Vitamin D analogs, leukemia and WAF1.
Vitamin D compounds induce differentiation of human leukemic cells and have potential for the treatment of leukemia. In this review we summarize some of the basic mechanisms underlying the action of vitamin D compounds. A variety of vitamin D analogues were synthesized until now, some of which have enhanced antileukemic activity and a decreased propensity to cause hypercalcemia. Most actions of vitamin D compounds are mediated by nuclear receptors. In vivo, vitamin D binding protein interacts with free vitamin D compounds. Both in normal and leukemic cells, vitamin D compounds cause a differentiation to monocytes and macrophages. A variety of genes are regulated by vitamin D compounds. Recently, the cell cycle inhibitory gene p21/WAF-1/CIP-1 was characterized. The expression de novo of WAF-1 in blasts of acute myelogenous leukemia is an independent factor of unfavorable prognosis. In HL-60 leukemic cells treated with vitamin D analogs, WAF-1 can be induced by nano- or picomolar concentrations of vitamin D analogs and correlates with the induction of a differentiated phenotype. When vitamin D analogs are combined in-vitro with retinoids, an irreversible differentiation is observed. Clinical trials of vitamin D analogs are indicated in the situation of minimal residual disease and in combination with standard chemotherapy.
Munker
R
R
Medizinische Klinik III der LMU (Klinikum Grosshadern) Munich, Germany. munker@gsf.de
Zhang
W
W
Elstner
E
E
Koeffler
H P
HP
D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D014807:Vitamin D