The use of embryonic stem cells for regulatory developmental toxicity testing in vivo - The current status of test development

Current Pharmaceutical Design

Volumn 10, Issue 22, 2004, Pages 2733-2747

  Bremer, Susanne ^a   Hartung, T ^a  

^a JOINT RESEARCH CENTRE   (Italy)

Author keywords

Alternative method; Chemical policy; Developmental toxicity; Embryonic stem cells; Test strategy

Indexed keywords

6 AMINONICOTINAMIDE; ARABINOSIDE; BORIC ACID; BROXURIDINE; CADMIUM CHLORIDE; CAFFEINE; CYCLOPHOSPHAMIDE; CYTARABINE; DEXAMETHASONE; DIMETHADIONE; FLUOROURACIL; GREEN FLUORESCENT PROTEIN; HYDROXYUREA; INDOMETACIN; ISONIAZID; LITHIUM CHLORIDE; MESSENGER RNA; METHOTREXATE; METHOXYACETIC ACID; METHYLMERCURIC CHLORIDE; MONOCLONAL ANTIBODY; PENICILLIN G; PHENYTOIN; POLYCLONAL ANTIBODY; RETINOIC ACID; SACCHARIN; SALICYLIC ACID; THALIDOMIDE; UNINDEXED DRUG; VALPROIC ACID;

ANIMAL TESTING ALTERNATIVE; BODY WEIGHT DISORDER; CARDIOTOXICITY; CELL DIFFERENTIATION; CELL INTERACTION; CONGENITAL MALFORMATION; CYTOTOXICITY; DEVELOPMENTAL DISORDER; EMBRYO; EMBRYO CELL; EMBRYOTOXICITY; EUROPEAN UNION; EXPERIMENTAL MODEL; FLOW CYTOMETRY; GENETIC ENGINEERING; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; INTERMETHOD COMPARISON; POLICY; POLYMERASE CHAIN REACTION; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN EXPRESSION; PROTEIN MICROARRAY; REPORTER GENE; REVIEW; SAFETY; SKELETON MALFORMATION; STEM CELL; STILLBIRTH; TECHNOLOGY; TERATOGENICITY; TOXICITY TESTING; WORKSHOP;

ABNORMALITIES, DRUG-INDUCED; ANIMAL TESTING ALTERNATIVES; ANIMALS; EMBRYO; FEMALE; HUMANS; PREGNANCY; STEM CELLS; TOXICITY TESTS;

EID: 4344562814     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/1381612043383700     Document Type: Review

References (110)

