Anticancer drug discovery from the marine environment

Recent Patents on Anti-Cancer Drug Discovery

Volumn 7, Issue 2, 2012, Pages 218-232

  Nastrucci, Candida ^a   Cesario, Alfredo ^a,b   Russo, Patrizia ^a  

^a IRCCS SAN RAFFAELE PISANA   (Italy)

^b CATHOLIC UNIVERSITY   (Italy)

Author keywords

Anticancer therapy; Clinical trials cancer; Human diseases; Marine drugs; Mechanism of action; Multitargets; Patent

Indexed keywords

AE 941; ANTINEOPLASTIC AGENT; BRYOSTATIN 1; CYTARABINE; CYTOSAR U1; DEHYDRODIDEMNIN B; DIAZONAMIDE A; DISCODERMOLIDE; DOXORUBICIN; E 7974; ELISIDEPSIN; ERIBULIN; ES 285; GEMCITABINE; HEMIASTERLIN; KAHALALIDE F; LAF 389; LAULIMALIDE; MARINE NATURAL PRODUCT; NATURAL PRODUCT; NSC 654663; PACLITAXEL; PELORUSIDE A; PI 0052; PM 00104; SALINOSPORAMIDE A; SOBLIDOTIN; SORAFENIB; SPISULOSINE; SUNITINIB; SYNTHADOTIN; TALTOBULIN; TASIDOTIN; TEMSIROLIMUS; TRABECTEDIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; YONDELIS 1; ZALYPSIS;

ACUTE LYMPHOCYTIC LEUKEMIA; ADVANCED CANCER; ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; AUTOPHAGY; BREAST CANCER; BREAST METASTASIS; CANCER SURVIVAL; CANCER THERAPY; CHILDHOOD LEUKEMIA; CLINICAL TRIAL (TOPIC); COLON CANCER; COLORECTAL CANCER; DIGESTIVE SYSTEM CANCER; DRUG APPROVAL; DRUG CLASSIFICATION; DRUG EFFICACY; DRUG ISOLATION; DRUG MARKETING; DRUG MECHANISM; DRUG PROTEIN BINDING; DRUG RESEARCH; DRUG STRUCTURE; EUROPEAN AGENCY FOR THE EVALUATION OF MEDICINAL PRODUCTS; EWING SARCOMA; FOOD AND DRUG ADMINISTRATION; GASTROESOPHAGEAL CANCER; HEALTH CARE ORGANIZATION; HUMAN; KIDNEY CANCER; LEUKEMIA; LIVER CARCINOMA; LUNG CANCER; LUNG NON SMALL CELL CANCER; LYMPHOMA; MARINE ENVIRONMENT; MELANOMA; MULTIPLE MYELOMA; NONHUMAN; OVARY CANCER; PANCREAS CANCER; PATENT; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROSTATE CANCER; REVIEW; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTINEOPLASTIC AGENTS; AQUATIC ORGANISMS; BIOLOGICAL AGENTS; CLINICAL TRIALS, PHASE II AS TOPIC; CLINICAL TRIALS, PHASE III AS TOPIC; DNA; DNA-DIRECTED DNA POLYMERASE; DRUG APPROVAL; DRUG DISCOVERY; HUMANS; LYSOSOMES; MICE; MICROTUBULES; PATENTS AS TOPIC; PROTEIN KINASE C;

EID: 84860287730     PISSN: 15748928     EISSN: None     Source Type: Journal    
DOI: 10.2174/157489212799972963     Document Type: Review

References (135)

1. Berenbaum MR. The chemistry of defense: theory and practice. Proc Natl Acad Sci USA 1995; 92: 2-8.
2. Adams CP, Brantner VV. Spending on new drug development. Health Econ 2010; 19: 130-41.
3. Light DW, Warburton R. Drug R&D Costs Questioned. Widely Quoted Average Cost to Bring Drugs to Market Doesn't Appear to Hold Up to Scrutiny. Genetic Engineering & Biotechnology News 2011; 31. Available at: http://www.genengnews.com/keywordsandtools/print/1/23475/ (Accessed September 26, 2011).
