Skip to main content
SpringerLink
Log in

Ligand Structure—Function Relationships in the Vitamin D Endocrine System from the Perspective of Drug Development (Including Cancer Treatment)

  • Conference paper
Vitamin D Analogs in Cancer Prevention and Therapy

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 164))

Abstract

It has become readily apparent to many scientists and pharmaceutical companies that the vitamin D endocrine system offers a wide array of drug development opportunities. There are already successes, as noted by la,25(OH)2D3(Roche, and Abbott) for renal osteodystrophy and osteoporosis and la(OH)D3(Leo, Chugai, Teijin) for renal osteodystrophy and (in Japan) osteoporosis, la,24(OH)2-24-cyc1opropy1-D3(Dovonex) and la,24(OH)2D3(Teijin) for psoriasis, and 19-nor-la,25(OH)2D2(Abbott) for renal osteodystrophy, as well as drugs under active development. Yet there are still many important and challenging drug development frontiers, particularly in the area of cancer treatment and immune system disorders where exploration is only in the initial early stages. In addition, the application of vitamin D-related drugs in neurology and brain pathology should not be overlooked. It is to be hoped that the cellular and molecular basis for the vexing problem of analog-induced hypercalcemia will be elucidated. Given that there are believed to be over 2000 analogs of la,25(OH)2D3already available for consideration, it is to be expected that over the next decade a significant number of new vitamin D structure-function drug development projects will be brought to conclusion.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Norman AW, Bouillon R, Thomasset M (eds) (1997) Vitamin D: Chemistry, biology and clinical applications of the steroid hormone. University of California, Riverside

    Google Scholar 

  2. Norman AW, Bouillon R, Thomasset M (eds) (2000) Vitamin D endocrine system: structural, biological, genetic and clinical aspects. In: Proceedings of the eleventh workshop on vitamin D. University of California, Riverside, pp 1–1014

    Google Scholar 

  3. Abe E, Miyaura C, Sakagami H, Takeda M, Konno K, Yamazaki T, Yoshiki S, Suda T (1981) Differentiation of mouse myeloid leukemia cells induced by la,25-dihydroxyvitamin D3. Proc Natl Acad Sci U S A 78:4990–4994

    Article  PubMed  CAS  Google Scholar 

  4. Akhter J, Lu Y, Finlay I, Pourgholami MH, Morris DL (2001) ía,25-Dihydroxyvitamin D3and its analogues, EB1089 and CB1093, profoundly inhibit the in vitro proliferation of the human hepatoblastoma cell line HepG2. AN Z J Surg 71:414–417

    Article  CAS  Google Scholar 

  5. Barbour GL, Coburn JW, Slatopolsky E, Norman AW, Horst RL (1981) Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D. New Engl J Med 305:440–443

    Article  PubMed  CAS  Google Scholar 

  6. Bellido T, Girasole G, Passeri G, Yu X-P, Mocharla H, Jilka RL, Notides A, Manolagas SC (1993) Demonstration of estrogen and vitamin D receptors in bone marrow-derived stromal cells: up-regulation of the estrogen receptor by 1,25-dihydroxyvitamin-D3. Endocrinology 133:553–562

    Article  PubMed  CAS  Google Scholar 

  7. Berg JP, Torjesen PA, Haug E (1991) Calcitriol receptors in rat thyroid follicular cells (FRTL- 5). Acta Endocr (Copenh) 125:574–580

    CAS  Google Scholar 

  8. Berger U, McClelland RA, Wilson P, Greene GL, Haussier MR, Pike JW, Colston K, Easton D, Coombes RC (1991) Immunocytochemical determination of estrogen receptor, progesterone receptor, and 1,25-dihydroxyvitamin D3receptor in breast cancer and relationship to prognosis. Cancer Res 51:239–244

    PubMed  CAS  Google Scholar 

  9. Bidmon H-J, Stumpf WE (1994) Distribution of target cells for 1,25-dihydroxyvitamin D3in the brain of the yellow bellied turtleTrachemys scripta.Brain Res 640:277–285

    Article  PubMed  CAS  Google Scholar 

  10. Binderup L, Kragballe K (1992) Origin of the use of calcipotriol in psoriasis treatment. Rev Contemp.Pharmacother. 3:357–365

    Google Scholar 

  11. Binderup L, Latini S, Binderup E, Bretting C, Calverley M, Hansen K (1991) 20-Epi-vitamin D3analogues: a novel class of potent regulators of cell growth and immune responses. Biochem Pharm 42:1569–1575

    Article  PubMed  CAS  Google Scholar 

  12. Biroc SL (1969) A possible receptor site for a metabolite of vitamin D3in the supernatant fraction of hen egg shell gland (personal communication)

    Google Scholar 

  13. Bishop JE, Collins ED, Okamura WH, Norman AW (1994) Profile of ligand specificity of the vitamin D binding protein for la,24(OH)2-vitamin D3and its analogs. J Bone Miner Res 9:1277–1288

    Article  PubMed  CAS  Google Scholar 

  14. Boehm MF, Fitzgerald P, Zou A, Elgort MG, Bischoff ED, Mere L, Mais DE, Bissonnette RP, Heyman RA, Madzan AM, Reichman M, Allegretto EA (1999) Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3. Chem Bio16:265–275

    Article  Google Scholar 

  15. Boland R, Norman AW, Ritz E, Hasselbach W (1992) Presence of a 1,25-dihydroxyvitamin D3receptor in chick skeletal muscle myoblasts. Biochem Biophys Res Commun 128:305311

    Google Scholar 

  16. Bouillon R, Okamura WH, Norman AW (1995) Structure-function relationships in the vitamin D endocrine system. Endocr Rev 16:200–257

