Novel vitamin D analogs that modulate leukemic cell growth and differentiation with little effect on either intestinal calcium absorption or bone mobilization.
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.
Zhou
J Y
JY
Department of Medicine, UCLA 90024.
Norman
A W
AW
Lübbert
M
M
Collins
E D
ED
Uskokovic
M R
MR
Koeffler
H P
HP
D000818:Animals; D015152:Blotting, Northern; D001842:Bone and Bones / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002645:Chickens; D002999:Clone Cells; D004100:Dihydroxycholecalciferols / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007938:Leukemia / Q000188:drug therapy*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc; D013329:Structure-Activity Relationship; D013997:Time Factors; D014407:Tumor Cells, Cultured
D004100:Dihydroxycholecalciferols; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D002118:Calcium