4. The American Society of Pharmacognosy. Pharmacognosy In Action. U. S. Research Institutions. Chapter 8. Available at: http://www.pharmacognosy.us/wordpress/wp-content/uploads/ ASP-History-Chapter-8.pdf (Accessed September, 26, 2011).
5. Developmental Therapeutics Program NCI/NIH. Natural Products Repository. Available at: http://dtp.nci.nih.gov/branches/ npb/repository.html (Accessed September 26, 2011).
6. Pharmamar Papers and Research. Presentation by Simon Munt, R&D. Available at: http://www.eumbio.org/papers/biohealthcare/ SimonMunt.pdf (Accessed September 26, 2011).
7. FierceBiotech for FDA Approvals, FDA Regulations and Clinical Trials. Available at: www.fiercebiotech.com/fda_approval (Accessed August 3, 2011).
8. European Medicines Agency. Committee for medicinal products for human use. CHMP. Summary of opinion on Halaven (Eribilin). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Summar y_of_opinion_-_Initial_authorisation/human/002084/ WC500101044.pdf (Accessed September 26, 2011).
9. PR Newswire. United Business Media. Latest News. National Cancer Institute Research Identifies Unique Mechanism of Brostallicin's Anti-Tumor Effectiveness. Available at: http://www.prnewswire.com/news-releases/national-cancerinstitute-research-identifies-unique-mechanism-of-brostallicinsanti-tumor-effectiveness-62235902.html (Accessed September 26, 2011).
10. PubMed search for Soblidotin phase I. Available at: http://www. ncbi.nlm.nih.gov/pubmed?term=Soblidotin%20phase%20I (Accessed September 26, 2011).
11. PubMed search for Tasidotin phase I. Available at: http://www. ncbi.nlm.nih.gov/pubmed?term=Tasidotin%20phase%20I. (Accessed September 26, 2011).
12. National Cancer Institute at the National Institutes of Health. Available at: http://www.cancer.gov/cancertopics/druginfo/ cytarabine (Accessed September 26, 2011).
13. Lu C, Lee JJ, Komaki R, Herbst RS, Feng L, Evans WK, et al. Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trial. J Natl Cancer Inst 2010; 102: 859-65.
14. Cancer Solution. Kahalalide F: Phase II trials for lung cancer, melanoma and hepatocellular carcinoma. Available at: http://www.cancersolution.tk/2011/05/kahalalide-f-phase-ii-trialsfor-lung.html (Accessed September 26, 2011).
15. Goliath. Business Knowledge on demand. Kahalalide F Enters phase II with a trial in liver carcinoma. Available at: http://goliath.ecnext.com/coms2/gi_0199-4064239/Kahalalide-FEnters-Phase-II.html (Accessed September 26, 2011).
16. PubMed search for Aplidin phase II. Available at: http://www.ncbi.nlm.nih.gov/pubmed?term=Aplidin%20phase%20II. (Accessed September 26, 2011).
17. Zonder JA, Shields AF, Zalupski M, Chaplen R, Heilbrun LK, Arlauskas P, et al. A phase II trial of bryostatin 1 in the treatment of metastatic colorectal cancer. Clin Cancer Res 2001; 7:38-42.
18. Nereus Pharmaceuticals. Completes Enrollment of Phase 2 ADVANCE Clinical Trial of Plinabulin in Non-Small Cell Lung Cancer. Available at: http://www.nereuspharm.com/news_06222010. shtml. (Accessed September 26, 2011).
19. National Institute of Health. ClinicalTrials. gov-Study of Zalypsis® (PM00104) in Patients With Unresectable Locally Advanced and/or Metastatic Ewing Family of Tumors (EFT) Progressing After at Least One Prior Line of Chemotherapy. Available at: http://clinicaltrials.gov/ct2/show/NCT01222767. (Accessed September 26, 2011).
20. American Society of Clinical Oncology. 2011 ASCO Annual Meeting. Abstract No: TPS169 Citation: J Clin Oncol 29: 2011 (suppl; abstr TPS169). IMAGE, a randomized phase Ib/II study of elisidepsin in pretreated advanced gastroesophageal cancer. Available at: http://abstract.asco.org/AbstView_102_75992.html (Accessed September 26, 2011).
21. Dumez H, Gall H, Capdeville R, Dutreix C, van Oosterom AT, Giaccone G. A phase I and pharmacokinetic study of LAF389 administered to patients with advanced cancer. Anticancer Drugs 2007; 18: 219-25.
