8 juli 2012: dat chemo bij prostaatkanker effectief zou zijn staat wel ter discussie. Dat aanvullende calcitriol, een vorm van vitamine D wel een rol kan spelen wordt steeds aannemelijker. Als aanvulling op onderstaande informatie staat onderaan een abstract plus deeplink naar gratis in te zien volledig studierapport over vitamine D bij prostaatkanker.

12 juli 2004: FDA geeft toestemming Taxotere te gebruiken als medicijn bij uitbehandelde prostaatkankerpatiënten. Lees meer daarover verderop.

1/10/2002: onder dit bericht een studie calcitriol uit Pubmed toegevoegd:

30/9/2002: Onderzoekers aan de Oregon Health and Science University hebben een grootschalige gerandomiseerde dubbelblinde studie opgezet naar het effect van vitamine D -calcitriol -als aanvulling op de chemo docetaxel (taxotere) nadat uit een eerdere studie is gebleken dat deze aanvulling met calcitriol bij 81% van de deelnemende prostaatkankerpatiënten de PSA waarde voor meer dan 50% verminderde tegenover een PSA vermindering van 38 tot 46% met 50% of meer bij prostaatkankerpatiënten in vier studies met alleen docetaxel. Een verdubbeling van het resultaat dus. Interessant is natuurlijk dat als een prostaatkankerpatiënt overstapt op het Houtsmullerdieet met als aanvulling bepaalde voedingssuppletie, waaronder vitamine E en D enz. de PSA waarde vaak ook drastisch naar beneden gaat. Althans dat hebben we nu al van verschillende patiënten gehoord. Bovendien lijkt Prostasol, opvolger van PC-Spes, de goede werking van PC-Spes te bevestigen. Belangrijk is natuurlijk wel dat onderstaande studie uitgaat van vergevorderde prostaatkanker dus waarschijnlijk met uitzaaiingen in de botten.

19/09/02 - Researchers at the Oregon Health & Science University in the US on Thursday announced the launch of a national study to investigate the effect of high-dose vitamin D in combination with the chemotherapy agent docetaxel (Taxotere), for patients with advanced prostate cancer.

The ASCENT (AIPC Study of Calcitriol Enhancing Taxotere) study is a multicentre, randomised, double-blind trial based on the results of a preliminary study in Oregon. ASCENT will determine whether a high dose of an active form of vitamin D, called calcitriol, taken once a week in combination with docetaxel, is any more effective than docetaxel alone for patients with androgen-independent prostate cancer (AIPC), an advanced form of prostate cancer.
"Late-stage prostate cancer patients have few treatment options, and we are cautiously hopeful that this study will further confirm and extend the promising results we've already seen with docetaxel in combination with high-dose pulse administration (HDPA) calcitriol," said OHSU Cancer Institute oncologist Tomasz Beer, study chairman and assistant professor of medicine (hematology and medical oncology) in the OHSU School of Medicine.

The study will enroll approximately 232 patients at about 20 medical centres in the United States, including OHSU. Additional sites will be added during the next several months.

The study hopes to achieve a reduction of 50 per cent or more in prostate specific antigen (PSA) levels in patients. PSA is a substance produced within the prostate gland, and a high PSA level may indicate the presence of cancer. In patients with advanced prostate cancer, many clinicians use elevated PSA levels as an indicator of disease progression.

Results from the initial OHSU study were presented by Beer at the American Society of Clinical Oncology conference last May. In that trial, 81 per cent (30 of 37) of patients treated with HDPA calcitriol in combination with docetaxel had a reduction in PSA levels of more than 50 per cent. Four other studies of docetaxel without calcitriol have reported that 38 per cent to 46 per cent of the patients had more than a 50 per cent reduction in PSA levels, about half the rate as those patients on the combination therapy.

Prostate cancer is the most common cancer in men, with approximately 189,000 new cases diagnosed and roughly 30,200 deaths in the United States each year (2002 Cancer Facts and Figures, American Cancer Society).