    PubMed  CAS  Google Scholar 

  17. Brickman AS, Coburn JW, Friedman GR, Okamura WH, Massry SG, Norman AW (1976) Comparison of effects of 1-hydroxy-vitamin D3and 1,25-dihydroxy-vitamin D3in man. J Clin Invest 57:1540–1547

    Article  PubMed  CAS  Google Scholar 

  18. Brickman AS, Coburn JW, Kurokawa K, Bethune JE, Harrison HE, Norman AW (1973) Actions of 1,25-dihydroxycholecalciferol in patients with hypophosphatemic vitamin D-resistant rickets. New Engl J Med 289:495–498

    Article  PubMed  CAS  Google Scholar 

  19. Brickman AS, Coburn JW, Norman AW (1972) Action of 1,25-dihydroxycholecalcifero1, a potent, kidney-produced metabolite of vitamin D3in uremic man. New Engl J Med 287:891–895

    Article  PubMed  CAS  Google Scholar 

  20. Brown AJ, Finch J, Slatopolsky E (2002) Differential effects of 19-nor-1,25-dihydroxyvitamin D2 and 1,25- dihydroxyvitamin D3on intestinal calcium and phosphate transport. J Lab Clin Med 139:279–284

    Article  PubMed  CAS  Google Scholar 

  21. Bula CM, Bishop JE, Ishizuka S, Norman AW (2000) 25-Dehydro-la-hydroxyvitamin D326,235-iacton antagonizes the nuclear vitamin D receptor by mediating a unique noncovalent conformational change. Mol Endocrinol 14, 1788–1796

    Article  PubMed  CAS  Google Scholar 

  22. Norman AW, Manchand PS, Uskokovic MR, Okamura WH, Takeuchi JA, Bishop, JE, Hisatake JI, Koeffler HP, Peleg S (2000) Characterization of a novel analogue of la,25(OH)2-vitamin D3with two side chains: Interaction with its nuclear receptor and cellular actions. J Med Chem 43.2719–2730

    Article  CAS  Google Scholar 

  23. Cade C, Norman AW (1987) Rapid normalization/stimulation by 1,25(OH)2-vitamin D3of insulin secretion and glucose tolerance in the vitamin D-deficient rat. Endocrinology 120:1490–1497

    Article  PubMed  CAS  Google Scholar 

  24. Caffrey JM, Farach-Carson MC (1989) Vitamin D3metabolites modulate dihydropyridine-sensitive calcium currents in clonal rat osteosarcoma cells. J Biol Chem 264:2026520274

    Google Scholar 

  25. Campbell MJ, Koeffler HP (1997) Toward therapeutic intervention of cancer by vitamin D compounds. J Natl Cancer Inst 89:182–185

    Article  PubMed  CAS  Google Scholar 

  26. Chen TL, Feldman D (1981) Regulation of 1,25-dihydroxyvitamin D3receptors in cultured mouse bone cells. J Biol Chem 256:5561–5566

    PubMed  CAS  Google Scholar 

  27. Chen TL, Hirst MA, Feldman D (1979) A receptor-like binding macromolecule for la,25dihydroxycholecalciferol in cultured mouse bone cells. J Biol Chem 254:7491–7494

    PubMed  CAS  Google Scholar 

  28. Cheskis B, Freedman LP (1994) Ligand modulates the conversion of DNA-bound vitamin D3receptor (VDR) homodimers into VDR-retinoid X receptor heterodimers. Mol Cell Biol 14:3329–3338

    PubMed  CAS  Google Scholar 

  29. Christakos S, Norman AW (1981) Studies on the mode of action of calciferol XXIX—biochemical characterization of 1,25-dihydroxyvitamin D3receptors in chick pancreas and kidney cytosol. Endocrinology 108:140–149

    Article  PubMed  CAS  Google Scholar 

  30. Clark SA, Stumpf WE, Bishop CW, DeLuca HF, Park DH, Joh TH (1986) The adrenal—a new target organ of the calciotropic hormone 1,25-dihydroxyvitamin-D3. Cell Tissue Res 243:299–302

    Article  PubMed  CAS  Google Scholar 

  31. Colston KW, Berger U, Wilson P, Hadcocks L, Naeem I, Earl HM, Coombes RC (1988) Mammary gland 1,25-dihydroxyvitamin D3receptor content during pregnancy and lactation. Mol Cell Endocrinol 60:15–22

    Article  PubMed  CAS  Google Scholar 

  32. Colston KW, Mackay AG, James SY, Binderup L, Chander S, Coombes RC (1992) EB1089: a new vitamin D analogue that inhibits the growth of breast cancer cells in vivo and in vitro. Biochem Pharm 44:2273–2280

    Article  PubMed  CAS  Google Scholar 

  33. Colston KW, Mork HC (2002) Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer. Endocr Relat Cancer 9:45–59

    Article  PubMed  CAS  Google Scholar 

  34. Cooke NE, Haddad JG (1997) Vitamin D binding protein. In: Feldman D, Glorieux FH, Pike JW (eds) Vitamin D. Academic Press, San Diego, pp 87–101

    Google Scholar 

  35. Dahlback H, Wikvall K (1988) 25-Hydroxylation of vitamin D3by a cytochrome P-450 from rabbit liver mitochondria. Biochem J 252:207–213

    PubMed  CAS  Google Scholar 

  36. Danan J, Delorme A, Cuisinier-Gleizes P (1981) Biochemical evidence for a cytoplasmic ía,25-dihydroxyvitamin D3receptor-like protein in rat yolk sac. J Biol Chem 256:48474850

    Google Scholar 

  37. Dokoh S, Donaldson CA, Marion SL, Pike JW, Haussler MR (1983) The ovary: a target organ for ía,25-dihydroxyvitamin D3. Endocrinology 112:200–206