22. American Society of Clinical Oncology. 2008 Gastrointestinal Cancers Symposium. Abstract No: 326. A phase I trial of E7974 administered on day 1 of a 21-day cycle in patients with advanced solid tumors. Available at: http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_ detail_view&confID=53& abstractID=10443 (Accessed September 26, 2011).
23. American Society of Clinical Oncology. Meeting: 2003 ASCO Annual Meeting. Abstract No: 516. Citation: Proc Am Soc Clin Oncol 22: 2003 (abstr 516). Phase 1 and pharmacological study of HTI-286, a novel antimicrotubule agent: Correlation of neutropenia with time above a threshold serum concentration. Available at: http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_de tail_view&confID=23&abstractID=100694. (Accessed September 26, 2011).
24. American Society of Clinical Oncology. Meeting: 2004 ASCO Annual Meeting. Abstract No: 2025 Citation: Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 2025. A phase I pharmacokinetic (PK) trial of XAA296A (Discodermolide) administered every 3 wks to adult patients with advanced solid malignancies. Available at: http://www.asco.org/ ascov2/ Meetings/Abstracts?&vmview=abst_detail_view&conf ID=26&abstractID=1741. (Accessed September 26, 2011).
25. Schöffski P, Dumez H, Ruijter R, Miguel-Lillo B, Soto-Matos A, Alfaro V, et al. Spisulosine (ES-285) given as a weekly three-hour intravenous infusion: results of a phase I dose-escalating study in patients with advanced solid malignancies. Cancer Chemother Pharmacol 2011, Apr 5. [Epub ahead of print].
26. Marine Pharmacology. A.M.S. Mayer, Ph.D. Professor of Pharmacology. Department of Pharmacology. Midwestern University. Marine pharmaceuticals: The clinical pipeline. The clinical pharmaceuticals pipeline page presents the status as of July 2011 of marine-derived compounds which are either been FDA-approved or are in Phase III, II or I of drug development (as determined at http://clinicaltrials.gov/). Available at: http://marinepharmacology. midwestern.edu/clinPipeline.htm (Accessed September 26, 2011).
27. Dumontet C, Jordan MA. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat Rev Drug Discov 2010; 9: 790-803.
28. Calligaris D, Verdier-Pinard P, Devred F, Villard C, Braguer D, Lafitte D. Microtubule targeting agents: From biophysics to proteomics. Cell Mol Life Sci 2010; 67: 1089-104.
29. Kavallaris M. Microtubules and resistance to tubulin-binding agents. Nat Rev Cancer 2010; 10: 194-204.
30. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med 2002; 53: 615-27.
31. Berrieman H K, Lind M J, Cawkwell L. Do β-tubulin mutations have a role in resistance to chemotherapy? Lancet Oncol 2004; 5: 158-64.
32. Sale S, Sung R, Shen P, Yu K, Wang Y, Duran GE, et al. Conservation of the class I β-tubulin gene in human populations and lack of mutations in lung cancers and paclitaxel-resistant ovarian cancers. Mol. Cancer Ther 2002; 1: 215-25.
33. Kamath K, Wilson L, Cabral F, Jordan MA βIII-tubulin induces paclitaxel resistance in association with reduced effects on microtubule dynamic instability. J Biol Chem 2005; 280: 12902-7.
34. Caracciolo V, D'Agostino L, Dráberová E, Sládková V, Crozier-Fitzgerald C, Agamanolis DP, et al. Differential expression and cellular distribution of γ-tubulin and βIII-tubulin in medulloblastomas and human medulloblastoma cell lines. J Cell Physiol 2010; 223(2)519-29.
35. Verrills NM, Liem NL, Liaw TY, Hood BD, Lock RB, Kavallaris M. Proteomic analysis reveals a novel role for the actin cytoskeleton in vincristine resistant childhood leukemia-an in vivo study. Proteomics 2006; 6: 1681-94.
36. Verrills NM, Po'uha ST, Liu ML, Liaw TY, Larsen MR, Ivery MT, et al. Alterations in γ-actin and tubulin-targeted drug resistance in childhood leukemia. J. Natl Cancer Inst 2006; 98: 1363-74.
