20-EPI-Vitamin D3 Analogs

Potent Modulators of Proliferation and Differentiation of Breast Cancer Cell Lines in Vitro
  • E. Elstner
  • D. Heber
  • H. P. Koeffler
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 399)


Breast cancer is a devastating disease. New approach in therapy are needed. In this chapter, we describe our efforts to identify novel vitamin D3 analogs which may have a potent antiproliferative effect on breast cancer without causing hypercalcemia.


Breast Cancer Breast Cancer Cell Breast Cancer Cell Line Clonal Proliferation Leukemic Cell Growth 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Reichel H, Koeffler HP, Norman AW: The role of the vitamin D endocrine system in health and disease. New Engl J Med 1989; 320:980–991.PubMedCrossRefGoogle Scholar
  2. 2.
    Garland FC, Garland CF, Gorham ED, Young JF: Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Preventive Medicine 1990; 19:614–622.PubMedCrossRefGoogle Scholar
  3. 3.
    Gorham ED, Garland FC, Garland CF: Sunlight and breast cancer incidence in the USSR. International J of Epidemiology 1990; 19:820–824.CrossRefGoogle Scholar
  4. 5.
    Berger U, Wilson P, McClelland RA, Colston K, Haussler MR, Pike JW, Coombes RC: Immunocyto-chemical detection of 1,25-dihydroxyvitamin D receptors in breast cancer. Cancer Res 1987; 47:6793–6799.PubMedGoogle Scholar
  5. 6.
    Eisman JA, Macintyre I, Martin TJ, Frampton RJ, King RJB: Normal and malignant breast tissue is a target organ for l,25(OH)2 vitamin D3. Clin Endocrinol 1980; 13:267–272.CrossRefGoogle Scholar
  6. 7.
    Feldman D, Chen T, Hirst M, Colston K, Karasek M, Cone C: Demonstration of 1,25-dihydroxyvitamin D3 receptors in human skin biopsies. J Clin Endocrinol Metab 1980; 51:1463–1465.PubMedCrossRefGoogle Scholar
  7. 8.
    Colston KW, Berger U, Coombes RC: Possible role for vitamin D in controlling breast cancer cells proliferation. Lancet 1989;28:188–191.CrossRefGoogle Scholar
  8. 9.
    Becker AR, McDonnell DP, Hausier MR, Pike JW, Shine J, O’Malley BW: Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Nat Acad Sci USA 1988; 85:3294–3298.CrossRefGoogle Scholar
  9. 10.
    Minghetti PP, Norman AW: l,25(OH)2-vitamin D3 receptors: gene regulation and genetic circuitry. FASEB J 1988; 2:3043–3053.PubMedGoogle Scholar
  10. 11.
    Haussler MR, Mangelsdorf D, Komm BS, Terpening CM, Yamaoka K, Allegretto EA, Baker AR, Shine J, McDonnell DP, Hughes M, Weigel NL, O’Malley BW, Pike JW: Molecular biology of the vitamin D hormone. Recent Prog Horm Res 1988; 44:263–305.PubMedGoogle Scholar
  11. 12.
    Colston K, Colston MJ, Fieldsteel AH, Feldman D: 1,25 dihydroxyvitamin D3 receptor in human epithelial cancer cell lines. Cancer Res 1982; 42:856–859.PubMedGoogle Scholar
  12. 13.
    Eisman JA, Martin TJ, Macintyre I, Moseley JM: l,25-dihydroxyvitamin-D3 receptor in breast cancer cells. Lancet 1979; Dec 22/29:1335–1336.Google Scholar
  13. 14.
    Frampton RJ, Omond SA, Eisman JA: Inhibition of human cancer cell growth by 1,25-dihydroxyvitamin D3 metabolites. Cancer Res 1983; 43:443–447.Google Scholar
  14. 15.
    Abe E, Miyaura C, Sakagami H, Takeda M, Konno K, Yamazaki T, Yoshiki S, Suda T: Differentiation of mouse myeloid leukemia cells induced by 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 1981; 76:4990–4994.CrossRefGoogle Scholar
  15. 16.
    Colston KW, Chander SK, Mackay AG, Coomes RC: Effects of synthetic vitamin D analogues on breast cancer cell proliferation in vivo and in vitro. Biochem Pharmacology 1992; 44:693–702.CrossRefGoogle Scholar
  16. 17.
    Danielpour D, Kadomatsu K, Anzano MA, Smith JM, Sporn MB: Development and characterization of nontumorigenic and tumorigenic epithelial cell lines from rat dorsal-lateral prostate. Cancer Res 1994; 54:3413–21.PubMedGoogle Scholar
  17. 18.