1. Anon (2003) Third Report from the Commission to the Council and the European Parliament on the statistics on the number of animals used for experimental and other scientific purposes in the member states of the European Union/ COM/2003/0019final. http://europa.eu.int/eur-lex/ en/com/rpt/2003/com2003_0019en01.pdf (Accessed. 20.6.2003)
2. Anon (2001) White Paper on a Strategy for a Future Chemicals Policy. Brussels: Commission of the European Communities. http://europa.eu.int/comm/environment/chemicals/whitepaper.htm (Accessed: 27.5.2003)
3. Anon (2003) Directive 2003/15/EC of the European Parliament and of the Council of 27 February 2003 amending Council Directive 76/768/EEC on the approximation of the laws of the Member States relating to cosmetic products. http://europa.eu.int/eur-lex/pri/en/oj/dat/2003/ 1_066/1_06620030311en00260035.pdf (Accessed 20.6.2003)
4. Nelson K, Holmes LB. Malformations due to presumed spontaneous mutations in newborn infants N Engl J Med 1989; 320: 19-23.
5. Holmes LB. Impact of the detection and prevention of developmental abnormalities in human studies. Reprod Toxicol 1997; 11: 267-9
6. Brown AK, Damus K, Kim MH, King K, Harper R, Campbell D, et al. Factors relating to readmission of term and near-term neonates in the first two weeks of life. Early Discharge Survey Group of the Health Professional Advisory Board of the Greater New York Chapter of the March of Dimes. J Perinat Med 1999; 27, 263-75
7. Wilson JG. Teratogenic effects of environmental chemicals. Fed.Proc. 1977; 36: 1698-703
8. European chemicals buero. http://ecb.jrc.it/new-chemicals/ (Accessed 20.6.2003)
9. Kitamura S. Epidemiology of Minamata disease - epidemiological approach to the organomercury poisoning. Saishin Igaku 1971; 26: 1966-72
10. Harada M. Congenital Minamata disease: intrauterine methylmercury poisoning. Teratology 1978; 18: 285-8
11. McBride WG. Thalidomide and congenital abnormalities. The Lancet 1961; 2: 1358.
12. Lenz W. Malformations caused by drugs in pregnancy. Am J Dis Child 1966; 112: 99-106.
13. Petrini J, Damus K, Johnston RB Jr. An overview of infant mortality and birth defects in the United States. Teratology 1997; 56: 8-10.
14. Brown NA. Teratogenicity testing in vitro: status of validation studies. Arch Toxicol Suppl 1987; 11: 105.
15. Harris C. In: Comprehensive Toxicology 10 Boekelhade K Ed, In vivo and in vitro methods in developmental toxicology. Elsevier Pergamon. 1997; 607-17.
16. Armstrong L, Lako M; Lincoln J; Cairns PM, Hole N. mTert expression correlates with telomerase activity during the differentiation of murine embryonic stem cells. Mech Dev 2000; 97: 109-116.
17. Spielmann H. Reproduction and Development. Environmental Health Perspectives 1998; 106: 571-5.
18. Kimmel GLK, Smith MK, Kochhar DM, Pratt RM. Overview of in vitro teratogenicity testing: Aspects of validation and application to screening. Teratog Carcinog Mutagen 1981; 2: 221-9.
19. Schwetz BA, Morrissey RE, Welsch F, Kavlock RA. In vitro teratology. Environ Health Perspect 1991; 94: 265-8.
20. Brown NA, Spielmann H, Bechter R, Flint OP, Freemann RJ, Jelinek RJ, et al Screening chemicals for Reproductive Toxicity: The Current Alternatives. ATLA 1995;23: 868-86.
21. Pratt RM, Grove RI, Willis WD. Prescreening of environmental teratogens using cultured mesenchymal cells from the embryonic palate. Teratogenesis, Carciogenesis and Mutagenesis 1982; 2: 313-8.
22. Heuer J, Bremer S, Pohl I, Spielmann H. Development of an in vitro embryotoxicity test using murine embryonic stem cell cultures. Toxicol in vitro 1995; 7: 551-6.
23. Flint OP. In vitro tests for teratogens:desirable endpoints, test batteries and current status of the micromass teratogen test. Reprod Toxicol. 1993; 7:103-11.
24. Jelinek R. In: Neubert D, Merker HJ, Kwasigroch TE. Ed, Methods in prenatal toxicology, Stuttgart, G Thieme 1977; 381-6.
25. Dawson DA, Fort DJ, Newall DL, Bantle JA. Developmental toxicity testing with FETAX: evaluation of five compounds. Drug and Chemical Toxicology 1989; 12:67-75.
