|
|
 Previous Article | Table of Contents | Next Article 
Novel vitamin D analogs that modulate leukemic cell growth and
differentiation with little effect on either intestinal calcium absorption
or bone mobilization
JY Zhou, AW Norman, M Lubbert, ED Collins, MR Uskokovic and HP Koeffler
Department of Medicine, UCLA 90024.
Induction of terminal differentiation of leukemic and preleukemic cells is
a therapeutic approach to leukemia and preleukemia. The 1 alpha, 25-
dihydroxyvitamin D3 [1,25(OH)2D3], the hormonally active form of vitamin
D3, can induce differentiation and inhibit proliferation of leukemia cells,
but concentrations required to achieve these effects cause life-threatening
hypercalcemia. Seven new analogs of 1,25(OH)2D3 were discovered to be
either equivalent or more potent than 1,25(OH)2D3 as assessed by: (a)
inhibition of clonal proliferation of HL-60, EM-2, U937, and patients'
myeloid leukemic cells: and (b) induction of differentiation of HL-60
promyelocytes. Furthermore, these analogs stimulated clonal growth of
normal human myeloid stem cells. The most potent analog,
1,25-dihydroxy-16ene-23yne-vitamin D3, was about fourfold more potent than
1,25(OH)2D3. This analog decreased clonal growth and expression of c-myc
oncogene in HL-60 cells by 50% within ten hours of exposure. Effects on
calcium metabolism of these novel analogs in vivo was assessed by
intestinal calcium absorption (ICA) and bone calcium mobilization (BCM).
Each of the analogs mediated markedly less (10 to 200-fold) ICA and BCM as
compared with 1,25(OH)2D3. To gain insight into the possible mechanism of
action of these new analogs, receptor binding studies were done with
1,25(OH)2-16ene-23yne-D3 and showed that it competed only about 60% as
effectively as 1,25(OH)2D3 for 1,25(OH)2D3 receptors present in HL-60 cells
and 98% as effective as 1,25(OH)2D3 for receptors present in chick
intestinal cells. In summary, we have discovered seven novel vitamin D
analogs that are more potent than the physiologic 1,25(OH)2D3 as measured
by a variety of hematopoietic assays. In contrast, these compounds appear
to have the potential to be markedly less toxic (induction of
hypercalcemia). These novel vitamin D compounds may be superior to
1,25(OH)2D3 in a number of clinical situations including
leukemia/preleukemia; they will provide a tool to dissect the mechanism of
action of vitamin D seco-steroids in promoting cellular differentiation.
Volume 74,
Issue 1,
pp. 82-93,
07/01/1989
Copyright © 1989 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
L. A. Zella, N. K. Shevde, B. W. Hollis, N. E. Cooke, and J. W. Pike
Vitamin D-Binding Protein Influences Total Circulating Levels of 1,25-Dihydroxyvitamin D3 but Does Not Directly Modulate the Bioactive Levels of the Hormone in Vivo
Endocrinology,
July 1, 2008;
149(7):
3656 - 3667.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Albert, A. Kumar, S. A. Strugnell, S. R. Darjatmoko, J. M. Lokken, M. J. Lindstrom, and S. Patel
Effectiveness of Vitamin D Analogues in Treating Large Tumors and During Prolonged Use in Murine Retinoblastoma Models
Arch Ophthalmol,
September 1, 2004;
122(9):
1357 - 1362.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. E. Place, N. Suh, C. R. Williams, R. Risingsong, T. Honda, Y. Honda, G. W. Gribble, L. M. Leesnitzer, J. B. Stimmel, T. M. Willson, et al.