    Article  PubMed  CAS  Google Scholar 

  38. Abdaimi K, Dion N, Papavasiliou V, Cardinal PE, Binderup L, Goltzman D, Ste-Marie LG, Kremer R (2000) The vitamin D analogue EB 1089 prevents skeletal metastasis and prolongs survival time in nude mice transplanted with human breast cancer cells. Cancer Res 60:4412–4418

    PubMed  Google Scholar 

  39. Elstner E, Lee YY, Hashiya M, Pakkala S, Binderup L, Norman AW, Okamura WH, Koeffler HP (1994) ía,25-Dihydroxy-20-epi-vitamin D3: an extraordinarily potent inhibitor of leukemic cell growth in vitro. Blood 84:1960–1967

    PubMed  CAS  Google Scholar 

  40. Elstner E, Linker-Israeli M, Le J, Umiel T, Michl P, Said JW, Binderup L, Reed JC, Koeffler HP (1997) Synergistic decrease of clonal proliferation, induction of differentiation and apoptosis of acute promyelocytic leukemia cells after combined treatment with novel 20epi vitamin D3analogs and9-cisretinoic acid. J Clin Invest 99:349–360

    Article  PubMed  CAS  Google Scholar 

  41. Evans TR, Colston KW, Lofts FJ, Cunningham D, Anthoney DA, Gogas H, de Bono JS, Hamberg KJ, Skov T, Mansi JL (2002) A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer. Br J Cancer 86:680–685

    Article  PubMed  CAS  Google Scholar 

  42. Feldman D, Zhao XY, Krishnan AV (2000) Vitamin D and prostate cancer. Endocrinology 141:5–9

    CAS  Google Scholar 

  43. Figadère B, Norman AW, Henry HL, Koeffler HP, Zhou JY, Okamura WH (1991) Arocalciferols: synthesis and biological evaluation of aromatic side-chain analogues of la,25-dihydroxyvitamin D3. J Med Chem 34.2452–2463

    Article  PubMed  Google Scholar 

  44. Folgueira MA, Federico MH, Roela RA, Maistro S, Katayama ML, Brentani MM (2000) Differential regulation of vitamin D receptor expression in distinct leukemic cell lines upon phorbol ester-induced growth arrest. Braz J Med Biol Res 33:559–568

    Article  PubMed  CAS  Google Scholar 

  45. Gabriels S, Van Haver D, Vandewalle M, De Clercq P, Verstuyf A, Bouillon R (2001) Development of analogues of ía,25-dihydroxyvitamin D3with biased side chain orientation: methylated des-C,D-homo analogues. Chemistry 7:520–532

    Article  PubMed  CAS  Google Scholar 

  46. Guyton KZ, Kensler TW, Posner GH (2001) Cancer chemoprevention using natural vitamin D and synthetic analogs. Annu Rev Pharmacol Toxicol 41:421–442

    Article  PubMed  CAS  Google Scholar 

  47. Hannah SS, Norman AW (1994) la,24(OH)2-vitamin D3-regulated expression of the eukaryotic genome. Nutr Rev 52:376–382

    Article  PubMed  CAS  Google Scholar 

  48. Hansen CM, Binderup L, Hamberg KJ, Carlberg C (2001) Vitamin D and cancer: effects of 1,25(OH)2D3and its analogs on growth control and tumorigenesis. Front Biosci 6:D820–D848

    Article  PubMed  CAS  Google Scholar 

  49. Harper KD, Iozzo RV, Haddad JG (1989) Receptors for and bioresponses to 1,25-dihydroxyvitamin D in a human colon carcinoma cell line (HT-29). Metabolism 38:1062–1069

    Article  PubMed  CAS  Google Scholar 

  50. Hartenbower DL, Stanley TM, Coburn JW, Norman AW (1977) Serum and renal histologic changes in the rat following administration of toxic amounts of 1,25-dihydroxyvitamin D3in Vitamin D In: Norman AW, Schaefer K, von Herrath D, Grigoleit H-G, Coburn JW, DeLuca HF, Mawer EB, Berlin ST, de Gruyter W (eds) Biochemical, chemical and clinical aspects related to calcium metabolism.

    Google Scholar 

  51. Haussler MR, Norman AW (1969) Chromosomal receptor for a vitamin D metabolite: a nutrition classic. Nutr Rev.43:181–183

    Article  Google Scholar 

  52. Haussler MR, Whitfield GK, Haussler CA, Hsieh JC, Thompson PD, Selznick SH, Dominguez CE, Jurutka PW (1998) The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res 13:325–349

    Article  PubMed  CAS  Google Scholar 

  53. Henry HL (1992) Vitamin D hydroxylases. J Cell Biochem 49:4–9

    Article  PubMed  CAS  Google Scholar 

  54. Henry HL, Norman AW (1974) Studies on calciferol metabolism. IX. Renal 25-hydroxyvitamin D3–1-hydroxylase. Involvement of cytochrome P-450 and other properties. J Biol Chem 249:7529–7535

    PubMed  CAS  Google Scholar 

  55. Henry HL, Norman AW (1975) Localization of 1,25-dihydroxy-vitamin D3in chick parathyroid glands. Biochem Biophys Res Commun 62:781–788

    Article  PubMed  CAS  Google Scholar 

  56. Ishida H, Norman AW (1988) Demonstration of high affinity receptor for 1,25-dihydroxyvitamin D3in rat pancreas. Mol Cell Endocrinol 60:109–117

    Article  PubMed  CAS  Google Scholar 

  57. Issa LL, Leong GM, Sutherland RL, Eisman JA (2002) Vitamin D analogue-specific recruitment of vitamin D receptor coactivators. J Bone Miner Res 17:879–890