26. Sadler TW, Horton WE, Warner CW. Whole embryo culture: a screening technique for teratogens? Teratogenesis, Carcinogenesis and Mutagenesis 1982; 2:243-53.
27. Anon (2000) Frog Embryo Teratogenesis Assay-Venopus (FETAX) http://iccvam.niehs.nih.gov/methods/fetax.htm (Accessed 20.6. 2003).
28. Genschow E, Spielmann H, Scholz G, Seiler A, Brown N, Piersma A, et al. The ECVAM international validation study on in vitro embryotoxicity tests: results of the definitive phase and evaluation of prediction models. ATLA 2000; 30: 151-76.
29. Genschow E, Spielmann H, Scholz G, Pohl I, Seiler A, Bremer S, et al. Validation of the embryonic stem cell test (EST) in the international ECVAM validation study of three in vitro embryotoxicity tests Manuscript accepted in ATLA.
30. Okabe S, Forsberg-Nilsson K. Spiro AC, Segal M, McKay RD. Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mech Dev 1996; 59: 89-102.
31. Bagutti C, Wobus AM, Fassler R, Watt FM. Differentiation of embryonal stem cells into keratinocytes: comparison of wild-type and beta 1 integrin-deficient cells. Dev Biol 1996; 179: 184-96.
32. Zur Nieden NI, Kempka G, Ahr HJ. In vitro differentiation of embryonic stem cells into mineralized osteoblasts. Differentiation 2000; 71: 18-27.
33. Nakayama N, Duryea D, Manoukian R, Chow G, Han CY. Macroscopic cartilage formation with embryonic stem-cell-derived mesodermal progenitor cells. J Cell Sci 2003; 116: 2015-28.
34. Maltsev VA, Rohwedel J, Hescheler J, Wobus AM. Embryonic stem cells differentiate in vitro into cardiomyocytes representing sinusnodal, atrial and ventricular cell types. Mech Dev 1993; 44: 41-50.
35. Dani C. Embryonic stem cell-derived adipogenesis. Cells Tissues Organs 1999; 165: 173-80.
36. Newall DR, Beedles KE. The stem cell test-a novel in vitro assay for teratogenic potential. Toxicology in vitro 1994; 8: 697-701.
37. Scholz G, Pohl I, Genschow E, Klemm M, Spielmann H. Embryotoxicity screening using embryonic stem cells in vitro: correlation to in vivo teratogenicity. Cells Tissues Organs 1999; 165: 203-11.
38. Laschinski G, Vogel R, Spielmann H. Cytotoxicity test using blastocyst-derived euploid embryonal stem cells: a new approach to in vitro teratogenesis screening. Reprod Toxicol 1991; 5: 57-64.
39. Spielmann H, Pohl I, Doering B, Liebsch M, Moldenhauer F. The embryonic stem cell test (EST), an in vitro embryotoxicity test using two permanent mouse cell lines: 3T3 fibroblasts and embryonic stem cells. In Vitro Toxicology 1997; 10: 119-27.
40. Scholz G, Pohl I, Seiler A, Bremer S, Brown NA, Piersma AH, et al. Results of the first phase of The ECVAM project " prevalidation and validation of three in vitro embryotoxicity tests. ALTEX 1998; 15: 3-8.
41. Brown NA. Selection of test chemicals for the ECVAM international validation study on in vitro embryotoxicity tests. European Centre for the Validation of Alternative Methods. ATLA 2002; 30: 177-98.
42. Worth A, Balls M. The importance of the prediction model in the validation of alternative methods. ATLA 2001; 29: 135-43.
43. Maltsev VA, Rohwedel J, Hescheler J, Wobus AM. Embryonic stem cells differentiate in vitro into cardiomyocytes representing sinusnodal, atrial and ventricular cell types. Mech Dev 1993; 44: 41-50.
44. Baker RK, Lyons GE. Embryonic stem cells and in vitro muscle development. Curr Top Dev Biol 1996; 33: 263-79.
45. Doevendans PA, Kubalak SW, An RH, Becker DK, Chien KR, Kass RS. Differentiation of cardiomyocytes in floating embryoid bodies is comparable to fetal cardiomyocytes. Mol Cell Cardiol 2000; 32: 839-51.
46. Rohwedel J, Guan K, Hegert C, Wobus AM. Embryonic stem cells as an in vitro model for mutagenicity, cytotoxicity and embryotoxicity studies: present state and future prospects. Toxicol In Vitro 2001; 15: 741-53.
47. Rudnicki M, Jackowski G, Saggin L, McBurney M. Actin and Myosin expression during development of cardiac muscle from cultured embryonal carcinoma cells. Dev Biol 1990; 138:348-58.
