Antiproliferative Activity and in Vivo Toxicity of Double-Point Modified Analogs of 1,25-Dihydroxyergocalciferol.
Analogs of 1,25-dihydroxyergocalciferol, modified in the side-chain and in the A-ring, were tested for their antiproliferative activity against a series of human cancer cell lines in vitro and in vivo toxicity. The proliferation inhibition caused by the analogs was higher than that of the parent compounds, while the toxicity, measured as the serum calcium level, was lower. All analogs were able to induce, in HL-60 and MV4-11 leukemic cells, G₀/G₁ cell cycle arrest and differentiation expressed as morphological signs typical for monocytes. The analogs also induced the expression of CD11b and/or CD14 cell-differentiation markers. The most potent analogs, PRI-5105, PRI-5106, PRI-5201 and PRI-5202, were also able to induce vitamin D receptor (VDR) protein expression, mainly in the cytoplasmic fraction of HL-60 or MV4-11 cells. The most active analogs were the 19-nor ones with an extended and rigidified side-chain (PRI-5201 and PRI-5202), as in the former analogs PRI-1906 and PRI-1907. Epimerization at C-24 (PRI-5101) or introduction of an additional hydroxyl at C-23 (PRI-5104) reduced the toxicity of the analog with retained antiproliferative activity.
Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Weigla, 53-114 Wrocław, Poland. justyna.trynda@iitd.pan.wroc.pl.
Justyna
J
Trynda
Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Weigla, 53-114 Wrocław, Poland. turlej@iitd.pan.wroc.pl.
Eliza
E
Turlej
Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Weigla, 53-114 Wrocław, Poland. milczarek@iitd.pan.wroc.pl.
Magdalena
M
Milczarek
Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland. a.pietraszek@ifarm.eu.
Anita
A
Pietraszek
Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland. m.chodynski@ifarm.eu.
Michał
M
Chodyński
Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland. a.kutner@ifarm.eu.
Andrzej
A
Kutner
Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Weigla, 53-114 Wrocław, Poland. wietrzyk@iitd.pan.wroc.pl.|Institute of Chemistry, Environmental Protection and Biotechnology, Jan Długosz University, 13/15 Armii Krajowej Ave., 42-200 Częstochowa, Poland. wietrzyk@iitd.pan.wroc.pl.
Joanna
J
Wietrzyk
D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004872:Ergocalciferols / Q000737:chemistry / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D018167:Receptors, Calcitriol / Q000378:metabolism
D004872:Ergocalciferols; D018167:Receptors, Calcitriol; C003564:1,25-dihydroxyergocalciferol
1,25-dihydroxyergocalciferol analogs; CD11b and CD14 cell-surface markers; VDR and MARRS mRNA expression; antiproliferative activity in vitro; calcitriol and analogs; cell cycle; cytoplasmic vacuolization; human cancer  cell lines