    Article  PubMed  CAS  Google Scholar 

  58. Johnson CS, Hershberger PA, Bernardi RJ, McGuire TF, Trump DL (2002) Vitamin D receptor: a potential target for intervention. Urology 60:123–130

    Article  PubMed  Google Scholar 

  59. Jones G, Calverley MJ (1993) A dialogue on analogues: newer vitamin-D drugs for use in bone disease, psoriasis and cancer. Trends Endocrinol Metab 4:297–303

    Article  PubMed  CAS  Google Scholar 

  60. Kajikawa M, Ishida H, Fujimoto S, Mukai E, Nishimura M, Fujita J, Tsuura Y, Okamoto Y, Norman AW, Seino Y (1999) An insulinotropic effect of vitamin D analog with increasing intracellular Cat+concentration in pancreatic ß-cells through nongenomic signal transduction. Endocrinology 140:4706–4712

    Article  PubMed  CAS  Google Scholar 

  61. Kawa S, Yoshizawa K, Tokoo M, Imai H, Oguchi H, Kiyosawa K, Homma T, Nikaido T, Furihata K (1996) Inhibitory effect of 22-oxa-1,25-dihydroxyvitamin D3on the proliferation of pancreatic cancer cell lines. Gastroenterology 110:1605–1613

    Article  PubMed  CAS  Google Scholar 

  62. Kivineva M, Bläuer M, Syvälä H, Tammela T, Tuohimaa P (1998) Localization of 1,25-dihydroxyvitamin D3receptor (VDR) expression in human prostate. J Steroid Biochem Mol Biol 66:121–127

    Article  PubMed  CAS  Google Scholar 

  63. Klaus G, Merke J, Eing H, Hügel U, Milde P, Reichel H, Ritz E, Mehls 0 (1991) 1,25(OH) 2D3receptor regulation and 1,25(OH)2D3effects in primary cultures of growth cartilage cells of the rat. Calcif Tissue Int 49:340–348

    Article  PubMed  CAS  Google Scholar 

  64. Kleuser B, Cuvillier 0, Spiegel S (1998) ía,25-Dihydroxyvitamin D3inhibits programmed cell death in HL-60 cells by activation of sphingosine kinase. Cancer Res 58:1817–1824

    PubMed  CAS  Google Scholar 

  65. Kream BE, Jose M, Yamada S, DeLuca HF (1977) A specific high-affinity binding macromolecule for 1,25-dihydroxycholecalciferol in fetal bone. Science 197:1086–1088

    Article  PubMed  CAS  Google Scholar 

  66. Mangelsdorf DJ, Koeffler HP, Donaldson CA, Pike JW, Haussler MR (1984) 1,25-Dffhydroxyvitamin D3-induced differentiation in a human promyelocytic leukemia cell line (HL-60): receptor-mediated maturation to macrophage-like cells. J Cell Biol 98:391–398

    Article  PubMed  Google Scholar 

  67. Manolagas SC, Provvedini DM, Murray EJ, Tsoukas CD, Deftos LJ (1986) The antiproliferative effect of calcitriol on human peripheral-blood mononuclear-cells. J Clin Endocr Me-tab 63:394–400

    Article  CAS  Google Scholar 

  68. Martin KJ, González EA, Gellens M, Hamm LL, Abboud H, Lindberg J (1998) 19-Nor-1-a25-dihydroxyvitamin D2 (paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis. J Am Soc Nephrol 9:1427–1432

    PubMed  CAS  Google Scholar 

  69. Mathiasen IS, Sergeev IN, Bastholm L, Elling F, Norman AW, Jaattela M (2002) Calcium and calpain as key mediators of apoptosis-like death induced by vitamin D compounds in breast cancer cells. J Biol Chem 277:30738–30745

    Article  PubMed  CAS  Google Scholar 

  70. Menaa C, Barsony J, Reddy SV, Cornish J, Cundy T, Roodman GD (2002) 1,25-dihydroxyvitamin D3hypersensitivity of osteoclast precursors from patients with Paget’s disease. J Bone Miner Res 15:228–235

    Google Scholar 

  71. Merke J, Hofmann W, Goldschm D, Ritz E (1987) Demonstration of 1,25(OH)2vitamin-D3receptors and actions in vascular smooth-muscle cells in vitro. Calcif Tissue Int 41:112–114

    Article  PubMed  CAS  Google Scholar 

  72. Messer G, Degitz K, Plewig G, Rocken M (2001) Pretreatment of psoriasis with the vitamin D3derivative tacalcitol increases the responsiveness to 311-nm ultraviolet B: results of a controlled, right/left study. Br J Dermatol 144:628–629

    Article  PubMed  CAS  Google Scholar 

  73. Miller GJ, Stapleton GE, Ferrara JA, Lucia MS, Pfister S, Hedlund TE, Upadhya P (1992) The human prostatic carcinoma cell line LNCaP expresses biologically active, specific receptors for ía,25-dihydroxyvitamin D3. Cancer Res 52:515–520

    PubMed  CAS  Google Scholar 

  74. Miura D, Manabe K, Gao Q, Norman AW, Ishizuka S (1999) ía,25-Dihydroxyvitamin D326,23-lactone analogs antagonize differentiation of human leukemia cells (HL-60 cells) but not of human acute promyelocytic leukemia cells (NB4 cells). FEBS Lett 460:297–302

    Article  PubMed  Google Scholar 

  75. Miyaguchi S, Watanabe T (2001) The role of vitamin D3receptor mRNA in the proliferation of hepatocellular carcinoma. Hepatogastroenterology 47:468–472