    Bower M, Colston KW, Stein RC, Hedley A, Gazet JC, Ford HT, Coombes RC: Topical calcipotriol treatment in advanced breast cancer. Lancet 1991; 337:701–702.PubMedCrossRefGoogle Scholar
  18. 19.
    Eisman JA, Barkla DH, Tutton PJM: Suppression of in vivo growth of human cancer solid tumor xenografts by l,25(OH)2 vitamin D3. Cancer Research 1987; 47:21–25.PubMedGoogle Scholar
  19. 20.
    Honma Y, Hozumi M, Abe E, Konno K, Fukushima M, Hata S, Nishil Y, DeLuca HF, Suda T: 1-α-hydroxyvitamin D3 prolong survival time of mice inoculated with myeloid leukemia cells. Proc Acad Sci USA 1983; 80:201–204.CrossRefGoogle Scholar
  20. 21.
    Sato T, Takusagawa K, Asoo N, Konno K: Effects of 1-αhydroxyvitamin D3 on metastasis of rat ascites hepatoma K-231. Br J Cancer 1984;50:123–125.PubMedCrossRefGoogle Scholar
  21. 22.
    Zhou JY, Norman AW, Chen DL, Sun GW, Uskokovic M, Koeffler HP: l,25-Dihydroxy-16-ene-23-yne-vitamin D3 prolong survival time of leukemic mice. Proc Natl Sci USA 1990; 87:3929–3932.CrossRefGoogle Scholar
  22. 23.
    Frappait L, Falette N, Lefebvre M, Bremond A, Vauzelle JL, Saez S: in vitro study of effects of 1,25 dihydroxyvitamin D3 on the morphology of human breast cancer cell line BT 20. Differentiation 1989; 40:63–69.CrossRefGoogle Scholar
  23. 24.
    Binderup L, Latini S, Binderup E, Bretting C, Calverley M, Hansen K: 20-epi-vitamin D3 analogues: A novel class of potent regulators of cell growth and immune responses. Biochem Pharmac 1991; 42:1569–1575.CrossRefGoogle Scholar
  24. 25.
    Mathiasen IS, Colston KW, Binderup L: EB 1089, a novel vitamin D analogue, has strong antiproliferative and differentiation inducing effects on cancer cells. J Steroid Biochem Molec Biol 1993; 46:365–371.PubMedCrossRefGoogle Scholar
  25. 26.
    Dokoh S, Donaldson CA, Haussler MR: Influence of 1,25 dihydroxyvitamin D3 on cultured osteogenic sarcoma cells; connection with 1,25 dihydroxyvitamin D3 receptor. Cancer Res 1984; 44:2103–2109.PubMedGoogle Scholar
  26. 27.
    Miyaura C, Abe E, Kuribayashi T, Tauka H, Konno K, Nishil Y, Suda T: 1,25-dihydroxyvitamin D3 induces differentiation of human myeloid leukemia cells. Biochem Biophys Res Common 1981; 102:937–943.CrossRefGoogle Scholar
  27. 28.
    Brehier A, Thomasset M: Human colon cell line HT-29. Characterization of 1,25-dihydroxyvitamin D3 receptor and induction of differentiation by the hormone. J Steroid Biochem 1988; 29:265–270.PubMedCrossRefGoogle Scholar
  28. 29.
    Norman AW, Zhou JH, Henry HL, Uskokovic MR, Koeffler HP: Structure-function studies on analogues of 1-α,25-dihydroxyvitamin D3: differential effects on leukemic cell growth, differentiation, and intestinal absorption. Cancer Res 1990; 50:6857–6864.PubMedGoogle Scholar
  29. 30.
    Kragballe K, Wildfang I: Calcipotriol (MC903), a novel vitamin D3 analogue, stimulates terminal differentiation and inhibits proliferation of cultured human keratinocytes. Dermatol Res 1990; 282:164–167.CrossRefGoogle Scholar
  30. 31.
    Mangelsdorf DJ, Koeffler HP, Donaldson CA, Pike JW, Haussler MR: Induced differentiation in a human promyelocytylic leukemia cell line (HL-60): receptor-mediated maturation to macrophage-like cells. J Cell Biol 1984;98:391–398.PubMedCrossRefGoogle Scholar
  31. 32.
    Rigby WFC, Shen L, Ball ED, Juyre PM, Fanger FW: Differentiation of a human monocytic cell line by l,25dihydroxyvitamin D3 (calcitrol): A morphologic, phenotypic, and functional analysis. Blood 1984; 64:1110–1115.PubMedGoogle Scholar
  32. 33.
    McCarthy DJ, Hibbin JF, San Miguel JF, Freake HC, Rodriguez B, Andrews C, Pining A, Catovsky D, Goldman JM: The effect of vitamin D3 metabolites on normal and leukemic bone marrow cells in vitro. Int J Cell Cloning 1984; 2:227–242.PubMedCrossRefGoogle Scholar
  33. 34.