Further information on the study can be obtained from Martin Munguia at the Oregon Health & Science University: munguiam@ohsu.edu

1/10/2002: Een bezoeker van de site en zelf een prostaatkankerpatiënt die al jaren naar zijn zeggen calcitriol gebruikt stuurde me deze studie op over hoge doses calcitriol. Waarvoor dank.

Urology 2002 Sep;60(3 Suppl 1):123-30; discussion 130-1

Vitamin D receptor: a potential target for intervention.

Johnson CS, Hershberger PA, Bernardi RJ, Mcguire TF, Trump DL Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. johnsoncs@msx.upmc.edu

Epidemiologic data suggest that low exposure to vitamin D or 1alpha,25-dihydroxycholecalciferol (calcitriol) increases the risk of prostate cancer. Calcitriol, a central factor in bone and mineral metabolism, is also a potent antiproliferative agent in a wide variety of malignant cell types. We have demonstrated that calcitriol has significant antitumor activity in vitro and in vivo in prostate and squamous cell carcinoma model systems. Calcitriol, in these models, induces a significant G0/G1 arrest and modulates p21(Waf1/Cip1) and p27(Kip1), the cyclin-dependent kinase inhibitors. Calcitriol induces poly (adenosine diphosphate-ribose) polymerase cleavage, increases bax/bcl-2 ratio, reduces levels of phosphorylated mitogen-activated protein kinases (P-MAPKs; also known as extracellular signal-related kinase 1/2) and phosphorylated Akt, induces caspase-dependent mitogen-activated protein kinase kinase (MEK) cleavage and upregulation of MEK kinase-1, all potential markers of the apoptotic pathway. We also have demonstrated that dexamethasone (dex) potentiates the antitumor effect of calcitriol through effects on the vitamin D receptor and decreases calcitriol-induced hypercalcemia. We initiated phase 1 and phase 2 trials of calcitriol, either alone or in combination with carboplatin, paclitaxel, or dex. Data from these studies indicate that high-dose calcitriol is feasible on an intermittent schedule, the maximum tolerated dose (MTD) is unclear, and dex or paclitaxel appear to ameliorate hypercalcemia. Studies continue to define the MTD of calcitriol on this intermittent schedule, either alone or with other agents, and to evaluate the mechanisms of calcitriol effects in prostate cancer models.

Novel vitamin D analogs for prostate cancer therapy

Source: ISRN Urol. 2011;2011:301490. Epub 2011 Sep 19. Reed full study report>>>>>>

Published online 2011 September 19. doi: 10.5402/2011/301490

PMCID: PMC3195751

Novel Vitamin D Analogs for Prostate Cancer Therapy

Tai C. Chen^{1 ,}^* and Atsushi Kittaka²

Author information ► Article notes ► Copyright and License information ►

This article has been cited by other articles in PMC.

Go to:

Abstract

Prostate cells contain specific receptors for 1α,25-dihydroxyvitamin D [1α,25(OH)₂D] or calcitriol, the active form of vitamin D. 1α,25(OH)₂D is known to inhibit the proliferation and invasiveness of prostate cancer cells. These findings support the use of 1α,25(OH)₂D for prostate cancer therapy. However, 1α,25(OH)₂D can cause hypercalcemia, analogs of 1α,25(OH)₂D that are less calcemic but exhibit potent antiproliferative activity would be attractive as therapeutic agents. To accomplish these goals, different strategies, based on metabolism, molecular mechanism of actions, and structural modeling, have been taken to modify the structure of vitamin D molecule with the aims to improve the efficacy and decrease the toxicity of vitamin D to treat different diseases. During the past four decades, over 3,000 analogs have been synthesized. In this paper, we discuss the development and the biological analysis of a unique class of vitamin D analogs with a substitution at the carbon 2 of 19-nor-1α,25(OH)₂D₃ molecule for potential application to the prevention and treatment of prostate cancer as well as other cancers.

