Potentiation by 1-alpha,25-dihydroxyvitamin D3 of cytotoxicity to HL-60 cells produced by cytarabine and hydroxyurea.
A short (4-hr) exposure to 1-4 X 10(-7) M 1,25-dihydroxyvitamin D3 [(1,25(OH)2D3); 1-alpha,25-dihydroxycholecalciferol] induced transient differentiation in a clone (R2AB2) of human promyelocytic leukemia cells (HL-60) but caused no permanent growth impairment and no detectable cytotoxicity. This treatment with 1,25(OH)2D3 also produced an inhibition of DNA synthesis that was promptly reversed when 1,25(OH)2D3 was removed. When such treatment with 1,25(OH)2D3 immediately followed a sublethal exposure to drugs that inhibit DNA synthesis, including the cancer chemotherapeutic agents cytarabine and hydroxyurea, the proportion of HL-60 cells lethally damaged was increased. This finding was demonstrated by morphologic evidence of cell damage and disintegration, an increased permeability to trypan blue, loss of cells from culture, and a reduced clonogenic potential of the treated cells. Exposure to 1,25(OH)2D3 before treatment with a cytotoxic agent had a slightly protective rather than a damaging effect. These observations suggest that the presence of 1,25(OH)2D3 markedly reduces the capacity of HL-60 cells to repair DNA damage or to reduce the intracellular concentration of cytotoxic agents.
Studzinski
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Bhandal
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Brelvi
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D002117:Calcitriol / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004357:Drug Synergism; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology
D004273:DNA, Neoplasm; D003561:Cytarabine; D002117:Calcitriol; D006918:Hydroxyurea