    Koeffler HP, Armatruda T, Ikekawa N, Kobayashi Y, DeLuca HF: Induction of macrophage differentiation of human normal and leukemic myeloid stem cells by 1,25-dihydroxyvitamin D3 and its fluorinated analogues. Cancer Res 1984; 44:5624–5628.PubMedGoogle Scholar
  34. 35.
    Koeffler HP: Study of normal and abnormal hematopoiesis using human leukemic cell lines. UCLA Symposia on Molecular and Cellular Biology. New Series, Vol.9. New York, New York: Alan R Liss, Inc 1983; 179–195.Google Scholar
  35. 36.
    Reichel H, Koeffler HP, Barbers R, Munker R, Norman A: 1,25 dihydroxyvitamin D3 and the hematopoietic system. In: Norman AW, Schaefer K, Grigoleit HG, Herrath DV eds. Vitamin D: Chemical, biochemical and Clinical Update. Berlin, Germany: Walter de Gruyter 1985; 167–176.Google Scholar
  36. 37.
    Reichel H, Koeffler HP, Bishop JE, Norman AW: Effects of lipopolysaccharides on conversion of 25-hydroxyvitamin D3 by normal human macrophages. In:Norman AW, Schaefer K, Grigoleit HG, Herrath DV eds. Vitamin D:Chemical, Biochemical and Clinical Update. Berlin, Germany: Walter de Gruyter 1985; 61–62.Google Scholar
  37. 38.
    Bishop JE, Reichel H, Koeffler HP, Norman AW: l,25(OH)2D3 receptor in pulmonary alveolar macrophages. In: Norman AW, Schaefer K, Grigoleit HG, Herrath DV eds. Vitamin D: Chemical, Biochemical and Clinical Update. Berlin, Germany:Walter de Gruyter 1985; 127–128.Google Scholar
  38. 39.
    Koeffler HP, Reichel H, Munker R, Barbers R, Norman A: Interaction of 1,25-Dihydroxyvitamin D3 and the hematopoietic systems. In: Gale RP and Golde DW eds. Leukemia: Recent Advances in Biology and Treatment. Vol.28. New York, New York: Alan R. Liss, Inc. 1985; 399–413.Google Scholar
  39. 40.
    Koeffler HP: Study of differentiation and proliferation of leukemic cells using myeloid leukemia lines. In: Bloomfield CD ed. Adult Leukemias 2. The Hague, Netherlands: Martinus Nijhoff Publishers 1985; 27–68.Google Scholar
  40. 41.
    Koeffler HP: Vitamin D: Myeloid differentiation and proliferation. Current Trends in Human Leukemia VI. In: Gallo R, Neth H, Moore M. eds. Hematology and Blood Transfusion Vol.29. Modern Trends in Human Leukemia. Berlin, Germany: Springer-Verlag 1985; 409–417.Google Scholar
  41. 42.
    Reichel H, Koeffler HP, Bishop JE, Norman AW: Interactions between lymphocytes and macrophages mediated by 1,25-dihydroxyvitamin D3 and τ-interferon. In: Cohen DV, Martin TV, Meunier PJ, eds. Calcium Regulation and Bone Metabolism: Basic and clinical aspects. Vol 9. amsterdam, Holland: Excerpta Medica 1987; 371–376.Google Scholar
  42. 43.
    Koeffler HP, Tobler A, Reichel H, Norman AW: Interaction of 1,25-dihydroxyvitamin D3 with normal and abnormal hematopoiesis. In: Aarbakke J, Chiang PK, Koeffler HP eds. Tumor Cell Differentiation, Biology and Pharmacology. Clifton, New Jersey: The Humana Press 1987; 137–157.Google Scholar
  43. 44.
    Lubbert M, Koeffler HP: Leukemic cell lines as a paradigm for myeloid differentiation. In: Olsson, L. ed. in chief. Cancer Reviews, Vol 10. Copenhagen, Denmark: Munksgaard International Publishers, Ltd 1988; 33–62.Google Scholar
  44. 45.
    Collins ED, Jones GI, Uskokovic M, Koeffler HP, Norman AW: l,25(OH)2 vitamin D3 analogs: Comparison of l,25(OH)2D3 receptor ligand specificity and biological activity in the chick and human promyelocytic (HL-60) cells. In: Norman AW, Schaefer K, Grigoleit HG, Herrath DV eds. Vitamin D:Molecular, Cellular and clinical Endocrinology. Berlin, West Germany: Walter de Gruyter 1988; 433–434.Google Scholar
  45. 46.