37. Ferlini C, Raspaglio G, Cicchillitti L, Mozzetti S, Prislei S, Bartollino S, et al. Looking at drug resistance mechanisms for microtubule interacting drugs: Does TUBB3 work? Curr Cancer Drug Targets 2007; 7: 704-12.
38. Balasubramani M, Nakao C, Uechi GT, Cardamone J, Kamath K, Leslie KL, et al. Characterization and detection of cellular and proteomic alterations in stable stathmin-overexpressing, taxol-resistant BT549 breast cancer cells using offgel IEF/PAGE difference gel electrophoresis. Mutat Res 2011; 722: 154-64.
39. Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ, et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature 2011; 471: 110-4.
40. Long BH, Carboni JM, Wasserman AJ, Cornell LA, Casazza AM, Jensen PR, et al. Eleutherobin, a novel cytotoxic agent that induces tubulin polymerisation, is similar to paclitaxel (Taxol). Cancer Res 1998; 58: 1111-15.
41. Hamel E, Sackett DL, Vourloumis D, Nicolaou KC. The coralderived natural products eleutherobin and sarcodictyins A and B: Effects on the assembly of purified tubulin with and without microtubule-associated proteins and binding at the polymer taxoid site. Biochemistry 1999; 38: 5490-98.
42. Altmann KH, Gertsch J. Anticancer drugs from nature-natural products as a unique source of new microtubule-stabilizing agents. Nat Prod Rep 2007; 24: 327-57.
43. Kingston DGI. Tubulin-interactive natural products as anticancer agents. J Nat Prod 2009; 72: 507-15.
44. Saito S. Toxins affecting actin filaments and microtubules. Prog Mol Subcell Biol 2009; 46: 187-219.
45. Cormier A, Marchand M, Ravelli RBG, Knossow M, Gigant B. Structural insight into the inhibition of tubulin by vinca domain peptide ligands. Embo Reports 2008; 9: 1101-6.
46. Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther 2005; 4: 1086-95.
47. Kuznetsov G, TenDyke K, Towle MJ, Cheng H, Liu J, Marsh JP, et al. Tubulin-based antimitotic mechanism of E7974, a novel analogue of the marine sponge natural product hemiasterlin. Mol Cancer Ther 2009; 8: 2852-60.
48. Derry WB, Wilson L, Jordan MA. Low potency of taxol at microtubule minus ends: Implication for its anti-mitotic and therapeutic mechanism. Cancer Res 1998; 58: 1177-84.
49. Ray A, Okouneva T, Manna T, Miller HP, Schmid S, Arthaud L, Luduena R, et al. Mechanism of action of the microtubule-targeted antimitotic depsipeptide tasidotin (formerly ILX651) and its major metabolite tasidotin C-carboxylate. Cancer Res 2007; 67: 3767-76.
50. Canales A, Rodriguez-Salarichs J, Trigili C, Nieto L, Coderch C, Andreu JM, et al. Insights into the interaction of discodermolide and docetaxel with tubulin. Mapping the binding sites of microtubule-stabilizing agents by using an integrated nmr and computational approach. ACS Chem Biol 2011; 6: 789-99.
51. Kowalski RJ, Giannakakou P, Gunasekera SP, Longley RE, Day BW, Hamel E. The microtubule-stabilizing agent discodermolide competitively inhibits the binding of paclitaxel (Taxol) to tubulin polymers, enhances tubulin nucleation reactions more potently than paclitaxel, and inhibits the growth of paclitaxel-resistant cells. Mol Pharmacol 1997; 52: 613-22.
52. Klein LE, Freeze BS, Smith AB 3rd, Horwitz SB. The microtubule stabilizing agent discodermolide is a potent inducer of accelerated cell senescence. Cell Cycle 2005; 4: 501-7.
53. Natsume T, Watanabe J, Tamaoki S, Fujio N, Miyasaka K, Kobayashi M. Characterization of the interaction of TZT-1027, a potent antitumor agent, with tubulin. Jpn J Cancer Res 2000; 91: 737-47.
54. Kobayashi M, Natsume T, Tamaoki S, Watanabe J, Asano H, Mikami T, et al. Antitumor activity of TZT-1027, a novel dolastatin 10 derivative. Jpn J Cancer Res 1997; 88: 316-27.
