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ESTABLISHING OF ANIMAL MODEL (TRANSGENIC MICE) TO SUPPORT THE RESEARCH IN CANCER

ESTABLISHING OF ANIMAL MODEL (TRANSGENIC MICE) TO SUPPORT THE RESEARCH IN CANCER. Ahmad Aulia Jusuf Department of Histology Faculty of Medicine University of Indonesia 2009. Agenda. Introduction Definition and useful of transgenic mice The method of producing transgenic mice

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ESTABLISHING OF ANIMAL MODEL (TRANSGENIC MICE) TO SUPPORT THE RESEARCH IN CANCER

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  1. ESTABLISHING OF ANIMAL MODEL (TRANSGENIC MICE) TO SUPPORT THE RESEARCH IN CANCER Ahmad Aulia Jusuf Department of Histology Faculty of Medicine University of Indonesia 2009

  2. Agenda • Introduction • Definition and useful of transgenic mice • The method of producing transgenic mice • The using of transgenic mice in studying the carcinogenesis and in searching the substance or chemical agent including the herb in the treatment of cancer Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  3. Introduction • Transgenic mice • Used widely in the biomedical research • History2,3,4,5,6 • Palmitter dan Brinster (1981) • Generating the transgenic mice firstly • Insertion of viral thymidinekinase gene into the fertilized eggs • Palmitter (1986), Jaenisch (1988) dan Hanahan (1989) • Gordon (1983), Hogan 1994 • Injection of gene into pronuclear fertilized egg __________________________________________________________________________________________________________________________________________________2Jusuf, A.A : Transgenic and gene disruption techniques from a concept to a tool in studying the basic pathogenesis of various human disease. Medical Journal Of Indonesia. 1998: 7; 2 : 55-64 3Brinster R, Chen H, Trumbauer M et al : Somatic expression of herpes thymidine kinase in mice following injection of a fusion gene into eggs. Cell 1981: 27: 223-2314Palmitter R.D and Brinster R.L: Germ-line transformation of mice. Annu. Rev. Genet 1986: 20; 465-4995Jaenisch R : Transgenic animals. Science 1988: 240; 146814746Hanahan D. : Transgenic mice as probes into complex system. Science 1989: 246; 1265-12757Hogan B, ConstantiniF, Lacy E. : Manipulating the mouse embryos: A laboratory manual.2nd Ed .New York : Cold Spring Harbor: 1994 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  4. Introduction • Transgenic mice • Used as animal model to study 1,2,3,10 • The regulation of gene associated with the development of the tissue • The function of specific gene involved in the tissue development • Regulation of oncogenes and tumor suppressor • The effects of substances or chemical substance in the therapy of cancer __________________________________________________________________________________________________________________________________________________2Jusuf, A.A : Transgenic and gene disruption techniques from a concept to a tool in studying the basic pathogenesis of various human disease. Medical Journal Of Indonesia. 1998: 7; 2 : 55-64 3Brinster R, Chen H, Trumbauer M et al : Somatic expression of herpes thymidine kinase in mice following injection of a fusion gene into eggs. Cell 1981: 27: 223-2314Palmitter R.D and Brinster R.L: Germ-line transformation of mice. Annu. Rev. Genet 1986: 20; 465-4995Jaenisch R : Transgenic animals. Science 1988: 240; 146814746Hanahan D. : Transgenic mice as probes into complex system. Science 1989: 246; 1265-12757Hogan B, ConstantiniF, Lacy E. : Manipulating the mouse embryos: A laboratory manual.2nd Ed .New York : Cold Spring Harbor: 1994 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  5. Definition and useful of transgenic mice • Transgenic Mice1,2 • An organism (mice) whose genome • has been artificially modified by means of genetic engineering • has to be transmitted hereditary • expression of exogenous gene • over-expression of endogenous gene ______________________________________________________________________________________________________________________________________________________1Aguzzi A, Brandner S, Isenmann S, Steinbach JP, and Sure U : Transgenic and gene disruption techniques in the study of neurocarcinogenesis. Glia 1995: 15: 348-3642Jusuf, A.A : Transgenic and gene disruption techniques from a concept to a tool in studying the basic pathogenesis of various human disease. Medical Journal of Indonesia. 1998: 7; 2 : 55-64 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  6. Definition and useful of transgenic mice • DNA fragments or gene inserted into the cell • ligated end to end to the genome by the intracellular ligation enzyme • randomly integrated into a site in the chromosome • arranged in the tandem manner 2,9 ________________________________________________________________________________________________________________________________________________________2Jusuf, A.A : Transgenic and gene disruption techniques from a concept to a tool in studying the basic pathogenesis of various human disease. Medical Journal of Indonesia. 