    Paquette R, Koeffler HP: Retinoids and 1,25 dihydroxyvitamin D3: Role in myelodysplastic syndromes and leukemia. In: Proceedings of International Symposium on Myelodysplastic Syndromes: Pathophysiology and Treatment Kyoto, Japan. The Netherlands: Elsevier Science Publishers 1988; 173–186.Google Scholar
  46. 47.
    Paquette RL, Koeffler HP: Myelodysplastic Syndrome: Culture Studies and Therapy. In: Mufti GJ and Glaton DAG eds. Churchill Livingstone Monograph of Myelodysplastic Syndromes. Amsterdam, The Netherlands: Elsevier Science Publishers 1992.Google Scholar
  47. 48.
    Koeffler HP, Norman AW: Interaction between the hematopoietic system and the vitamin D endocrine system. In: Norman AW, Schaefer K, Grigoleit HG, Herrath DV eds. Vitamin D: Molecular, cellular and clinical endocrinology. Berlin: Walter De Gruyther 1988; 263–266.Google Scholar
  48. 49.
    Koeffler HP, Reichel H, Tobler A, Norman AW: Macrophages and vitamin D3. In: Ahserson GL, Zembala M. eds. The Human Monocyte. London, England: Academic Press Limited 1989; 345–351.Google Scholar
  49. 50.
    Miller CW, Koeffler HP: In vivo and in vitro differentiation of myeloid leukemic cells. In: Mauer AM, ed. The biology of Human Leukemia. Baltimore, Maryland: Johns Hopkins Press 1990; 152–176.Google Scholar
  50. 51.
    Reichel H, Koeffler HP, Norman AW: Production of la, 25-dihydroxyvitamin D3 in hematopoietic cells. In: Peterlik M, Bronner F. eds. Molecular and cellular regulation of calcium and phosphate metabolism. New York, New York: Alan R. Liss, Inc. 1990; 81–97.Google Scholar
  51. 52.
    Kizaki M, Koeffler HP: 1,25-dihydroxyvitamin D3 and hematopoietic cells. In: Vitamins and Cancer Prevention. Laidlaw SA, Swendseid ME eds. New York, New York: Wiley and Liss. Inc. 1991; 91–102.Google Scholar
  52. 53.
    Jordan SC, Sakai R, Koeffler HP, Lemire J, Adams JS: Immunoregulatory and Prodifferentiating effects of 1,25-dihydroxyvitamin D3 in human mononuclear cells. Nutrient Modulation of the Immune response. Marcel Dekker, Inc., 1992; 3–29.Google Scholar
  53. 54.
    Kizaki M, Koeffler HP: Differentiation inducing agents in the treatment of MDS. Seminars in Oncology, Myelodysplastic Syndromes 1992; 95–105.Google Scholar
  54. 55.
    Tobler A, Koeffler HP: Differentiation inducers and their potential use in the treatment of acute myelogenous leukemia (MJ Waring and BAJ Ponder, ed.) Kluwer Academic Publishers 1991; 163–183.Google Scholar
  55. 56.
    Paquette R, Koeffler HP: Differentiation therapy for myelodysplastic syndromes. North American Clinics of Hematology (HP Koeffler, ed.), W.B. Sunders Company 1992; 687–706.Google Scholar
  56. 57.
    Akashi M, Koeffler HP: Differentiation therapy in leukemia. Focus on CML/MM. KK Standard McIntyre Co. Tokyo, Japan. 1994; 5–7.Google Scholar
  57. 58.
    Elstner E, Dawson MI, de Vos S, Pakkala S, Binderup L, Okamura W, Uskokovic M, Koeffler HP: Myeloid differentiation mediated through new potent retinoids and vitamin D3 analogs. In: Hematology and blood Transfusion, Buechaer, Hiddenmann (eds), Springer-Verlag, accepted, 1994.Google Scholar
  58. 59.
    Koeffler HP: Induction of differentiation of human acute myelogenous leukemia cells: Therapeutic implications. Blood 1983;62:709–721.PubMedGoogle Scholar
  59. 60.
    Koeffler HP, Hiriji K, Itri L: 1,25-dihydroxyvitamin D3: In vivo and in vitro effects on human preleukemic and leukemic cells. Cancer Treatment Rep 1985; 69(12): 1399–1407.Google Scholar
  60. 61.
    Koeffler HP, Reichel H, Bishop, Norman AW: y-interferon stimulates production of 1,25-dihydroxyvitamin D3 by human pulmonary macrophages. Biochem Biophys Res Commun 1985; 127:596–603.PubMedCrossRefGoogle Scholar
  61. 62.