55. Shimoyama T, Hamano T, Natsume T, Koizumi F, Kiura K, Tanimoto M, et al. Reference profiling of the genomic response induced by an antimicrotubule agent, TZT-1027 (Soblidotin), in vitro. Pharmacogenomics J 2006; 6: 388-96.
56. Watanabe J, Natsume T and Kobayashi M: Anti-vascular effects of TZT-1027 (Soblidotin) on murine Colon 26 adenocarcinoma. Cancer Sci Cancer Sci 2006; 97: 1410-16.
57. Watanabe J, Endo Y, Shimada N, Natsume T, Sasaki T, Kobayashi M. Antiangiogenic activity of TZT-1027 (soblidotin) on chick chorioallantoic membrane and human umbilical vein endothelial cells. In vivo 2007; 21: 297-304.
58. West LM, Northcote PT. Peloruside A: A potent cytotoxic macrolide isolated from the New Zealand marine sponge Mycale sp. J Org Chem 2000; 65: 445-9.
59. Mooberry SL, Tien G, Hernandez AH, Plubrukarn A, Davidson BS. Laulimalide and isolaulimalide, new paclitaxel-like microtubule-stabilizing agents. Cancer Res 1999; 59: 653-60.
60. Huzil JT, Chik JK, Slysz GW, Freedman H, Tuszynski J, Taylor RE, et al. A unique mode of microtubule stabilization induced by peloruside A. J Mol Biol 2008; 378: 1016-30.
61. Bennett MJ, Barakat K, Huzil JT, Tuszynski J, Schriemer DC. Discovery and characterization of the laulimalide-microtubule binding mode by mass shift perturbation mapping. Chem Biol 2010; 17: 725-34.
62. Rustum YM, Raymakers RA. Beta-arabinofuranosylcytosine in therapy of leukemia: Preclinical and clinical overview. Pharmacol Ther 1992; 56: 307-21.
63. Goffin J, Lacchetti C, Ellis PM, Ung YC, Evans WK. Lung Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-Based Care. First-line systemic chemotherapy in the treatment of advanced non-small cell lung cancer: A systematic review. J Thorac Oncol 2010; 5: 260-74.
64. D'Incalci M, Galmarini CM. A review of trabectedin (ET-743): A unique mechanism of action. Mol. Cancer Ther 2010; 9:2157-63.
65. Pommier Y, Kohlhagen G, Bailly C, Waring M, Mazumder A, Kohn KW. DNA sequence-and structureselective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata. Biochemistry 1996; 35: 13303-9
66. Zewail-Foote M, Hurley L H. Ecteinascidin 743: A minor groove alkylator that bends DNA toward the major groove. J Med Chem 1999; 42: 2493-7.
67. Friedman D, Hu Z, Kolb EA, Gorfajn B, Scotto KW. Ecteinascidin-743 inhibits activated but not constitutive transcription. Cancer Res 2002; 62: 3377-81.
68. Minuzzo M, Marchini S, Broggini M, Faircloth G, D'Incalci M, Mantovani R. Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. Proc Natl Acad Sci USA 2000; 97: 6780-84.
69. Takebayashi Y, Pourquier P, Zimonjic DB, Nakayama K, Emmert S, Ueda T, et al. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med 2001; 7: 961-66,
70. Aune GJ, Takagi K, Sordet O, Guirouilh-Barbat J, Antony S, Bohr VA, Pommier Y. Von Hippel-Lindau-coupled and transcriptioncoupled nucleotide excision repair-dependent degradation of RNA polymerase II in response to trabectedin. Clin Cancer Res 2008; 14: 6449-55.
71. Guirouilh-Barbat J, Redon C, Pommier Y. Transcription-coupled DNA double-strand breaks are mediated via the nucleotide excision repair and the Mre11-Rad50-Nbs1 complex. Mol Biol Cell 2008; 19: 3969-81.
72. Bayet-Robert M, Lim S, Barthomeuf C, Morvan D. Biochemical disorders induced by cytotoxic marine natural products in breast cancer cells as revealed by proton NMR spectroscopy-based metabolomics. Biochem Pharmacol 2010; 80: 1170-9.