1998: 7; 2 : 55-64 9Albert, B., Bray, D., Lewis, J., Raff, M., Roberts, K., Watson, J.D. (1994), Cellular Mechaninsm of development in Molecular Biology of The Cell., 3rd Ed., Garland Publishing, New York and London, pp. Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  7. Definition and useful of transgenic mice • The useful of transgenic mice2,3,10 • Animal Model • to study the regulation of gene associated with the development of the tissue • to study the function of specific gene involved in the tissue development and the phenotype of those genes in the tissue • to study regulation of genes involved in the oncogenesis • The effects of substances or chemical substance in the therapy of cancer _____________________________________________________________________________________________________________________________________________________2Jusuf, A.A : Transgenic and gene disruption techniques from a concept to a tool in studying the basic pathogenesis of various human disease. Medical Journal Of Indonesia. 1998: 7; 2 : 55-64 3Brinster R, Chen H, Trumbauer M et al : Somatic expression of herpes thymidine kinase in mice following injection of a fusion gene into eggs. Cell 1981: 27: 223-23110Nagy A, Gertsenstein M, Vintersen K, Behringer R, Manipulating the mouse embryo: A laboratory manual. 3rd Ed New York: Cold SpringHarbor: 2003 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  8. The procedures of producing transgenic mice • The processes of making transgenic mice • difficult and complicated • take time, energy and high cost • 2 methods19,20 • Pronuclear microinjection • Embryonic Stem (ES) cell electroporation and subsequent blastocyst injection Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  9. Method of making transgenic mice Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  10. The procedures of producing transgenic mice • The steps • preparation of transgen which will be injected into pronuclear of fertilized eggs • preparation of mice • preparation of tools and material • preparation of detection system Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  11. The procedures of producing transgenic mice • Preparation of transgen which will be injected into pronuclear of fertilized eggs • DNA fragment or transgene • promoter, complete protein coding region, < satu intron dan polyadenylation site11 • the length of DNA transgene is unlimited • from several kilo base pair (Kbp) until 1000 kb (Lamb et 1999)13 • ideal length of DNA fragment is 2 - 20 Kb • amplification of DNA fragment by using PCR • gene construction, amplification and purification the DNA fragment by using the molecular biology protocols • has to be purified and free from the sequence of prokaryotic vector12 • concentration of 1-2 µg/ml ______________________________________________________________________ 11 Brinster R, Allen J, BehringerR, Gelimas R et al.: Intron s increase transcriptional efficiency in transgenic mice. Proc Natl. Acad.Sci.USA 1988: 85; 836-40 12Chada K, Magram J, Raphael K, Radice G, Lacy E and Constantini F. Spesific expression of a foreign beta globin gene in eryrthroid cells of transgenic mice . Nature.1985: 314: 377-380 13Lamb B.T, Bardel K.A, Kulnane L.S. Anderson J.J, Holtz G, Wagner S.L, Sisodia S.S, and Hoeger E.J. Amyloid production and deposition in mutant amyloid precursor protein and presenilin-1 yeast artificial chromosome transgenic mice. Natl. Neurosci. 1999: 2; 695-697 19Transgenic mice, diunduh dari htpp://cancer ucsd.edu/tgm/pronuclear.asp Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  12. The procedures of producing transgenic mice • Preparation of transgen which will be injected into pronuclear of fertilized eggs Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  13. The procedures of producing transgenic mice • Preparation of transgen which will be injected into pronuclear of fertilized eggs • Endogenous transgene • insertion of oligonucleotide in the untranslated region of DNA fragment14,15 • insertion the small gene that express small RNA in transgene16 • fusion of protein transgen with protein Green Fluorescent Protein (GFP) encoded by gene reporter alkaline phosphatase17 ______________________________________________________________________ 14Peschon J.J, Behringer R.R, Brinster R.L, and Palmiter R.D. Spermatide-specific expression of protamine 1 in transgenic mice. Proc Natl.Acad.Sci.USA. 1987:84; 5316-5319 15Shi Y, Son H.J, Shahan K, Rodriguez M, Constantini F and Derman E. Silent genes in the mouse major urinary protein gene family. Proc Natl.Acad.Sci.USA. 1989:86; 4584-4588 16Krumlauf R, Hammer R.E, Tilghman S.M, and Brinster R.L Developmental regulation of alpha-fetoprotein genes in transgenic mice.Mol.Cell. Biol. 1985:5; 1639-1648. 