48. Wobus AM, Rohwedel J, Maltsev V, Hescheler J. In vitro differentiation of embryonic stem cells into cardiomyocytes and skeletal muscle cells is specifically modulated by retinoic acid. Roux's Arch Dev Biol 1994; 204: 36-45
49. Anon (2001) OECD Guidelines for testing of chemicals, Guideline 414: Prenatal developmental toxicity study. http://www.sourceoecd.org/content/templates/co/ coīn_oecdguid.htm?comm=oecdguid (Accessed: 30.6.2003)
50. Bigot K, Clothier R, Bremer S. An embryotoxicological investigation of protein expression during embryonic stem cell differentiation. ATLA 1999; 27: 291.
51. Bigot K, de Lange J, Archer G, Clothier R, Bremer S. The relative semi-quantitative expression as useful toxicological endpoint for identification of embryotoxic/teratogenic substances. Toxicology in vitro 1999; 13: 619-23.
52. Paparella M, Kollossov E, Fleischmann B, Hescheler J, Balls M, Bremer S. The use of quantitative image analysis in the assessment of in vitro embryotoxicity endpoints based on a novel embryonic stem cell clone with endoderm-related GFP expression. Toxicology In Vitro 2002; 16: 589-97.
53. Zur Nieden NI, Ruf L, Kempka G, Hildebrand H, Ahr HJ. Molecular markers in embryonic stem cells. Toxicol In Vitro 2001; 15: 455-61.
54. Bremer S, Bigot K. Comparison of three different toxicological endpoints in the establishment of an in vitro embryotoxicity screening system based on embryonic stem cells. Eur J Cell Biol 1997; 74: 26.
55. Spielmann H, Scholz G, Pohl I, Genschow E, Klemm M, Visan A. The use of transgenic embryonic stem cells and molecular markers of differentiation for improving the embryonic stem cell test. Congenital Anomalies 2000; 40: 8-18.
56. Seiler A, Visan A, Pohl I, Genschow E, Buesen R, Spielmann H. Improving the embryonic stem cell test (EST) by establishing molecular endpoints of tissue specific development using murine embryonic stem cells (D3 cells). ALTEX 2002;19: 55-63.
57. Zur Nieden NI, Kempka G, Ahr HJ. In vitro differentiation of embryonic stem cells into mineralized osteoblasts. Differentiation 2003; 71: 18-27.
58. Zur Nieden NI, Kempka G, Ahr HJ. Molecular multiple endpoint embryonic stem cell test-an approach for testing the teratogenic potential of compounds. (Manuscript submitted).
59. Metzger J, Wan-In L, Samuelson LC. Vital staining of cardiac myocytes during embryonic stem cell cardiogenesis in vitro. Circulation Research 1996; 78: 547-52.
60. Kolossov E, Fleischmann B, Liu Q, Bloch W, Viatchenko-Karpinski S, Manzke O, et al. Functional Characteristics of ES cell - derived Cardiac Precursor cells identified by tissue-specific expression of the green fluorescent protein Journal of cell biology 1998; 143: 2045-55.
61. Fleischmann M, Bloch W, Kolossov E, Andressen C, Muller M, Brem G, et al. Cardiac specific expression of the green fluorescent protein during early murine embryonic development. FEBS Lett. 1998; 440: 370-6.
62. Meyer N, Jaconi M, Landopoulou A, Fort P, Puceat M. A fluorescent reporter gene as a marker for ventricular specification in ES-derived cardiac cells. FEBS Lett 2000; 478: 151-8.
63. Bremer S, van Dooren M, Paparella M, Kolossov E, Fleischmann B, Hescheler J. Effects of embryotoxic chemicals on the in vitro differentiation of genetically engineered ES cells into cardiac cells. Toxicology In Vitro 1999; 13: 645-50.
64. Bremer S, Worth A, Paparella M, Bigot K, Kolossov E, Fleischmann B, et al. Establishment of an in vitro reporter gene assay for developmental cardiac toxicity. Toxicology In Vitro 2001; 15: 215-23.
65. Paparella M, Kolossov E, Fleischmann B, Hescheler J, Balls M, Bremer S. The use of quantitative image analysis in the assessment of in vitro embryotoxicity endpoints based on a novel embryonic stem cell clone with endoderm-related GFP expression. Toxicology In Vitro 2002; 16: 589-97.
66. Committee on Developmental Toxicology Board on Environmental Studies and Toxicology Commission of Life Sciences Signaling Pathways in Development. In: Scientific Frontiers in Developmental toxicology and risk assessment; The National Academy of Sciences; Washington 2000, National Academy Press; 124-36.