73. Sewell JM, Mayer I, Langdon SP, Smyth JF, Jodrell DI, Guichard SM. The mechanism of action of Kahalalide F: Variable cell permeability in human hepatoma cell lines. Eur J Cancer 2005; 41: 1637-44.
74. Herrero AB, Astudillo AM, Balboa MA, Cuevas C, Balsinde J, Moreno S. Levels of SCS7/FA2H-mediated fatty acid 2-hydroxylation determine the sensitivity of cells to antitumor PM02734. Cancer Res 2008; 68: 9779-87.
75. Suárez Y, González L, Cuadrado A, Berciano M, Lafarga M, Muñoz A. Kahalalide F, a new marine-derived compound, induces oncosis in human prostate and breast cancer cells. Mol Cancer Ther 2003; 2: 863-72.
76. Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 1995; 146: 3-15.
77. Tracy K, Macleod KF. Regulation of mitochondrial integrity, autophagy and cell survival by BNIP3. Autophagy 2007; 3: 616-9.
78. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation and tumorigenesis. Cancer Cell 2006; 10: 51-64.
79. Maclean KH, Dorsey FC, Cleveland JL, Kastan MB. Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J Clin Invest 2008; 118: 79-88.
80. Kanzawa T, Zhang L, Xiao L, Germano IM, Kondo Y, Kondo S. Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. Oncogene 2005; 24: 980-91.
81. Gargini R, García-Escudero V, Izquierdo M. Therapy mediated by mitophagy abrogates tumor progression. Autophagy 2011; 7: 466-76.
82. Janmaat ML, Rodriguez JA, Jimeno J, Kruyt FA, Giaccone G. Kahalalide F induces necrosis-like cell death that involves depletion of ErbB3 and inhibition of Akt signaling. Mol Pharmacol 2005; 68:502-10.
83. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002;298: 1912-34.
84. Griner EM, Kazanietz MG. Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer 2007; 7:281-94.
85. Reyland ME. Protein kinase C isoforms: Multi-functional regulators of cell life and death. Front Biosci 2009; 14: 2386-99.
86. Faircloth, G.T., Marín, P.M.A., Lepage, D., Izquierdo, J.S.M., Pandiella, A. Antitumoral treatments. US20090246168 (2009).
87. Lepage, D., Marín, P.M.A., Guillen M.J. Anticancer treatments. US20110009335 (2011).
88. Yusri, A. E. Anticancer treatments. US20100009906 (2010).
89. Cvitkovich, E., Demetri, G.D., Guzman, C., Jimeno, J., Lazaro, L.L., Misset, J.L. Twelves, C., Von Hoff, D.D. Compositions and uses of ET743 for treating cancer. US20070275942 (2007).
90. Takahashi, N., Weitman, S., D'incalci, M., Faircloth, G.T., Giavazzi, R., Gescher, A. Effective antitumor treatments. US20090324744 (2009).
91. Jonker DM, Visser SA, van der Graaf PH, Voskuyl RA, Danhof M. Towards a mechanism-based analysis of pharmacodynamic drugdrug interactions in vivo. Pharmacol Ther 2005; 106:1-18.
92. Carrick S, Parker S, Thornton CE, Ghersi D, Simes J, Wilcken N. Single agent versus combination chemotherapy for metastatic breast cancer. Cochrane Database Syst Rev 2009; 15: CD003372.
93. European Medicines Agency. ASSESSMENT REPORT FOR YONDELIS International non-proprietary name/Common name: trabectedin. Procedure No. EMEA/H/C/000773/II/0008. Available at:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR _-_Assessment_Report_-Variation/human/000773/WC500059175. pdf. (Accessed September 26, 2011).
94. Del Campo JM, Muñoz-Couselo E, Diaz de Corcuera I, Oaknin A. Trabectedin combined with liposomal doxorubicin in women with relapsed ovarian cancer. Expert Rev Anticancer Ther 2010; 10: 795-805.
95. Barr PM, Lazarus HM, Cooper BW, Schluchter MD, Panneerselvam A, Jacobberger JW, et al. Phase II study of bryostatin 1 and vincristine for aggressive non-Hodgkin lymphoma relapsing after an autologous stem cell transplant. Am J Hematol 2009; 84:484-7.
