Effects of analogs of 1,25(OH)2 vitamin D3 on the proliferation and differentiation of the human chronic myelogenous leukemia cell line, RWLeu-4.
We evaluated the proliferative and differentiative effects of analogs of 1,25(OH)2 vitamin D3 [1,25(OH)2D3] on a chronic myelogenous leukemia cell line, RWLeu-4, which is growth-inhibited and differentiates in response to 1,25(OH)2D3 (ED50 = 3-10 nM). Side-chain-fluorinated analogs were more potent (ED50 = 0.7-2 nM) while most of those with altered saturation of the D ring or side-chain carbon-carbon bonds were equally or less effective than 1,25(OH)2D3. However, the two analogs with either two additional double bonds or an extra double and triple bond in the D ring had greater antiproliferative activity [1,25(OH)2-16,23-diene D3 (ED50 = 2.7 nM) and 1,25(OH)2-16-ene-23-yne D3 (ED50 = 0.7 nM)]. Since the latter of these has been reported to be less potent at mobilizing calcium than 1,25(OH)2D3, it (or a similar compound) may be a candidate for clinical use as an antineoplastic agent.
Division of Hematology/Oncology Roger Williams General Hospital, Providence, Rhode Island 02908.
J W
JW
Clark
M R
MR
Posner
J M
JM
Marsella
A
A
Santos
M
M
Uskokovic
C
C
Eil
S R
SR
Lasky
D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000473:pathology*; D018950:Lipopolysaccharide Receptors; D016177:Macrophage-1 Antigen / Q000032:analysis; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018950:Lipopolysaccharide Receptors; D016177:Macrophage-1 Antigen; D002117:Calcitriol