67. Kelly DL, Rizzino A. DNA microarray analyses of genes regulated during the differentiation of embryonic stem cells. Mol Reprod Dev 2000; 56: 113-23.
68. Tanaka TS, Kunath T, Kimber WL, Jaradat SA, Stagg CA, Usuda M, et al. Gene expression profiling of embryo-derived stem cells reveals candidate genes associated with pluripotency and lineage specificity. Genome Res 2002; 12: 1921-28.
69. Kriz V, Anneren C, Lai C, Karlsson J, Mares J, Welsh M. The SHB adapter protein is required for efficient multilineage differentiation of mouse embryonic stem cells. Exp Cell Res 2003; 286: 40-56.
70. Bishop JB, Witt K, Sloane RAGenetic toxicities of human teratogens. Mutat Res 1997; 396: 9-43.
71. Kimmel GL, Smith K, Kochhar DM, Pratt RM. Proceedings of the consensus workshop on in vitro teratogenesis testing. Teratogenesis Carcinog Mutagen 1982; 2: 221-374.
72. Brown NA, Freeman SJ. Alternative tests for teratogenicity. ATLA 1984; 12: 7.
73. Christian MS, Dansky L, Gabel BEG. Use of the adult developmetal relationship in pre-screening for developmental hazards. Teratogen Carcinogen Mutagen 1987; 7: 273.
74. Kimmel GL. In: In vitro assays in developmental toxicology: Their potential application in risk assessment. Ed. Kimmel GL, Kochhar DM. CRC press inc. Boca Raton Florida 1990; 163-73.
75. Bremer S, Pellizzer C, Coecke S, Paparella M, Catalani P. Detection of the embryotoxic Potential of Cyclophosphamide by Using a combined System of Metabolic competent Cells and Embryonic stem cells. ATLA 2002; 30: 77-85.
76. Pellizzer C, Adler S, Corvi R, Hartung T, Bremer S. Monitoring of teratogenic effects in vitro by analysing a selected gene expression. Toxicol In Vitro 2004; 18: 325-35.
77. Taniguchi M, Miura K, Iwao H, Yamanaka S. Quantitative assessment of DNA microarrays-comparison with Northern blot analyses. Genomics 2001; 71: 34-9.
78. Shamblott MJ, Axelman J, Wang S, Bugg EM, Littlefield JW, Donovan PJ, et al. Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc Natl Acad Sci USA 1998; 95:13726-31.
79. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science 1998; 282: 1145-7.
80. Anon (2003) Commission staff working paper. Report on human embryonic stem cells research. http://europa.eu.int/comm/research/conferences/2003/bioethics/p df/sec2003-441report_en.pdf (Accessed 19.6.2003)
81. Anon (2000) Ethical aspects of human stem cell research and use http://europa.eu.int/comm/europeano_group_ethics/docs/avis15_en.pdf (Accessed 2.7.2003)
82. Anon (2002) Ethical aspects of patenting inventions involving human stem cells http://europa.eu.int/comm/european_group_ethics/avis3_en.htm (Accessed 2.7.2003)
83. Westfall MV, Samuelson LC, Metzger JM. Troponin I isoform expression is developmentally regulated in differentiating embryonic stem cell-derived cardiac myocytes. Dev. Dyn. 1996; 206: 24-38.
84. Darmon M, Buc-Caron MH, Paulin D, Jacob F. Control by the extracellular environment of differentiation pathways in 1003 embryonal carcinoma cells: study at the level of specific intermediate filaments. EMBO J 1982; 1: 901-6.
85. Zur Nieden NI, Ruf LJ, Kempka G, Hildebrand H, Ahr HJ. Molecular markers in embryonic stem cells. Toxicology in vitro 2001; 15: 455-61.
86. Rudnicki MA, Jackowski G, Saggin L, McBurney MW. Actin and myosin expression during development of cardiac muscle from cultured embryonal carcinoma cells. Dev Biol 1990; 138: 348-58.
87. Rohwedel J, Kleppisch T, Pich U, Guan K, Jin S, Zuschratter W, et al. Formation of postsynaptic-like membranes during differentiation of embryonic stem cells in vitro. Exp Cell Res 1998; 239:214-25.
88. Fraichard A, Chassande O, Bilbaut G, Dehay C, Savatier P, Samarut J. In vitro differentiation of embryonic stem cells into glial cells and functional neurons. J Cell Sci 1995; 108: 3181-8.
89. Bader D, Masaki T, Fischman DA. Immunochemical analysis of myosin heavy chain during avian myogenesis in vivo and in vitro. J Cell Biol. 1982; 95: 763-70.