    Google Scholar 

  76. Nemere I, Dormanen MC, Hammond MW, Okamura WH, Norman AW (1994) Identification of a specific binding protein for ía,25-dihydroxyvitamin D3in basal-lateral membranes of chick intestinal epithelium and relationship to transcaltachia. J Biol Chem 269:23750–23756

    PubMed  CAS  Google Scholar 

  77. Nemere I, Yoshimoto Y, Norman AW (1984) Studies on the mode of action of calciferol. LIV. Calcium transport in perfused duodena from normal chicks: enhancement with 14 minutes of exposure to ía,25-dihydroxyvitamin D3. Endocrinology 115:1476–1483

    Article  PubMed  CAS  Google Scholar 

  78. Nguyen TM, Guillozo H, Marin L, Dufour ME, Tordet C, Pike JW, Garabedian M (1990) 1,25-Dihydroxyvitamin D3receptors in rat lung during the perinatal period: regulation and immunohistochemical localization. Endocrinology 127:1755–1762

    Article  PubMed  Google Scholar 

  79. Nielsen SP, Binderup E, Godtredsen WO, Jensen H, Ladefoged J (1976) la-Hydroxycholecalciferol. Long-term treatment of patients with uraemic osteodystrophy. Nephron 16:359–370

    Article  PubMed  Google Scholar 

  80. Norman AW (1998) Receptors for la,25(OH)2D3: past, present, and future. J Bone Miner Res 13:1360–1369

    Article  PubMed  CAS  Google Scholar 

  81. Norman AW, Bouillon R, Farach-Carson MC, Bishop JE, Zhou L-X, Nemere I, Zhao J, Muralidharan KR, Okamura WH (1993) Demonstration that lß,25-dihydroxyvitamin D3is an antagonist of the nongenomic but not genomic biological responses and biological profile of the three A-ring diastereomers of ía,25-dihydroxyvitamin D3. J Biol Chem 268:20022–20030

    Google Scholar 

  82. Norman AW, Frankel BJ, Heldt AM, Grodsky GM (1980) Vitamin D deficiency inhibits pancreatic secretion of insulin. Science 209:823–825

    Article  Google Scholar 

  83. Norman AW, Ishizuka S, Okamura WH (2001) Ligands for the vitamin D endocrine system: different shapes function as agonists and antagonists for genomic and rapid response receptors or as a ligand for the plasma vitamin D binding protein. J Steroid Biochem Mol Biol 76:49–59

    Article  Google Scholar 

  84. Norman AW, Manchand PS, Uskokovic MR, Okamura WH, Takeuchi JA, Bishop JE, Hisatake JI, Koeffler HP, Peleg S (2000) Characterization of a novel analogue of la,25(OH)Z-vitamin D3with two side chains: interaction with its nuclear receptor and cellular actions. J Med Chem 43.2719–2730

    Article  CAS  Google Scholar 

  85. Norman AW, Okamura WH, Hammond MW, Bishop JE, Dormanen MC, Bouillon R, Van Baelen H, Ridall AL, Daane E, Khoury R, Farach-Carson MC (1997) Comparison of6-s-cisand6-s-translocked analogs of la,25(OH)2-vitamin D3indicates that the6-s-cisconformation is preferred for rapid nongenomic biological responses and that neither6-s-cisnor 6-s-trans locked analogs are preferred for genomic biological responses. Mol Endocrinol 11:1518–1531

    Article  PubMed  CAS  Google Scholar 

  86. Norman AW, Sergeev IN, Bishop JE, Okamura WH (1993) Selective biological response by target organs (intestine, kidney, and bone) to 1,25-dihydroxyvitamin D3and two analogues. Cancer Res 53:3935–3942

    PubMed  CAS  Google Scholar 

  87. O’Connell TD, Simpson RU (1996) Immunochemical identification of the 1,25-dihydroxyvitamin D3receptor protein in human heart. Cell Biol Int 20:621–624

    Article  PubMed  Google Scholar 

  88. Ohyama Y, Okuda K (1991) Isolation and characterization of a cytochrome P-450 from rat kidney mitochondria that catalyzes the 24-hydroxylation of 25-hydroxyvitamin D3. J Biol Chem 266:8690–8695

    PubMed  CAS  Google Scholar 

  89. Okamura WH, Palenzuela JA, Plumet J, Midland MM (1992) Vitamin D: structure-function analyses and the design of analogs. J Cell Biochem 49:10–18

    Article  PubMed  CAS  Google Scholar 

  90. Osmundsen BC, Huang HFS, Anderson MB, Christakos S, Walters MR (1989) Multiple sites of action of the vitamin D endocrine system: FSH stimulation of testis 1,25-dihydroxyvitamin D-3 receptors. J Steroid Biochem Mol Biol 34:339–343

    CAS  Google Scholar 

  91. Park WH, Seol JG, Kim ES, Binderup L, Koeffler HP, Kim BK, Lee YY (2002) The induction of apoptosis by a combined 1,25(OH)2D3analog, EB1089 and TGF-betal in NCI-H929 multiple myeloma cells. Int J Oncol 20:533–542

    PubMed  CAS  Google Scholar 

  92. Park WH, Seol JG, Kim ES, Hyun JM, Jung CW, Lee CC, Binderup L, Koeffler HP, Kim BK, Lee YY (2000) Induction of apoptosis by vitamin D3analogue EB1089 in NCI-H929 myeloma cells via activation of caspase 3 and p38 MAP kinase. Br J Haematol 109:576583

    Google Scholar 

  93. Peleg S, Sastry M, Collins ED, Bishop JE, Norman AW (1995) Distinct conformational changes induced by 20-epi analogues of ía,25-dihydroxyvitamin D3are associated with enhanced activation of the vitamin D receptor. J Biol Chem 270:10551–10558