96. Lam AP, Sparano JA, Vinciguerra V, Ocean AJ, Christos P, Hochster H, et al. Phase II study of paclitaxel plus the protein kinase C inhibitor bryostatin-1 in advanced pancreatic carcinoma. Am J Clin Oncol 2010; 33:121-4.
97. Morgan RJ Jr, Leong L, Chow W, Gandara D, Frankel P, Garcia A, et al. Phase II trial of bryostatin-1 in combination with cisplatin in patients with recurrent or persistent epithelial ovarian cancer: a California cancer consortium study. Invest New Drugs 2010 Oct 9. [Epub ahead of print].
98. Wender, P.A., Lippa, B., Park, C.-M., Hinkle, K.W. Bryostatin analogues, synthetic methods and uses. US7256286 (2007).
99. Pettit, G.R., Xu, J.-P. Synthesis and complete stereochemical assignment of psymberin/irciniastatin for use as antitumor compounds. US7439265 (2008).
100. Martinez, V., Flores, M., Gallego, P., Cuevas, C., Munt, S., Manzanares, I. Antitumoral derivatives of ET-743. US7759345 (2010).
101. Harran, P., Wang, X., Wang, G. Ornithine aminotransferase (OAT): A target for anticancer drugs. US7622289 (2009).
102. Barrasa, V.M., Gallego, P., Cuevas, C., Munt, S., Manzanares, I., Menchaca, R., Rodriguez, N., Rodriguez, A. Synthesis of naturally occuring ecteinascidins and related compounds. US7947671 (2011).
103. Ling, T., Danishefsky, S. Total synthesis of Salinosporamide A and analogs thereof. US8003802 (2011).
104. Bertino, J.R., Barnejee, D., Guray, S., Jimeno, J., Faircloth, G.T. Antitumoral treatments. US7576188 (2009).
105. Fenical, W.H., Jensen, P. R. Method for the production of bioactive substances from the novel Actinomycete Taxa MAR3A, MAR3B and MAR4 belonging to the family of treptomycetaceae. US20090142331 (2004).
106. Strand, M., Sundberg, P. Sustainable method for synthesizing tetrodotoxin (TTX). US20110081690 (2010).
107. McIntosh, M.C. Novel isobenzofuran analogs of sclerophytin A. US20100331370 (2010).
108. Williams NS, Burgett AW, Atkins AS, Wang X, Harran PG, McKnight SL. Therapeutic anticancer efficacy of a synthetic diazonamide analog in the absence of overt toxicity. Proc Natl Acad Sci USA 2007; 104: 2074-9.
109. Williams NS, Burgett AW, Atkins AS, Wang X, Harran PG, McKnight SL. Diazonamide toxins reveal an unexpected function for ornithine delta-amino transferase in mitotic cell division. Proc Natl Acad Sci USA 2007; 104(7): 2068-73.
110. Hongpaisan J, Sun MK, Alkon DL. PKCå activation prevents synaptic loss, Aâ elevation, and cognitive deficits in Alzheimer's disease transgenic mice. J Neurosci 2011; 31:630-43.
111. Mehla R, Bivalkar-Mehla S, Zhang R, Handy I, Albrecht H, Giri S, et al. Bryostatin modulates latent HIV-1 infection via PKC and AMPK signaling but inhibits acute infection in a receptor independent manner. PLoS One 2010; 5(6): e11160.
112. Choi SH, Hyman T, Blumberg PM. Differential effect of bryostatin 1 and phorbol 12-myristate 13-acetate on HOP-92 cell proliferation is mediated by down-regulation of protein kinase C delta. Cancer Res 2006; 66: 7261-9.
113. Cole G, Dobkins KR, Hansen LA, Terry RD, Saitoh T. Decreased levels of protein kinase C in Alzheimer brain. Brain Res 1988; 452: 165-74.
114. Lewin SR, Rouzioux C. HIV cure and eradication: How will we get from the laboratory to effective clinical trials? AIDS 2011; 25: 885-97.
115. Keck GE, Poudel YB, Cummins TJ, Rudra A, Covel JA. Total synthesis of bryostatin 1. J Am Chem Soc 2011; 133: 744-7.
116. Russo P, Nastrucci C, Cesario A. From the sea to anticancer therapy. Curr Med Chem 2011; 18: 3551-62.
117. Mini E, Nobili S, Caciagli B, Landini I, Mazzei T. Cellular pharmacology of gemcitabine. Ann Oncol 2006; 17 (Suppl 5): v7-12.