    Koeffler HP, Yelton L, Prokocimer M, Hirji K: Study of differentiation of fresh myelogenous leukemic cells by compounds that induce a human promyelocytic leukemic line (HL-60) to differentiate. Leukemia Res 1985;9:73–81.CrossRefGoogle Scholar
  62. 63.
    Munker R, Norman A, Koeffler HP: Vitamin D compounds: Effect on clonal proliferation and differentiation of human myeloid cells. J Clin Invest 1986; 78:474–480.CrossRefGoogle Scholar
  63. 64.
    Reichel H, Koeffler HP, Norman A: Regulation of 25-hydroxyvitamin D3 metabolism in a human promyelocytic leukemia cell line (HL-60): 1,25 dihydroxyvitamin D3 stimulates the synthesis of 24,25-dihydroxyvitamin D3. Arch Biochem Biophys 1986; 251:222–231.PubMedCrossRefGoogle Scholar
  64. 65.
    Munker M, Munker R, Saxton RE, Koeffler HP: Effect of recombinant monokines, lymphokines and other agents on clonal proliferation of cells from human lung cancer lines. Cancer Res 1987; 47:4081–4085.PubMedGoogle Scholar
  65. 66.
    Reichel H, Koeffler HP, Tobler A, Norman AW: 1,25-dihydroxyvitamin D3 inhibits y-interferon synthesis by normal human peripheral blood lymphocytes. Proc Natl Acad Sci USA 1987; 84:3385–3389.PubMedCrossRefGoogle Scholar
  66. 67.
    Reichel H, Koeffler HP, Norman AW: Synthesis in vitro of 1,25-dihydroxyvitamin D3and 24,25 dihydroxyvitamin D3 by interferon gamma stimulated normal human and alveolar bone marrow macrophages. J Bio Chem 1987; 262(23):10931–10937.Google Scholar
  67. 68.
    Reichel H, Koeffler HP, Norman AW: 25-hydroxyvitamin D3 metabolism by human T-lymphotropic virus transformed lymphocytes. J Clin Endocr Metab 1987; 5:519–526.CrossRefGoogle Scholar
  68. 69.
    Reichel H, Koeffler HP, Bishop JE, Norman AW: 25-hydroxyvitamin D3: metabolism by lipopolysaccha-ride-stimulated normal human macrophages. J Clin Endoc and Metab 1987; 64:1–9.CrossRefGoogle Scholar
  69. 70.
    Reichel H, Koeffler HP, Barbers R, Norman AW: Regulation of 1,25-dihydroxyvitamin D3 production by cultured alveolar macrophages from normal human donors and from patients with pulmonary sarcoidosis. J Clin Endocr Metab 1987; 65:1201–1209.PubMedCrossRefGoogle Scholar
  70. 71.
    Tobler A, Koeffler HP: Differentiation of human acute myelogenous leukemia cells: Therapeutic possibilities. Acta Haematologica 1987; (78)1:127–135.CrossRefGoogle Scholar
  71. 72.
    Tobler A, Gasson J, Reichel H, Norman AW, Koeffler HP: Granulocyte-macrophage colony stimulating factor: sensitive and receptor-mediated regulation by 1,25-dihydroxyvitamin D3 in normal human peripheral blood lymphocytes. J Clin Invest 1987; 79:1700–1705.PubMedCrossRefGoogle Scholar
  72. 73.
    Lubbert M, Koeffler HP: Myeloid cell lines: Tools for studying differentiation of normal and abnormal hematopoietic cells. Blood Reviews 1988; 2:121–133.PubMedCrossRefGoogle Scholar
  73. 74.
    Tobler A, Miller C, Norman AW, Koeffler HP: 1,25-dihydroxyvitamin D3 modulates the expression of a lymphokine (granulocyte-monocyte colony stimulating factor) post-transcriptionally. J Clin Invest 1988: 81:1819–1823.PubMedCrossRefGoogle Scholar
  74. 75.
    Zhou JY, Norman AW, Lubbert M, Collins ED, Uskokovic MR, Koeffler HP: Novel vitamin D analogs that modulate leukemic cell growth and differentiation with little effect on either intestinal calcium absorption or bone calcium mobilization. Blood 1989; 74:82–93.PubMedGoogle Scholar
  75. 76.
    Koeffler HP, Bishop JE, Reichel H, Singer F, Nagler A, Tobler A, Walka W, Norman AW: Lymphocyte cell lines from vitamin D-dependent rickets type II show functional defects in the 1,25 dihydroxyvitamin D3 receptor. Mol and Cellul Endo 1990; 70:1–11.CrossRefGoogle Scholar
  76. 77.
    Reichel H, Koeffler HP, Norman AW: Production of 1 alpha, 25 dihydroxyvitamin D3 by hematopoietic cells. Progress in Clinical and Biological Research 1990; 332:81–97.PubMedGoogle Scholar
  77. 78.