    Article  PubMed  CAS  Google Scholar 

  94. Peleg S, Uskokovic M, Ahene A, Vickery B, Avnur Z (2002) Cellular and molecular events associated with the bone-protecting activity of the noncalcemic vitamin D analog RO-26–9228 in osteopenic rats. Endocrinology 143:1625–1636

    Article  PubMed  CAS  Google Scholar 

  95. Peterfy C, Tenenhouse A (1982) Vitamin D receptors in isolated rat parotid and acinar cells. Biochim Biophys Acta 721:158–163

    Article  PubMed  CAS  Google Scholar 

  96. Pike JW, Gooze LL, Haussler MR (1980) Biochemical evidence for 1,25-dihydroxyvitamin D3receptor macromolecules in parathyroid, pancreatic, pituitary, and placental tissues. Life Sci 26:407–414

    Article  PubMed  CAS  Google Scholar 

  97. Polek TC, Murthy S, Blutt SE, Boehm MF, Zou A, Weigel NL, Allegretto EA (2001) Novel nonsecosteroidal vitamin D receptor modulator inhibits the growth of LNCaP xenograft tumors in athymic mice without increased serum calcium. Prostate 49:224–233

    Article  PubMed  CAS  Google Scholar 

  98. Provvedini DM, Sakagami Y, Manolagas SC (1989) Distinct target cells and effects of ía,25-dihydroxyvitamin D3and glucocorticoids in the rat thymus gland. Endocrinology 124:1532–1538

    Article  PubMed  CAS  Google Scholar 

  99. Quack M, Carlberg C (2000) Ligand-triggered stabilization of vitamin D receptor/retinoid X receptor heterodimer conformations on DR4-type response elements. J Mol Biol 296:743–756

    Article  PubMed  CAS  Google Scholar 

  100. Raval-Pandya M, Freedman LP, Li H, Christakos S (1998) Thyroid hormone receptor does not heterodimerize with the vitamin D receptor but represses vitamin D receptor-mediated transactivation. Mol Endocrinol 12:1367–1379

    Article  PubMed  CAS  Google Scholar 

  101. Rebsamen MC, Sun J, Norman AW, Liao JK (2002) ía,25-dihydroxyvitamin D3induces vascular smooth muscle cell migration via activation of phosphatidylinositol 3-kinase. Circ Res 91:17–24

    Article  PubMed  CAS  Google Scholar 

  102. Reichrath J, Rafi L, Müller SM, Mink D, Reitnauer K, Tilgen W, Schmidt W, Friedrich M (1998) Immunohistochemical analysis of 1,25-dihydroxyvitamin D3receptor in cervical carcinoma. Histochem J 30:561–567

    Article  PubMed  CAS  Google Scholar 

  103. Reichrath J, Schilli M, Kerber A, Bahmer FA, Czarnetzki BM, Paus R (1994) Hair follicle expression of 1,25-dshydroxyvitamin D3receptors during the murine hair cycle. Br J Dermatol 131:477–482

    Article  PubMed  CAS  Google Scholar 

  104. Rochel N, Wurtz JM, Mitschler A, Klaholz B, Moras D (2000) The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol Cell 5:173–179

    Article  PubMed  CAS  Google Scholar 

  105. Roth J, Bonner-Weir S, Norman AW, Orci L (1982) Immunocytochemistry of vitamin D-dependent calcium binding protein in chick pancreas: exclusive localization in B-cells. Endocrinology 111:2216–2218

    Article  Google Scholar 

  106. Segura C, Alonso M, Fraga C, Caballero T, Guez C, Rez F (1999) Vitamin D receptor ontogenesis in rat liver. Histochem Cell Biol 112:163–167

    Article  PubMed  CAS  Google Scholar 

  107. Seo E-G, Schwartz Z, Dean DD, Norman AW, Boyan BD (1996) Preferential accumulation in vivo of 24R,25-dihydroxyvitamin D3in growth plate cartilage of rats. Endocrine 5:147–155

    Article  PubMed  CAS  Google Scholar 

  108. Shi H, Norman AW, Okamura WH, Sen A, Zemel MB (2001) ía,25-Dihydroxyvitamin D3modulates human adipocyte metabolism via nongenomic action. FASEB J 15:2751–2753

    PubMed  CAS  Google Scholar 

  109. Shi H, Norman AW, Okamura WH, Sen A, Zemel MB (2002) ía,25-dihydroxyvitamin D3inhibits uncoupling protein 2 expression in human adipocytes. FASEB J 16:1808–1810

    PubMed  CAS  Google Scholar 

  110. Simpson RU, DeLuca HF (1980) Chacterization of a receptor-like protein for 1,25-dihydroxyvitamin D3in rat skin. Proc Natl Acad Sci U S A 77:5822–5826

    Article  PubMed  CAS  Google Scholar 

  111. Simpson RU, Thomas GA, Arnold AJ (1985) Identification of 1,25 dihydroxyvitamin D3receptors and activities in muscle. J Biol Che. 260:8882–8891

    CAS  Google Scholar 

  112. Skowronski RJ, Peehl DM, Feldman D (1993) Vitamin D and prostate cancer: 1,25 dihydroxyvitamin D3receptors and actions in human prostate cancer cell lines. Endocrinology 132:1952–1960

    Article  PubMed  CAS  Google Scholar 

  113. Slatopolsky E, Cozzolino M, Finch JL (2002) Differential effects of 19-nor-1,25-(OH)2D2 and la-hydroxyvitamin D2 on calcium and phosphorus in normal and uremic rats. Kidney Int 62:1277–1284