90. Guan K, Furst DO, Wobus AM. Modulation of sarcomere organization during embryonic stem cell-derived cardiomyocyte differentiation. Eur J Cell Biol. 1999 ;78 :813-23.
91. Kemler R, Brulet P, Schnebelen MT, Gaillard J, Jacob F. Reactivity of monoclonal antibodies against intermediate filament proteins during embryonic development. J Embryol Exp Morphol 1981; 64: 45-60.
92. Bagutti C, Wobus AM, Fassler R, Watt FM. Differentiation of embryonal stem cells into keratinocytes: comparison of wild-type and beta 1 integrin-deficient cells. Dev Biol 1996; 179: 184-96.
93. Fassler R, Rohwedel J, Maltsev V, Bloch W, Lentini S, Guan K, et al. Differentiation and integrity of cardiac muscle cells are impaired in the absence of beta 1 integrin. Cell Sci 1996; 109: 2989-99.
94. Weitzer G, Milner DJ, Kim JU, Bradley A, Capetanaki Y. Cytoskeletal control of myogenesis: a desmin null mutation blocks the myogenic pathway during embryonic stem cell differentiation. Dev Biol 1995; 172: 422-39.
95. Solter D, Knowles BB. Monoclonal antibody defining a stage specific mouse embryonic antigen (SSEA-1) Proc Natl Acad Sci USA 1978; 75: 5565-5569.
96. Angelov DN, Arnhold S, Andressen C, Grabsch H, Puschmann M, Hescheler J, et al. Temporospatial relationships between macroglia and microglia during in vitro differentiation of murine stem cells. Dev Neurosci 1998; 20: 42-51.
97. Han R, Su P, Shang KG. The specific labelling of mouse embryonic stem cells. Yi Chuan Xue Bao 2001; 28: 816-21.
98. Eiges R, Schuldiner M, Drukker M, Yanuka O, Itskovitz-Eldor J, Benvenisty N. Establishment of human embryonic stem cell-transfected clones carrying a marker for undifferentiated cells. Curr Biol 2001; 11: 514-8.
99. Armstrong L, Lako M, Lincoln J, Cairns PM, Hole N. mTert expression correlates with telomerase activity during the differentiation of murine embryonic stem cells. Mech Dev 2000; 97 :109-16.
100. Meyer N, Jaconi M, Landopoulou A, Fort P, Puceat M. A fluorescent reporter gene as a marker for ventricular specification in ES-derived cardiac cells. FEBS Lett 2000; 478: 151-8.
101. Schreiber KL, Calderone A, Rindt H. Distant upstream regulatory domains direct high levels of beta -myosin heavy chain gene expression in differentiated embryonic stem cells. J Mol Cell Cardiol 2000; 32: 585-98.
102. Kolossov E, Fleischmann BK, Liu Q, Bloch W, Viatchenko-Karpinski S, Manzke O, et al. Functional characteristics of ES cell-derived cardiac precursor cells identified by tissue-specific expression of the green fluorescent protein. J Cell Biol 1998; 143: 2045-56.
103. Takahashi T, Lord B, Schulze PC, Fryer RM, Sarang SS, Gullans SR, et al. Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation (2003); 107: 1912-6.
104. Tang F, Shang K, Wang X, Gu J. Differentiation of embryonic stem cell to astrocytes visualized by green fluorescent protein. Cell Mol Neurobiol 2002; 22: 95-101.
105. Lenka N, Lu ZJ, Sasse P, Hescheler J, Fleischmann BK. Quantitation and functional characterization of neural cells derived from ES cells using nestin enhancer-mediated targeting in vitro. Cell Sci 2002; 115: 1471-85.
106. Era T, Takagi T, Takahashi T, Bories JC, Nakano T. Characterization of hematopoietic lineage-specific gene expression by ES cell in vitro differentiation induction system. Blood 2000; 95: 870-8.
107. Kazemi S, Wenzel D, Kolossov E, Lenka N, Raible A, Sasse P, et al. Differential role of bFGF and VEGF for vasculogenesis. Cell Physiol Biochem 2002; 12: 55-62.
108. Ahn HS, Chackalamannil S, Boykow G, Graziano MP, Foster C. Development of proteinase-activated receptor 1 antagonists as therapeutic agents for thrombosis, restenosis and inflammatory diseases. Curr Pharm Design 2003; 9(28): 2349-65.
109. Ishikawa K. Heme oxygenase-1 against vascular insufficiency: roles of atherosclerotic disorders. Curr Pharm Design 2003; 9(30): 2489-97.
110. Kurowska EM. Nitric oxide therapies in vascular diseases. Curr Pharm Design 2002; 8(3): 155-66.