References

1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer Journal for Clinicians. 2009;59(4):225–249.

2. Kirby RS. Recent advances in the medical management of prostate cancer. British Journal of Clinical Practice. 1996;50(2):88–93. [PubMed]

3. Beltran H, Beer TM, Carducci MA, et al. New therapies for castration-resistant prostate cancer: efficacy and safety. European Urology. 2011;60(2):279–290. [PubMed]

4. Miller GJ. Vitamin D and prostate cancer: biologic interactions and clinical potentials. Cancer and Metastasis Reviews. 1999;17(4):353–360. [PubMed]

5. Osborn JL, Schwartz GG, Smith DC, Bahnson R, Day R, Trump DL. Phase II trial of oral 1,25-dihydroxyvitamin D (calcitriol) in hormone refractory prostate cancer. Urologic Oncology. 1995;1(5):195–198. [PubMed]

6. Gross C, Stamey T, Hancock S, Feldman D. Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D₃ (calcitriol) Journal of Urology. 1998;159(6):2035–2040. [PubMed]

7. McCollum EV, Simmonds N, Becker JE, Shipley PG, Bunting RW. Studies on experimental rickets. XXI. An experimental demonstration of the existence of a vitamin which promotes calcium deposition. Journal of Biological Chemistry. 1922;53:293–312.

8. DeLuca HF, Schnoes HK. Metabolism and mechanism of action of vitamin D. Annual Review of Biochemistry. 1976;45:631–666.

9. Airey FS. Vitamin D as a remedy for lupus vulgaris. Medical World. 1946;64:807–810. [PubMed]

10. Charpy J, Dowling GB, et al. Vitamin D in cutaneous tuberculosis. Lancet. 1947;2(6472):p. 398.

11. Holcik LJ. Treatment of psoriasis with large doses of vitamin D2. Ceskoslovenska Dermatologie. 1949;24(4):145–149. [PubMed]

12. Stumpf WE, Sar M, Reid FA, et al. Target cells for 1,25-dihydroxyvitamin D₃ in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid. Science. 1979;206(4423):1188–1190. [PubMed]

13. Colston K, Hirst M, Feldman D. Organ distribution of the cytoplasmic 1,25-dihydroxycholecalciferol receptor in various mouse tissues. Endocrinology. 1980;107(6):1916–1922. [PubMed]

14. Abe E, Miyaura C, Sakagami H. Differentiation of mouse myeloid leukemia cells induced by 1α,25-dihydroxyvitamin D₃. Proceedings of the National Academy of Sciences of the United States of America. 1981;78(8):4990–4994. [PMC free article] [PubMed]

15. Chen TC, Holick MF. Vitamin D and prostate cancer prevention and treatment. Trends in Endocrinology and Metabolism. 2003;14(9):423–430. [PubMed]

16. Brown AJ, Slatopolsky E. Vitamin D analogs: therapeutic applications and mechanisms for selectivity. Molecular Aspects of Medicine. 2008;29(6):433–452. [PubMed]

17. Colston KW, Mackay AG, James SY, Binderup L, Chander S, Coombes RC. EB1089: a new vitamin D analogue that inhibits the growth of breast cancer cells in vivo and in vitro. Biochemical Pharmacology. 1992;44(12):2273–2280. [PubMed]

18. Valrance ME, Brunet AH, Welsh J. Vitamin D receptor-dependent inhibition of mammary tumor growth by EB1089 and ultraviolet radiation in vivo. Endocrinology. 2007;148(10):4887–4894. [PubMed]

19. Bhatia V, Saini MK, Shen X, et al. EB1089 inhibits the parathyroid hormone-related protein-enhanced bone metastasis and xenograft growth of human prostate cancer cells. Molecular Cancer Therapeutics. 2009;8(7):1787–1798. [PMC free article] [PubMed]

20. Liu G, Oettel K, Ripple G, et al. Phase I trial of 1α-hydroxyvitamin D2 in patients with hormone refractory prostate cancer. Clinical Cancer Research. 2002;8(9):2820–2827. [PubMed]