    Norman AW, Zhou JY, Henry HL, Uskokovic MR, Koeffler HP: Structure-function studies on analogs of 1α,25-dihydroxyvitamin D3: Differential effects on leukemic cell growth, differentiation, and intestinal calcium absorption. Cancer Research 1990; 50:6857–6864.PubMedGoogle Scholar
  78. 79.
    Kizaki M, Norman AW, Bishop JE, Lin CW, Karmakar A, Koeffler HP: 1,25-dihydroxyvitamin D3 receptor RNA: expression in hematopoietic cells. Blood 1991;77:1238–1247.PubMedGoogle Scholar
  79. 80.
    Zhou JY, Norman AW, Akashi M, Chen DL, Uskokovic M, Aurrecocchea JM, Dauben WG, Okamura W, Koeffler HP: Development of a novel l,25(OH)2-Vitamin D3 analog with potent ability to induce HL-60 cell differentiation without modulating calcium metabolism. Blood 1991; 78:75–82.PubMedGoogle Scholar
  80. 81.
    Figadere B, Okamura WH, Norman AW, Henry HL, Koeffler HP, Zhou JY: Arocalciferols: Synthesis and biological evaluation of aromatic side chain analogues of 1α,25-dihydroxyvitamin D3. J Med Chem 1991; 34:2452–2463.PubMedCrossRefGoogle Scholar
  81. 82.
    Kizaki M, Koeffler HP: differentiation-inducing agents in the treatment of myelodysplastic syndromes. Seminars in Oncology 1992; 19:95–105.PubMedGoogle Scholar
  82. 83.
    Reichel H, Bishop JE, Koeffler HP, Norman AW: Evidence for 1,25-dihydroxyvitamin D3 production by cultured porcine alveolar macrophages. Mol Cell Endo 1991; 75:163–167.CrossRefGoogle Scholar
  83. 84.
    Norman AW, Koeffler HP, Bishop JE, Collins ED, Sergeev I, Zhou LX, Nemere I, Zhou J, Henry HL, Okamura: Structure-Function relationships in the vitamin D endocrine system for l,25(OH)2D3 analogs. Proceedings of the Eighth Workshop on Vitamin D 1991; 146–154.Google Scholar
  84. 85.
    Bishop JE, Henry HL, Okamura WH, Koeffler HP, Norman A: Acrocalciferols: New class of side-chain analogs of 1,25(OH)2D3 vitamin gene. Proceedings of the Eighth Workshop on Vitamin D 1991; 165–166.Google Scholar
  85. 86.
    Kizaki M, Simon KJ, Ikeda Y, Nanjo M, Koeffler HP: Effect of 1,25-dihydroxyvitamin D3 and its analogs on human immunodeficiency virus infection in monocytes/macrophages. Leukemia 1993; 7(10): 1525–1530.PubMedGoogle Scholar
  86. 87.
    Jung SJ, Lee YY, Pakkala S, de Vos S, Elstner E, Norman AW, Green J, Uskokovic M, Koeffler HP: l,25(OH)2–16ene-vitamin D3 is a potent antileukemic agent with low potential to cause hypercalcemia. Leukemia Research 1994; 18(6):453–463.PubMedCrossRefGoogle Scholar
  87. 88.
    Elstner E, Lee YY, Hashiya M, Pakkala S, Binderup L, Norman AW, Okamura WH, Koeffler HP: 1α,25-dihydroxy-20-epi-vitamin D3: an extraordinarily potent inhibitor of leukemic cell growth in vitro. Blood 1994; 84(6): 1960–1967.PubMedGoogle Scholar
  88. 89.
    Pakkala S, de Vos S, Elstner E, Rude RK, Uskokovic M, Binderup L, Koeffler HP: Vitamin D3 analogs: effect on leukemic clonal growth and differentiation, and on serum calcium levels. Leukemia Research 1995; 19:65–72.PubMedCrossRefGoogle Scholar
  89. 90.
    Imai Y, Pike JW, Koeffler HP: Potent vitamin D3 analogs: their abilities to enhance transactivation and to bind to the vitamin D3 response element. Leukemia Research, in press, 1994.Google Scholar
  90. 91.
    Elstner E, Said J, Umiel T, de Vos S, Israeli ML, Heber D, Binderup L, Uskokovic M, Koeffler HP: 20-epi-vitamin D3 analogs: a novel class of potent inhibitors of proliferation and inducers of differentiation in human estrogen receptor (ER)-positive and ER-negative breast cancer cell lines in vitro. Cancer Research, in press, 1995.Google Scholar
  91. 92.