118. Glaser KB, Mayer AM. A renaissance in marine pharmacology: From preclinical curiosity to clinical reality. Biochem Pharmacol 2009; 78: 440-8.
119. Mendola D. Aquaculture of three phyla of marine invertebrates to yield bioactive metabolites: process developments and economics. Biomol Eng 2003; 20: 441-58.
120. Wender PA, Baryza JL, Brenner SE, DeChristopher BA, Loy BA, Schrier AJ, et al. Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity. Proc Natl Acad Sci USA 2011; 108: 6721-6.
121. Nagelkerken I, Blaber S, Bouillon S, Green P, Haywood M, et al. The habitat function of mangroves for terrestrial and marine fauna: A review. Aquatic Biology 2008; 89: 155-85.
122. Valoti G, Nicoletti MI, Pellegrino A, Jimeno J, Hendriks H, D'Incalci M, et al. Ecteinascidin-743, a new marine natural product with potent antitumor activity on human ovarian carcinoma xenografts. Clinical Cancer Res 1998; 4: 1977-83.
123. Lipinski CA, Lombardo F, Domini BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997; 23: 3-25.
124. Ebada SS, Edrada RA, Lin W, Proksch P. Methods for isolation, purification and structural elucidation of bioactive secondary metabolites from marine invertebrates. Nat Protoc 2008; 3: 1820-31.
125. EUR-Lex. Access to European Union Law. 32008l0056-EN-. Title and Reference: Directive 2008/56/ec of the European Parliament and of the Council of 17 June 2008 establishing a framework for community action in the field of marine environmental policy (Marine Strategy Framework Directive). Available at: http://eurlex. europa.eu/lexuriserv/lexuriserv.do?uri=celex:32008l0056:en:no t (Accessed September 26, 2011).
126. International Maritime Organization. Available at: http://www.imo.org/Pages/home.aspx (Accessed September 26, 2011).
127. Ashburn TT, Thor KB. Drug repositioning: Identifying and developing new uses for existing drugs. Nat Rev Drug Discov 2004; 3: 673-83.
128. Evans DA, Carter PH, Carreira EM, Prunet JA, Charette AB, Lautens, M. Asymmetric synthesis of bryostatin 2. Angew Chem Int Ed 1998; 37: 2354-59.
129. Manaviazar S, Hale KJ. Total synthesis of bryostatin 1: A Short Route. Angew Chem Int Ed 2011; 50: 8786-9.
130. Pettit GR, Sengupta D, Blumberg PM, Lewin NE, Schmidt JM, Kraft AS. Structural modifications of bryostatin 2. Anticancer Drug Des 1992; 7:101-14.
131. Wender PA, Dechristopher BA, Schrier AJ. Efficient synthetic access to a new family of highly potent bryostatin analogues via a Prins-driven macrocyclization strategy. J Am Chem Soc 2008; 130: 6658-9.
132. Martinez EJ, Corey EJ. A new, more efficient, and effective process for the synthesis of a key pentacyclic intermediate for production of ecteinascidin and phthalascidin antitumor agents. Org Lett 2000; 27: 993-6.
133. Faulkner DJ. Marine pharmacology. Antonie van Leeuwenhoek 2000; 77: 135-45.
134. Maxwell S., Medicine from The Deep-The importance of Protecting the High Seas by the Natural Resources Defense Council (NRDC), Issue paper: March 2005; Available at: http://www.nrdc.org/water/oceans/medicines/contents.asp (Accessed September 26, 2011).
135. Matthew Gianni, High Seas Bottom Trawl Fisheries And Their Impacts On The Biodiversity of vulnerable Deep Sea Ecosystem: Options for International Action. IUCN-The World Conservation Union-2004. Report prepared for IUCN-The World Conservation Union, Natural Resources Defense Council (NRDC), WWF International and Conservation International. Published by: IUCN, Gland, Switzerland. Available at: http://www.illegalfishing. info/uploads/High_seas_bottom_trawl_fisheries_-_Gianni.pdf (Accessed September 26, 2011).