21. Liu G, Wilding G, Staab MJ, et al. Phase II study of 1α-hydroxyvitamin D₂ in the treatment of advanced androgen-independent prostate cancer. Clinical Cancer Research. 2003;9(11):4077–4083. [PubMed]

22. Abe J, Morikawa M, Miyamoto K, et al. Synthetic analogues of vitamin D₃ with an oxygen atom in the side chain skeleton. A trial of the development of vitamin D compounds which exhibit potent differentiation-inducing activity without inducing hypercalcemia. FEBS Letters. 1987;226(1):58–62. [PubMed]

23. Zhou JY, Norman AW, Lübbert 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(1):82–93. [PubMed]

24. Asou H, Koike M, Elstner E, et al. 19-nor vitamin-D analogs: a new class of potent inhibitors of proliferation and inducers of differentiation of human myeloid leukemia cell lines. Blood. 1998;92(7):2441–2449. [PubMed]

25. Mehta RG, Moriarty RM, Mehta RR, Penmasta R, Lazzaro G, Constantinou A. Prevention of preneoplastic mammary lesion development by a novel vitamin D analogue, 1α-hydroxyvitamin D5. Journal of the National Cancer Institute. 1997;89(3):212–218. [PubMed]

26. Boehm MF, Fitzgerald P, Zou A, et al. Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D₃. Chemistry and Biology. 1999;6(5):265–275. [PubMed]

27. Uskokovic MR, Manchand P, Marczak S, et al. C-20 cyclopropyl vitamin D₃ analogs. Current Topics in Medicinal Chemistry. 2006;6(12):1289–1296. [PubMed]

28. Adorini L, Penna G, Amuchastegui S, et al. Inhibition of prostate growth and inflammation by the vitamin D₃ receptor agonist BXL-628 (elocalcitol) Journal of Steroid Biochemistry and Molecular Biology. 2007;103(3-5):689–693. [PubMed]

29. Saito T, Okamoto R, Haritunians T, et al. Novel Gemini vitamin D3 analogs have potent antitumor activity. Journal of Steroid Biochemistry and Molecular Biology. 2008;112(1–3):151–156. [PMC free article] [PubMed]

30. Napoli JL, Sommerfeld JL, Pramanik BC, et al. 19-Nor-10-ketovitamin D derivatives: unique metabolites of vitamin D₃, vitamin D₂, and 25-hydroxyvitamin D₃. Biochemistry. 1983;22(15):3636–3640. [PubMed]

31. Perlman KL, Sicinski RR, Schnoes HK, DeLuca HF. 1α,25-Dihydroxy-19-nor-vitamin D₃, a novel vitamin D-related compound with potential therapeutic activity. Tetrahedron Letters. 1990;31(13):1823–1824.

32. Slatopolsky E, Finch J, Ritter C, et al. A new analog of calcitriol, 19-Nor-1,25-(OH)₂D₂, suppresses parathyroid hormone secretion in uremic rats in the absence of hypercalcemia. American Journal of Kidney Diseases. 1995;26(5):852–860. [PubMed]

33. Llach F, Keshav G, Goldblat MV, et al. Suppression of parathyroid hormone secretion in hemodialysis patients by a novel vitamin D analogue: 19-nor-1,25-dihydroxyvitamin D₂. American Journal of Kidney Diseases. 1998;32(2, supplement 2):S48–S54. [PubMed]

34. Sicinski RR, Rotkiewicz P, Kolinski A, et al. 2-Ethyl and 2-ethylidene analogues of 1α,25-dihydroxy-19-norvitamin D₃: synthesis, conformational analysis, biological activities, and docking to the modeled rVDR ligand binding domain. Journal of Medicinal Chemistry. 2002;45(16):3366–3380. [PubMed]