    Article  PubMed  CAS  Google Scholar 

  114. Slatopolsky E, Finch J, Ritter C, Takahashi F (1998) Effects of 19-nor-1,25(OH)2D2a new analogue of calcitriol, on secondary hyperparathyroidism in uremic rats. Am J Kidney Dis 32:S40–S47

    Article  PubMed  CAS  Google Scholar 

  115. Song X, Bishop JE, Okamura WH, Norman AW (1998) Stimulation of phosphorylation of mitogen-activated protein kinase by 1f16 a,25-dihydroxyvitamin D3in promyelocytic NB4 leukemia cells: a structure-function study. Endocrinology 139:457–465

    Article  PubMed  CAS  Google Scholar 

  116. Striem S, Bar A (1991) Modulation of quail intestinal and egg shell gland calbindin (Mr 28,000) gene expression by vitamin D31,25-dihydroxyvitamin D3 and egg laying. Mol Cell Endocrinol 75:169–177

    Article  PubMed  CAS  Google Scholar 

  117. Stumpf WE, Clark SA, O’Brien LP, Reid FA (1988) 1,24(OH)2vitamin D3sites of action in spinal cord and sensory ganglion. Anat Embryol 177:307–310

    Article  Google Scholar 

  118. Stumpf WE, Downs TW (1987) Nuclear receptors for 1,25(OH)2vitamin D3in thymus reticular cells studied by autoradiography. Histochemistry 87:367–369

    Article  PubMed  CAS  Google Scholar 

  119. Stumpf WE, O’Brien LP (1987) 1,24(OH)2vitamin D3sites of action in the brain. Histochemistry 87:393–406

    Article  PubMed  Google Scholar 

  120. Stumpf WE, Sar M (1975) Autoradiograph techniques for localizing steroid hormones. Methods Enzymol 36:135–140

    Article  PubMed  CAS  Google Scholar 

  121. Stumpf WE, Sar M, Reid FA, Tanaka Y, DeLuca HF (1979) Target cells for 1,25-dihydroxyvitamin D3in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid. Science 206:1188–1190

    Article  PubMed  CAS  Google Scholar 

  122. Sunn KL, Cock TA, Crofts LA, Eisman JA, Gardiner EM (2001) Novel n-terminal variant of human VDR. Mol Endocrinol 15:1599–1609

    CAS  Google Scholar 

  123. Takeshita A, Ozawa Y, Chin WW (2000) Nuclear receptor coactivators facilitate vitamin D receptor homodimer action on direct repeat hormone response elements. Endocrinology 141:1281–1284

    Article  PubMed  CAS  Google Scholar 

  124. The commission on the Nomenclature of Biological Chemistry (1960) Definitive rules for the nomenclature of amino acids, steroids, vitamins and carotenoids. J Am Chem Soc 82:5575–5586

    Article  Google Scholar 

  125. Theodoropoulos C, Demers C, Mirshahi A, Gascon-Barre M (2001) 1,25-Dihydroxyvitamin D3downregulates the rat intestinal vitamin D3–25-hydroxylase CYP27A. Am J Physiol Endocrinol Metab 281:E315–E325

    PubMed  Google Scholar 

  126. Tocchini-Valentini G, Rochel N, Wurtz JM, Mitschler A, Moras D (2001) Crystal structures of the vitamin D receptor complexed to superagonist 20-epi ligands. Proc Natl Acad Sci U S A 98:5491–5496

    Article  PubMed  CAS  Google Scholar 

  127. Tsai HC, Norman AW (1972) Studies on calciferol metabolism. VIII. Evidence for a cytoplasmic receptor for 1,25-dihydroxyvitamin D3in the intestinal mucosa. J Biol Chem 248:5967–5975

    Google Scholar 

  128. Tsoukas CD, Provvedini DM, Manolagas SC (1984) 1,25-Dihydroxyvitamin D3: a novel immunoregulatory hormone. Science 224:1438–1440

    Article  PubMed  Google Scholar 

  129. Tsurukami H, Nakamura T, Suzuki K, Sato K, Higuchi Y, Nishii Y (1994) A novel synthetic vitamin D analogue, 2ß-(3-hydroxypropoxy)la, 25-dihydroxyvitamin D3(ED-71), increases bone mass by stimulating the bone formation in normal and ovariectomized rats. Calcif Tissue Int. 54:142–149

    Article  PubMed  CAS  Google Scholar 

  130. Van den Bemd GJ, Pols HA, Van Leeuwen JP (2000) Anti-tumor effects of 1,25-dihydroxyvitamin D3and vitamin D analogs. Curr Pharm Des 6:717–732

    Article  PubMed  Google Scholar 

  131. Van Etten E, Branisteanu DD, Verstuyf A, Waer M, Bouillon R, Mathieu C (2000) Analogs of 1,25-dihydroxyvitamin D48 3 as dose-reducing agents for classical immunosuppressants. Transplantation 69:1932–1942

    Article  Google Scholar 

  132. Vandewalle B, Adenis A, Hornez L, Revillion F, Lefebvre J (1994) 1,25-Dihydroxyvitamin D3receptors in normal and malignant human colorectal tissues. Cancer Lett 86:67–73

    Article  PubMed  Google Scholar 

  133. Verboven C, Rabijns A, De Maeyer M, Van Baelen H, Bouillon R, De Ranter C (2002) A structural basis for the unique binding features of the human vitamin D-binding protein. Nat Struct Biol 9:131–136

    Article  PubMed  CAS  Google Scholar 

  134. Verlinden L, Verstuyf A, Quack M, Van Camp M, van Etten E, De Clercq P, Vandewalle M, Carlberg C, Bouillon R (2001) Interaction of two novel 14-epivitamin D3analogs with vitamin D3receptor-retinoid X receptor heterodimers on vitamin D3responsive elements. J Bone Miner Res 16:625–638