17van Roessel P and Brand A.H. Imaging into the future: visualizing gene expression and protein interactions with fluorescent proteins.Nat.Cell.Biol. 2002:4; 15-20 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  14. The procedures of producing transgenic mice • Preparation of transgen which will be injected into pronuclear of fertilized eggs • Efficiency of transgene integration8,10 • Shape of DNA • >> in the linearized DNA • Concentration of DNA • >> in the higher concentartion • Too high DNA concentration increase the toxicity for zygote • Concentration of DNA : 1.0-2 nanogram/microliter • Purity of DNA • Transgene has to be free from contamination (remaining phenol, ethanol or enzymes) • Buffer solution • TE buffer containing 1mM EDTA. ______________________________________________________________________ 8Hogan B, ConstantiniF, Lacy E. : Manipulating the mouse embryos: A laboratory manual.2nd Ed .New York : Cold Spring Harbor: 1994 10Nagy A, Gertsenstein M, Vintersen K, Behringer R, Manipulating the mouse embryo: A laboratory manual. 3rd Ed New York: Cold SpringHarbor: 2003 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  15. The procedures of producing transgenic mice • Preparation of Mice8 • Superovulated female mice • to get the fertilized eggs >> • Follicular development is stimulated with Pregnant Mare’s Serum Gonadotrophin (PMSG) • Ovulation is stimulated with Human Chorionic Gonadotrophin (HCG) • Age : 4-8 weeks • Mate with fertile stud mice • Check the copulation plug after mating ______________________________________________________________________ 8Hogan B, ConstantiniF, Lacy E. : Manipulating the mouse embryos: A laboratory manual.2nd Ed .New York : Cold Spring Harbor: 1994 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  16. The procedures of producing transgenic mice • Preparation of Mice8 • Fertile stud male mice • Mate with superovulated female mice • Age 6-8 weeks with good reproduction performance • Sterile male mice • has been vasectomized • mate with pseudopregnant female mice • Age of >> 8 weeks ______________________________________________________________________ 8Hogan B, ConstantiniF, Lacy E. : Manipulating the mouse embryos: A laboratory manual.2nd Ed .New York : Cold Spring Harbor: 1994 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  17. Vasectomization in the Sterile Male Mice Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  18. The procedures of producing transgenic mice • Preparation of Mice8 • Pseudopregnant female mice • age of 6-8 weeks with big infundibulum • mate with sterile male mice • check the copulation plug • receives the fertilized eggs that have contained the transgenes ______________________________________________________________________ 8Hogan B, ConstantiniF, Lacy E. : Manipulating the mouse embryos: A laboratory manual.2nd Ed .New York : Cold Spring Harbor: 1994 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  19. The procedures of producing transgenic mice • Preparation of tools and materials8 • Disposible syringe • Pregnant Mare’s Serum Gonadotrophin (PMSG) hormone • Human Chorionic Gonadotrophin (HCG) hormone • Culture solution • D-PBS or other solutions that have added bovine serum albumin (BSA), piruvate acid and antibiotic (penicillin and streptomycin) • Culture solutions that contain hyaluronidase enzyme • Incubator (37C, humidity 95% and 5% CO2 • Surgical set • Alcohol 70% • stereomicroscope • Mouth controlled pipette • 35 mm petri dish ______________________________________________________________________ 8Hogan B, ConstantiniF, Lacy E. : Manipulating the mouse embryos: A laboratory manual.2nd Ed .New York : Cold Spring Harbor: 1994 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  20. The procedures of producing transgenic mice • Preparation of tools and materials8 • Holding pipette • Borosilicate glass capilary • mechanical pipette puller • Injection pipette • Glass capillary tubing dengan internal glass filament • mechanical pipette puller ______________________________________________________________________ 8Hogan B, ConstantiniF, Lacy E. : Manipulating the mouse embryos: A laboratory manual.2nd Ed .New York : Cold Spring Harbor: 1994 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  21. The procedures of producing transgenic mice • Preparation of tools and materials8 • Microscope with micromanipulator • Paraffin oil • Petri dish injection chamber • Transgen • Detection of transgene • Southern blot • Northern blot • Western Blot ______________________________________________________________________ 8Hogan B, ConstantiniF, Lacy E. : Manipulating the mouse embryos: A laboratory manual.2nd Ed .New York : Cold Spring Harbor: 1994 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  22. Steps in Production of transgenic mice Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  23. Steps in Production of transgenic mice • Injection