    Ostrem VI, Tanaka Y, Prahl J, DeLuca HF, Ikekawa N: 24-and 26-homo 1,25-dihydroxyvitamin D3. Preferential activity in inducing differential of human leukemia cell HL-60 in vitro. Proc Natl Acad Sci USA 1987; 84:2610.Google Scholar
  92. 93.
    Elstner, E., Lee, Y Y, Hashiya, M., Pakkala, S., Binderup, L., Norman, A. W., Okamura, W. H., and Koeffler H. P.: 1α,25-dihydroxy-20-epi-vitamin D3: an extraordinarily potent inhibitor of leukemic cell growth in vitro. Blood, 84:1968–1968, 1994.94. Kiguchi, K., Giometti, C, Chubb, C. H., Fujiki, H., and Huberman, E.: Differentiation induction in human breast tumor cells by okadaic acid and related inhibitors of protein phosphatases 1 and 2A. Biochem and Biophysical Research Communications, 189:1261–1267, 1992.CrossRefGoogle Scholar
  93. 95.
    Sheehan, D. C: Theory and practice of histotechnology, 2nd ed C. V Mosby Company. St. Lous, p.209, 1980.Google Scholar
  94. 96.
    Bacus, S. S., Kiguchi, K., Chin, D., King, C. R., and Huberman, E. Differentiation of cultured human breast cancer cells (AU-565 and MCF-7) associated with loss of cell surface HER-2/neu antigen. Molecular Carcinogenesis, 3: 350–362, 1990.PubMedCrossRefGoogle Scholar
  95. 97.
    Martin, S. J. and Cotter T. G. Apoptosis of human leukemia: induction, morphology, and molecular mechanisms. In: Apoptosis II: Molecular basis of apoptosis in disease. Cold Spring Harbor Laboratory Press, p.1, 1994.Google Scholar
  96. 98.
    Sellins, K. S., and Cohen, J. J.: Gene induction by Gamma-irradiation leads to DNA fragmentation in lymphocytes. J. Immunology, 139: 3199–3206, 1987.Google Scholar
  97. 99.
    Said, J. W., Pinkus, G. S., Lones, M. A., Preston, M., and Shintaku, I. P. Expression of bcl-2 oncogene protein in malignant lymphomas, including Hodgkin’s disease and non-Hodgkin’s lymphomas of T-cell phenotype. Applied Immunohistochemistry, 1: 108–114, 1993.Google Scholar
  98. 100.
    Lones, M. A., Said, J. W., Pinkus, G. S. Bcl-2 oncogene protein in preferentially expressed in Reed Sternberg cells in Hodgkin’s disease of modular sclerosis subtype. Am J. Clin Pathol, (in press), 1994.Google Scholar
  99. 101.
    Walts, A. E., Said, J. W., and Koeffler, H. P. Is immunoreactivity for p53 useful in distinguishing benign from malignant effusions? Localization of p53 gene product in benign mesothelial and adenocarcinoma cells. Modern Pathol, (in press), 1994.Google Scholar
  100. 102.
    Banks, L., Matlashewski, G., and Crawford, L. Isolation of human p53 specific monoclonal antibodies and their use in the studies of human p53 expression. Eur. J. Biochem., 159: 529–534, 1986.PubMedCrossRefGoogle Scholar
  101. 103.
    Bartck, J. Iggo, R., Gannon, J., and Lane, D. P. Genetic and immunochemical analysis of mutant p53 in human breast cancer cell lines. Oncogene, 5: 893–9, 1990.Google Scholar
  102. 104.
    Miller, C. W., Chumakov, A., Said, J., Chen, D. L., Aslo, A., and Koeffler, H. P. Mutant p53 proteins have diverse intracellular abilities to oligomerize and activate transcription. Oncogene 8: 1815–1824, 1993.PubMedGoogle Scholar
  103. 105.
    Midland, M.M., Plumet, Y, and Okamura, W.H. Effect of C20 stereochemistry on the conformational profile of the side chains of vitamin D analogs. Bioorganic and Medicinal Chemistry Letters, 3: 1799–1804, 1993.CrossRefGoogle Scholar
  104. 106.
    Mangelsdorf, DJ, Koeffler HP, Donaldson CA, Pike JW, Haussler MR: Induced differentiation in a human promyelocytylic leukemia cell line (HL 60): receptor-mediated maturation to macrophage-like cells. J Cell Biol 1984;98:391–398.PubMedCrossRefGoogle Scholar
  105. 107.
    Collins, S. J., Ruscetti, F. W., Gallagher, R. E., and Gallo, R. C. Normal functional characteristics of cultured human promyelocytic leukemia cells (HL-60) after induction of differentiation by dimethylsul-foxide. J. Exp. Med., 149: 969–977, 1979.CrossRefGoogle Scholar
  106. 108.
