. Compound NP or Original NP/ Company/Institution Name Therapeutic Status Status Status Derivative Source Organism (City,State,Country) Area 2004141 (Trademark) 2009H21 201316 Bedford Cytarabin Spongothymidine NP (Cytosar-U (Bedford,OH,USA). Cancer FDA/EMEA sponge Approved Approved derivative Cryptotetlya crpta Enzon Depocvt) approved (Piscataway,NJ.USA) Spongouridine/ Vidarabine NP King Pharma FDA/EMEA US sponge (Vira-A) derivative Anti-viral Cnptotethya enpta (Tenafly,NJ.USA) approved Approved discontinued -Conotoxin Ziconotide Flan Corporation EDA NP Neuropahtic Pain FDA/EMEA (Prial" marine snail Coms magus (Dublin,Ireland) approved approved Approved Omeea-3-acid ethyl esters NP Omega-3-fatty acids/ glaxosmithkline FDA FDA/EMEA derivative fish (Brentford,UK) Hypertriglyceridemia (Lovaza") approved approved Approved Ecteinascidin 743/ Trabectedin PharmaMar EMEA EMEA (Yondelis") NP tunicate Cancer Ectein Madrid,Spain) approved approved NP derivative (Tokyo,Japan) Cancer PhaseI Phase III FDA/EMEA approved Brentuximab Dolastatin I0/ NP (Bothell.WA.USA) n (SG Cancer Phase II FDA/EMEA (Adcetris") approve (Osaka,Japan)
Mar. Drugs 2014, 12 1077 Table 1. The marine pharmaceutical clinical pipeline: 2004–2013 evolution. Compound Name (Trademark) NP or Derivative Original NP/ Source Organism Company/Institution (City, State, Country) Therapeutic Area Status 2004 [41] Status 2009 [42] Status 2013 [67] Cytarabine (Cytosar-U ® ; Depocyt® ) NP derivative Spongothymidine/ sponge Cryptotethya crypta Bedford (Bedford, OH, USA); Enzon (Piscataway, NJ, USA) Cancer FDA/EMEA approved Approved Approved Vidarabine (Vira-A ® ) NP derivative Spongouridine/ sponge Cryptotethya crypta King Pharma (Tenafly, NJ, USA) Anti-viral FDA/EMEA approved Approved US discontinued Ziconotide (Prial® ) NP ω-Conotoxin/ marine snail Conus magus Elan Corporation (Dublin, Ireland) Neuropahtic Pain FDA approved FDA/EMEA approved Approved Omega-3-acid ethyl esters (Lovaza® ) NP derivative Omega-3-fatty acids/ fish GlaxoSmithKline (Brentford, UK) Hypertriglyceridemia FDA approved FDA/EMEA approved Approved Trabectedin (Yondelis® ) NP Ecteinascidin 743/ tunicate Ecteinascidia turbinata PharmaMar (Colmenar Viejo, Madrid, Spain) Cancer Phase II/III EMEA approved EMEA approved Eribulin mesylate (Halaven® ) NP derivative Halichondrin B/ sponge Halichodria okadai Eisai (Tokyo, Japan) Cancer Phase I Phase III FDA/EMEA approved Brentuximab vedotin (SGN-35) (Adcetris® ) NP derivative Dolastatin 10/ sea hare Dolabella auricularia Seattle Genetics (Bothell, WA, USA); Takeda GRDC (Osaka, Japan) Cancer - Phase II FDA/EMEA approved