of hormone PMS and hHCG Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  24. Steps in Production of transgenic mice • Isolation and collecting of fertilized eggs Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  25. Steps in Production of transgenic mice • Isolation and collecting of fertilized eggs Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  26. Steps in Production of transgenic mice • Isolation and collecting of fertilized eggs Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  27. Steps in Production of transgenic mice • Isolation and collecting of fertilized eggs Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  28. Steps in Production of transgenic mice • Isolation and collecting of fertilized eggs Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  29. Steps in Production of transgenic mice • Injection of transgene into male pronuclear of fertilized eggs Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  30. Steps in Production of transgenic mice • Injection of transgene into male pronuclear of fertilized eggs Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  31. Steps in Production of transgenic mice • Injection of transgene into male pronuclear of fertilized eggs Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  32. Steps in Production of transgenic mice • Injection of transgene into male pronuclear of fertilized eggs Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  33. Steps in Production of transgenic mice • Injection of transgene into male pronuclear of fertilized eggs Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  34. Steps in Production of transgenic mice • Injection of transgene into male pronuclear of fertilized eggs Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  35. Steps in Production of transgenic mice • Injection of transgene into male pronuclear of fertilized eggs Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  36. Steps in Production of transgenic mice • Injection of transgene into male pronuclear of fertilized eggs Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  37. Steps in Production of transgenic mice • Transfer of fertilized eggs containing transgene into oviduct of pseudopregnant female mice Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  38. Steps in Production of transgenic mice • Transfer of fertilized eggs containing transgene into oviduct of pseudopregnant female mice Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  39. Steps in Production of transgenic mice • Transfer of fertilized eggs containing transgene into oviduct of pseudopregnant female mice Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  40. Steps in Production of transgenic mice • Maintain the “candidate” for transgenic mice Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  41. Steps in Production of transgenic mice • Detection of Transgenein the candidate of transgenic mice Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  42. The using of transgenic mice in studying the carcinogenesis • Transgenic mice • Patogenesis and patophysiology of cancer • Regulation of genes belongs to oncogene and tumor suppressor • Abnormality of tissue Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  43. The using of transgenic mice in studying the carcinogenesis • Transgenic mice • Green et.al21 • Transgenic mice as a model to study carcinoma of prostat • SV- 40 large tumor antigen coding region with prostate-specific rat probasin as its promoter • Phenotype of transgenic mice • ranging from mild intraepithelial hyperplasia to large multinodular malignant neoplasia • expression of gene p53 >> • expression of receptor androgen in the prostat << _____________________________________________________________________ 21Greenberg NM, Demayo FJ, Finegold M, et al Prostate cancer in a transgenic mouse. Proc Natl Acad Sci USA. 1995:92: 3439-43. Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  44. The using of transgenic mice in studying the carcinogenesis • Transgenic mice • Janz et.al22 • transgenic mice for Burkitt’s lymphoma • MYC transgene under its promoter • Rao et.al.23 • transgenic mice to study study the breast cancer • transgene of oncogen c-neu ______________________________________________________________________ 22Janz, HC Morse III, et al. Burkitt's lymphoma in the mouse. Journal of Experimental Medicine.2000: 92:8:1183-90 23Rao G.N., Ney,E., Herbert R.A. Influence of diet on mammary cancer in transgenic mice bearing an oncogene expressed in mammary tissue. Breast Cancer Research and treatment.1997:45:2:149-158(10) Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  45. The using of transgenic mice in studying the carcinogenesis • Transgenic mice • Kim et.al.24 • insertion entire HBx gene under its own regulatory elements • to study the role of that gene in patogenesis of hepatoma • results • progressive histopathological changes specifically in the liver, beginning with multifocal areas of altered hepatocytes, followed by the appearance of benign adenomas, and proceeding to the development of malignant carcinomas ______________________________________________________________________ 24Kim C.M., Koike.K., Saito, I., Miyamura, T.,  Jay, G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature. 