The Novel Synthetic Triterpenoid, CDDO-Imidazolide, Inhibits Inflammatory Response and Tumor Growth in Vivo
Clin. Cancer Res.,
July 1, 2003;
9(7):
2798 - 2806.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Bula, J. E. Bishop, S. Ishizuka, and A. W. Norman
25-Dehydro-1{alpha}-Hydroxyvitamin D3- 26,23S-Lactone Antagonizes the Nuclear Vitamin D Receptor by Mediating a Unique Noncovalent Conformational Change
Mol. Endocrinol.,
November 1, 2000;
14(11):
1788 - 1796.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
B. A. Scaglione-Sewell, M. Bissonnette, S. Skarosi, C. Abraham, and T. A. Brasitus
A Vitamin D3 Analog Induces a G1-Phase Arrest in CaCo-2 Cells by Inhibiting Cdk2 and Cdk6: Roles of Cyclin E, p21Waf1, and p27Kip1
Endocrinology,
November 1, 2000;
141(11):
3931 - 3939.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Marks, V. M. Richon, and R. A. Rifkind
Histone Deacetylase Inhibitors: Inducers of Differentiation or Apoptosis of Transformed Cells
J Natl Cancer Inst,
August 2, 2000;
92(15):
1210 - 1216.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Hofer, G.-m. Ho, M. Peterlik, M. R. Uskokovic, J. K. Lee, M. C. White, G. H. Posner, and H. S. Cross
Biological Effects of 1alpha -Hydroxy- and 1beta -(Hydroxymethyl)-Vitamin D Compounds Relevant for Potential Colorectal Cancer Therapy
J. Pharmacol. Exp. Ther.,
November 1, 1999;
291(2):
450 - 455.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
D. Miura, K. Manabe, K. Ozono, M. Saito, Q. Gao, A. W. Norman, and S. Ishizuka
Antagonistic Action of Novel 1alpha ,25-Dihydroxyvitamin D3-26,23-lactone Analogs on Differentiation of Human Leukemia Cells (HL-60) Induced by 1alpha ,25-Dihydroxyvitamin D3
J. Biol. Chem.,
June 4, 1999;
274(23):
16392 - 16399.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. H. Wang, R. J. Koenig, T. J. Giordano, A. Myc, N. W. Thompson, and J. R. Baker Jr.
1{alpha},25-Dihydroxyvitamin D3 Up-Regulates Bcl-2 Expression and Protects Normal Human Thyrocytes from Programmed Cell Death
Endocrinology,
April 1, 1999;
140(4):
1649 - 1656.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. J. Sabet, S. R. Darjatmoko, M. J. Lindstrom, and D. M. Albert
Antineoplastic Effect and Toxicity of 1,25-Dihydroxy-16-ene-23-yne-vitamin D3 in Athymic Mice With Y-79 Human Retinoblastoma Tumors
Arch Ophthalmol,
March 1, 1999;
117(3):
365 - 370.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Asou, M. Koike, E. Elstner, M. Cambell, J. Le, M. R. Uskokovic, N. Kamada, and H. P. Koeffler
19-nor Vitamin-D Analogs: A New Class of Potent Inhibitors of Proliferation and Inducers of Differentiation of Human Myeloid Leukemia Cell Lines
Blood,
October 1, 1998;
92(7):
2441 - 2449.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. S. Shternfeld, J. G. H. Lasudry, R. J. Chappell, S. R. Darjatmoko, and D. M. Albert
Antineoplastic Effect of 1,25-Dihydroxy-16-ene-23-yne-Vitamin D3 Analogue in Transgenic Mice With Retinoblastoma
Arch Ophthalmol,
November 1, 1996;
114(11):
1396 - 1401.
[Abstract]
[PDF]
|
|
|
|
|
|
|
S. Peleg, M. Sastry, E. D. Collins, J. E. Bishop, and A. W. Norman
Distinct Conformational Changes Induced by 20-epi Analogues of 1[IMAGE],25-Dihydroxyvitamin D[IMAGE] Are Associated with Enhanced Activation of the Vitamin D Receptor
J. Biol. Chem.,
May 5, 1995;
270(18):
10551 - 10558.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Gardezi, C. Nguyen, P. J. Malloy, G. H. Posner, D. Feldman, and S. Peleg
A Rationale for Treatment of Hereditary Vitamin D-resistant Rickets with Analogs of 1alpha ,25-Dihydroxyvitamin D3
J. Biol. Chem.,
July 27, 2001;
276(31):
29148 - 29156.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