35. Ono K, Yoshida A, Saito N, et al. Efficient synthesis of 2-modified 1α,25-dihydroxy-19-norvitamin D₃ with Julia olefination: high potency in induction of differentiation on HL-60 cells. Journal of Organic Chemistry. 2003;68(19):7407–7415. [PubMed]

36. Kittaka A, Saito N, Honzawa S, et al. Creative synthesis of novel vitamin D analogs for health and disease. Journal of Steroid Biochemistry and Molecular Biology. 2007;103(3-5):269–276. [PubMed]

37. Toyoda A, Nagai H, Yamada T, et al. Novel synthesis of 1α,25-dihydroxy-19-norvitamin D from 25-hydroxyvitamin D. Tetrahedron. 2009;65(48):10002–10008.

38. Hanazawa T, Wada T, Masuda T, Okamoto S, Sato F. Novel synthetic approach to 19-nor-1α,25-dihydroxyvitamin D₃ and its derivatives by Suzuki-Miyaura coupling in solution and on solid support. Organic Letters. 2001;3(24):3975–3977. [PubMed]

39. Huang P, Sabbe K, Pottie M, Vandewalle M. A novel synthesis of 19-nor 1α,25-dihydroxyvitamin D₃ and related analogues. Tetrahedron Letters. 1995;36(45):8299–8302.

40. Shimizu M, Miyamoto Y, Takaku H, et al. 2-Substituted-16-ene-22-thia-1α,25-dihydroxy-26,27-dimethyl-19-norvitamin D₃ analogs: synthesis, biological evaluation, and crystal structure. Bioorganic and Medicinal Chemistry. 2008;16(14):6949–6964. [PubMed]

41. Glebocka A, Sicinski RR, Plum LA, Clagett-Dame M, DeLuca HF. New 2-alkylidene 1α,25-dihydroxy-19-norvitamin D₃ analogues of high intestinal activity: synthesis and biological evaluation of 2-(3′-alkoxypropylidene) and 2-(3′-hydroxypropylidene) derivatives. Journal of Medicinal Chemistry. 2006;49(10):2909–2920. [PubMed]

42. Perlman KL, Swenson RE, Paaren HE, Schnoes HK, DeLuca HF. Novel synthesis of 19-nor-vitamin D compounds. Tetrahedron Letters. 1991;32(52):7663–7666.

43. Saito N, Honzawa S, Kittaka A. Recent results on A-ring modification of 1α,25-dihydroxyvitamin D₃: design and synthesis of VDR-agonists and antagonists with high biological activity. Current Topics in Medicinal Chemistry. 2006;6(12):1273–1288. [PubMed]

44. Saito N, Suhara Y, Kurihara M, et al. Design and efficient synthesis of 2α-(ω-hydroxyalkoxy)- 1α,25-dihydroxyvitamin D3 analogues, including 2-epi-ED-71 and their 20-epimers with HL-60 cell differentiation activity. Journal of Organic Chemistry. 2004;69(22):7463–7471. [PubMed]

45. Takahashi E, Nakagawa K, Suhara Y, et al. Biological activities of 2α-substituted analogues of 1α,25-dihydroxyvitamin D₃ in transcriptional regulation and human promyelocytic leukemia (HL-60) cell proliferation and differentiation. Biological and Pharmaceutical Bulletin. 2006;29(11):2246–2250. [PubMed]

46. Saito N, Matsunaga T, Saito H, et al. Further synthetic and biological studies on vitamin D hormone antagonists based on C24-alkylation and C2α-functionalization of 25-dehydro-1α- hydroxyvitamin D₃-26,23-lactones. Journal of Medicinal Chemistry. 2006;49(24):7063–7075. [PubMed]

47. Hourai S, Fujishima T, Kittaka A, et al. Probing a water channel near the A-ring of receptor-bound 1α,25-dihydroxyvitamin D₃ with selected 2α-substituted analogues. Journal of Medicinal Chemistry. 2006;49(17):5199–5205. [PubMed]

48. Yoshida A, Ono K, Suhara Y, Saito N, Takayama H, Kittaka A. Efficient and convergent coupling route for the short-step synthesis of enantiopure 2α- and 2β-alkylated 1α,25-dihydroxy-19-norvitamin D₃ analogues. Synlett. 2003;(8):1175–1179.