    Douer, D., and Koeffler, H. P. Inhibition of the clonal growth of human myeloid leukemia cells. J. Clin. Invest., 69: 277–283.Google Scholar
  107. 109.
    Fisher, D. E. Apoptosis in cancer therapy: crossing the threshold. Cell, 78: 539–542.Google Scholar
  108. 110.
    Raff, M. C. Social control on cell survival and cell death. Nature (Lond.), 356: 397 400, 1992.CrossRefGoogle Scholar
  109. 111.
    Oltval, Z. N., and Korsmeyer, S. J. Checkpoints of dueling dimers foil death wishes. Cell, 79: 189–192, 1994.CrossRefGoogle Scholar
  110. 112.
    Vaux, D. L., Cory, S., and Adams, J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature,335: 440–442, 1988.PubMedCrossRefGoogle Scholar
  111. 113.
    Hockenbery, D., Nu-ez, G., Milliman, C, Schreiber, R. D., and Korsmeyer, S. J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature, 348: 334–339, 1990.PubMedCrossRefGoogle Scholar
  112. 114.
    Hockenbery, D. M. The bcl-2 oncogene and apoptosis. Seminars in Immunology, 4: 413–420, 1992.PubMedGoogle Scholar
  113. 115.
    McDonnell, T. J., Deane, N., Platt, F.M., Nunez, G., Jaeger, U., McKearn, J. P., and Korsmeyer, S. J. Bcl-2 immunoglobin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell, 57: 79–88, 1989.PubMedCrossRefGoogle Scholar
  114. 116.
    El-Deiry, W. S., Tokino, T, Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, W. E., and Vogelstein, B. WAF1, a potential mediator of p53 tumor suppression. Cell, 75: 817–825, 1993.PubMedCrossRefGoogle Scholar
  115. 117.
    Herper, J. W., Adam G. R., Wei, N, Keyomarsi, K., and Elledge, S. J. The p21 cdk-interacting protein Cip 1 is a potent inhibitor of Gl cyclin-dependent kinases. Cell 75: 805–816, 1993.CrossRefGoogle Scholar
  116. 118.
    Symonds, H., Krall, L., Remington, L., Saenz-Robles, L., Lowe, S., Jacks, T., and Van Dyke, T. p53-dependent apoptosis suppresse tumor growth and progression in vivo. Cell, 78: 703–711, 1994.PubMedCrossRefGoogle Scholar
  117. 119.
    Yonish-Rouach, E., Resnitzky, D., Lotem, J., Sachs, L., Kimchi, A., and Oren, M. Wild-type p53 induces apoptosis of myeloid leukemic cells that is inhibited by interleukin-6. Nature (Lond.), 352: 345–347, 1991.CrossRefGoogle Scholar
  118. 120.
    Show, P., Bovey, R., Tardy, S., Sahli, R., Sordat, B., and Costa, J. Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. Proc. Natl. Acad. Sci. USA, 89: 4495–4499, 1992.CrossRefGoogle Scholar
  119. 121.
    Crawford, L. V., Pirn, D. C., And Lamb, P. The cellular protein p53 in human tumours. Mol. Biol. Med., 2: 261–272, 1984.PubMedGoogle Scholar
  120. 122.
    Cattoretti, G., Rilke, F., Andreola, S., D’Amato, L., and Domenico, D. p53 in breast cancer. Int. J. Cancer, 41: 178–183, 1988.PubMedCrossRefGoogle Scholar
  121. 123.
    Riou, G., L, M. G., Travagli, J. P., Moll, U. M., and Levine, A. J. Poor prognosis of p53 nuclear overexpression and mutation in inflammatory breast carcinoma. Proc. Amer. Assoc. Canc. Res., 35: Abstract 1314, 1994.Google Scholar
  122. 124.
    Mehta, R. R., Graves, J. M., and Das Gupta, T. K. p53 levels and breast tumor metastasis in experimental animals. Proc. Amer. Assoc. Canc. Res., 35: Abstract 286, 1994.Google Scholar
  123. 125.
    Moll, U. M., Riou, G., and Levine, J. Two distinct mechanisms alter p53 in breast cancer: Mutation and nuclear exclusion. Proc. Natl. acad. Sci. USA, 89: 7262–7266, 1992.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1996

Authors and Affiliations

  • E. Elstner
    • 1
  • D. Heber
    • 2
  • H. P. Koeffler
    • 1
  1. 1.Div. of Hematology-Oncology, Cedars-Sinai Medical CenterUCLA School of MedicinePhiladelphiaUSA
  2. 2.Division of Clinical NutritionUCLA School of MedicinePhiladelphiaUSA

Personalised recommendations