1991: 351: 317 - 320 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  46. The using of transgenic mice in studying the carcinogenesis • Transgenic mice that express the protein oncogen E6 and E7 of Human Papilloma Virus (HPV) • Arbeit et.al25 • Hyperplasia, papillomatosis, and dysplasia appeared at multiple epidermal and squamous mucosal sites including ear and truncal skin, face, snout and eyelids, and anus • The ears were the most consistently affected site, with pathology being present in all lines with 100% penetrance. _____________________________________________________________________ 25Arbeit, J.M., Munger,K., Howley,P.M.,Hanahan,D. Progessive squamous epithelial neoplasia in K14-human papillomavirus type 16 transgenic mice. J Virol. 1994: 68(7): 4358-4368 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  47. The using of transgenic mice in studying the carcinogenesis • Transgenic mice that express the protein oncogen E6 and E7 of Human Papilloma Virus (HPV) • Riley et.al.26 • Phenotype mimic to cervical carcinoma _____________________________________________________________________ 26Riley, R.R., Duensing,S., Brake,T., Münger,K., Lambert, P.F., Arbeit, J.M. Dissection of Human Papillomavirus E6 and E7 Function in Transgenic Mouse Models of Cervical Carcinogenesis. Cancer Research.2003: 63:4862-4871 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  48. Fig. 2. Histopathology of the CIN scoring system based on the K14-HPV mouse. The murine CIN grading system depicting degree of reproductive tract squamous epithelial dysplasia and neoplastic progression in estrogen treated K14-HPV transgenic mice (panels 2–6) and nontransgenic controls (panel 1). The squamous epithelium in nontransgenic mice is hyperplastic and mitotic figures are present only in basal cells (black arrow, panel 1). CIN I lesions (panel 2) evidence occasional anaplastic squamous epithelial cells that are persistent in the upper differentiated layers (white arrowhead). CIN II lesions (panel 3) display epithelial cell projections into the stroma (papillation, black arrows), and cells with an additional degree of nuclear anaplasia (white arrowheads). CIN III lesions (panel 4) are similar to CIN II except the frequency of anaplastic squamous epithelial cells is increased. CIS lesions (panel 5) are distinguished by additional cytological squamous epithelial cell progression and more irregularity of the epithelial-stromal border. Squamous cell carcinoma (SCC; panel 6) retain a well to moderate degree of squamous epithelial differentiation and invade into the stroma without evidence of encirclement by basement membrane (black arrows). SCCs often arise from glandular squamous metaplasia at the transformation zone (black arrowhead). Bar, panels 1–5 = 20 µm; panel 6 = 100 µm. _____________________________________________________________________ 26Riley, R.R., Duensing,S., Brake,T., Münger,K., Lambert, P.F., Arbeit, J.M. Dissection of Human Papillomavirus E6 and E7 Function in Transgenic Mouse Models of Cervical Carcinogenesis. Cancer Research.2003: 63:4862-4871 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  49. The using of transgenic mice in studying the carcinogenesis • Transgenic mice that express the protein oncogen E6 and E7 of Human Papilloma Virus (HPV) • Searle et.al.27 • solitary gland within the gastric mucosa became colonized with small dysplastic cells • the abnormal cell population spread within the glandular mucosa, invaded the submucosa and outer muscular wall of the stomach, and commonly metastasized to local lymph nodes and the liver _____________________________________________________________________ 27Searle, P.F., Thomas, D.P., Faulkner, K.B., Tinsley, J.M. Stomach Cancer in Transgenic Mice Expressing Human Papillomavirus Type 16 Early Region Genes From a Keratin Promoter. J Gen Virol. 1994: 75: 1125-1137 Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

  50. The using of transgenic mice in studying the carcinogenesis • Transgenic mice • Venkateswaran et.al28 • Using the lady transgenic mice • antioxidants (vitamin E, selenium, and lycopene) in the diet dramatically inhibits prostate cancer development and increases the disease free survival _____________________________________________________________________ 28Venkateswaran, V., Fleshner, N.E., Sugar,L.M., Klozt, L.H. Antioxidants block prostate cancer in lady transgenic mice. Cancer Research .2004:64:5891-96. Establishing of Animal Model (transgenic mice)/AAJ/Histo-FKUI/2009

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