49. Arai MA, Kittaka A. Novel 2-alkyl-1α,25-dihydroxy-19-norvitamin D₃: efficient synthesis with Julia olefination, evaluation of biological activity and development of new analyzing system for co-activator recruitment. Anticancer Research. 2006;26(4):2621–2631. [PubMed]

50. Arai MA, Takeyama KI, Ito S, Kato S, Chen TC, Kittaka A. High-throughput system for analyzing ligand-induced cofactor recruitment by vitamin D receptor. Bioconjugate Chemistry. 2007;18(3):614–620. [PubMed]

51. Chen TC, Schwartz GG, Burnstein KL, Lokeshwar BL, Holick MF. The in vitro evaluation of 25-hydroxyvitamin D₃ and 19-nor-1α,25- dihydroxyvitamin D₂ as therapeutic agents for prostate cancer. Clinical Cancer Research. 2000;6(3):901–908. [PubMed]

52. Chen TC, Holick MF, Lokeshwar BL, Burnstein KL, Schwartz GG. Evaluation of vitamin D analogs as therapeutic agents for prostate cancer. Recent results in cancer research. In: Reichrath J, Friedrich M, Tilgen W, editors. Vitamin D Analogs in Cancer Prevention and Therapy. Vol. 164. Berlin, Germany: Springer; 2003. pp. 273–288.

53. Chen TC, Persons KS, Zheng S, et al. Evaluation of C-2-substituted 19-nor-1α,25-dihydroxyvitamin D3 analogs as therapeutic agents for prostate cancer. Journal of Steroid Biochemistry and Molecular Biology. 2007;103(3-5):717–720. [PubMed]

54. Flanagan JN, Zheng S, Chiang KC, et al. Evaluation of 19-nor-2α(3-hydroxypropyl)-1α,25-dihydroxyvitamin D₃ as a therapeutic agent for androgen-dependent prostate cancer. Anticancer Research. 2009;29(9):3547–3553. [PubMed]

55. Ohyama Y, Ozono K, Uchida M, et al. Identification of a vitamin D-responsive element in the 5′-flanking region of the rat 25-hydroxyvitamin D₃ 24-hydroxylase gene. Journal of Biological Chemistry. 1994;269(14):10545–10550. [PubMed]

56. Flanagan JN, Young MV, Persons KS, et al. Vitamin D metabolism in human prostate cells: implications for prostate cancer chemoprevention by vitamin D. Anticancer Research. 2006;26(4):2567–2572. [PubMed]

57. Schuster I. Cytochromes P450 are essential players in the vitamin D signaling system. Biochimica et Biophysica Acta. 2011;1814(1):186–199. [PubMed]

58. Abe D, Sakaki T, Kusudo T, et al. Metabolism of 2α-propoxy-1α,25-dihydroxyvitamin D3 and 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D₃ by human CYP27A1 and CYP24A1. Drug Metabolism and Disposition. 2005;33(6):778–784. [PubMed]

59. Bernhard EJ, Gruber SB, Muschel RJ. Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells. Proceedings of the National Academy of Sciences of the United States of America. 1994;91(10):4293–4297. [PMC free article] [PubMed]

60. Bao BY, Yeh SD, Lee YF. 1α,25-dihydroxyvitamin D₃ inhibits prostate cancer cell invasion via modulation of selective proteases. Carcinogenesis. 2006;27(1):32–42. [PubMed]

61. Polly P, Herdick M, Moehren U, Baniahmad A, Heinzel T, Carlberg C. VDR-Alien: a novel, DNA-selective vitamin D3 receptorcorepressor partnership. FASEB Journal. 2000;14(10):1455–1463. [PubMed]

ca, vitamine D, prostaatkanker