    Article  PubMed  CAS  Google Scholar 

  135. Verlinden L, Verstuyf A, Van Camp M, Marcelis S, Sabbe K, Zhao XY, De Clercq P, Vandewalle M, Bouillon R (2000) Two novel 14-epi-analogues of 1,25-dihydroxyvitamin D3inhibit the growth of human breast cancer cells in vitro and in vivo. Cancer Res 60:2673–2679

    PubMed  CAS  Google Scholar 

  136. Verstuyf A, Verlinden L, van Etten E, Shi L, Wu Y, D’Halleweyn C, Van Haver D, Zhu G-D, Chen Y-J, Zhou X, Haussler MR, De Clercq P, Vandewalle M, Van Baelen H, Mathieu C, Bouillon R (2000) Biological activity of CD-ring modified ía,25-dihydroxyvitamin D analogues: C-ring and five membered D-ring analogues. J Bone Miner Res 15:237–252

    Article  PubMed  CAS  Google Scholar 

  137. Wakino S, Meguro M, Suzuki H, Saruta T, Ogishima T, Ishimura Y, Shinki T, Suda T (1996) Evidence for 54-kD protein in chicken kidney as a cytochrome P450 with a high molecular activity of 25-hydroxyvitamin D3la-hydroxylase. Gerontology 42:67–77

    Article  PubMed  CAS  Google Scholar 

  138. Walters MR (1982) 1,25-Dihydroxyvitamin D receptors in rat testes, epididymis, and uterus. Fed Proc 41 no. 4:1165

    Google Scholar 

  139. Walters MR, Fischette CT, Fetzer C, May B, Riggle PC, Tibaldo-Bongiorno M, Christakos S (1992) Specific 1,25-dihydroxyvitamin D3binding sites in choroid plexus. Eur J Pharmacol 213:309–311

    Article  PubMed  CAS  Google Scholar 

  140. Walters MR, Rosen DM, Norman AW, Luben RA (1982) 1,25-Dihydroxyvitamin D receptors in an established bone cell line: correlation with biochemical responses. J Biol Chem 257:7481–7484

    PubMed  Google Scholar 

  141. Wecksler WR, Henry HL, Norman AW (1977) Studies on the mode of action of calciferol XIII: subcellular localization of 1,25-dihydroxy vitamin D3in chicken parathyroid glands. Arch Biochem Biophys 183:168–175

    Article  PubMed  CAS  Google Scholar 

  142. Wecksler WR, Ross FP, Mason RS, Posen S, Norman AW (1980) Studies on the mode of action of calciferol. XXIV. Biochemical properties of the ía,25-dihydroxyvitamin D3cytoplasmic receptors from human and chick parathyroid glands. Arch Biochem Biophys 201:95–103

    Article  PubMed  CAS  Google Scholar 

  143. Weishaar RE, Simpson RU (1987) Vitamin D3and cardiovascular function in rats. J Clin Invest 79:1–7

    Article  Google Scholar 

  144. Wing RM, Okamura WH, Pirio MR, Sine SM, Norman AW (1974) Vitamin D38: conformations of vitamin D3la,25-dihydroxyvitamin D3and dihydrotachysterol3. Science 186:939–941

    Article  PubMed  CAS  Google Scholar 

  145. Yang G, Brune JL, Naylor SL, Cupples RL, Naberhause KH, Bowman BH: (1982) Human group-specific component (Gc) is a member of the albumin family. Proc Natl Acad Sci USA 82:7994–7998

    Article  Google Scholar 

  146. Zanello LP, Norman AW (1997) Stimulation by la,24(OH)2-vitamin D3of whole cell chloride currents in osteoblastic ROS 17/2.8 cells: a structure-function study. J Biol Chem 272:22617–22622

    Article  PubMed  CAS  Google Scholar 

  147. Zhou JY, Norman AW, Akashi M, Chen D-L, Uskokovic MR, Aurrecoechea JM, Dauben WG, Okamura WH, Koeffler HP (1991) Development of a novel 1,24(OH)2-vitamin D3analog with potent ability to induce HL-60 cell differentiation without modulating calcium metabolism. Blood 78:75–82

    PubMed  CAS  Google Scholar 

  148. Zhou JY, Norman AW, Chen D, Sun G, Uskokovic MR, Koeffler HP (1990) ía,25-Dihydroxy-16-ene-23-yne-vitamin D3prolongs survival time of leukemic mice. Proc Natl Acad Sci USA 87:3929–3932

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Biomedical Sciences, University of California, Riverside, CA, 92521, USA

    Anthony W. Norman, M. T. Mizwicki & W. H. Okamura

Authors
  1. Anthony W. Norman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. T. Mizwicki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W. H. Okamura
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Hautklinik und Poliklinik der Universitätskliniken des Saarlandes, Kirrberger Str., 66421, Homburg/Saar

    Jörg Reichrath  & Wolfgang Tilgen  & 

  2. Frauenklinik des Universitätsklinikums der Eberhard-Karls-Universität, Calwerstr. 7, 71076, Tübingen

    Michael Friedrich

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Norman, A.W., Mizwicki, M.T., Okamura, W.H. (2003). Ligand Structure—Function Relationships in the Vitamin D Endocrine System from the Perspective of Drug Development (Including Cancer Treatment). In: Reichrath, J., Tilgen, W., Friedrich, M. (eds) Vitamin D Analogs in Cancer Prevention and Therapy. Recent Results in Cancer Research, vol 164. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-55580-0_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-55580-0_4

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-62435-3

  • Online ISBN: 978-3-642-55580-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation