Liposomal 1,25 (OH)(2) vitamin D-3 compounds
block proliferation and induce differentiation
in myelomonocytic leukaemia cells.
Frankenberger M Hofmann B Emmerich B Nerl C Schwendener RA ZieglerHeitbrock HWL
Br J Haematol 1997 JUL;98(1):186-194
ZieglerHeitbrock HWL, Univ Munich, Inst Immunol,
Goethestr 31, D 80336 Munich, GERMANY
The vitamin D-3 derived hormone 1,25 (OH)(2) vitamin D-3 (1,25 D-3) is able to induce growth arrest and differentiation in myelomonocytic leukaemic cells. In order to allow for specific delivery to leukaemic cells the lipophilic compound was incorporated into the lipid membranes of liposomes. Liposomal 1,25 D-3 reduced proliferation as measured by H-3-thymidine incorporation in HL60 leukaemia cells by up to 60%. When liposomes were prepared at different concentrations of 1,25 D-3 65% inhibition was achieved at 48 nM. The MC 1288 stereoisomer of 1,25 D-3 was more potent and had the same activity at 4.8 nM. The effect of the liposomal compounds was specific to myeloid cells as they reduced proliferation in myelomonocytic HL60, monoblastic U937 and monocytic Mono Mac 6 cells but not in the T-cell lines Jurkat and Molt 4. The antiproliferative effect of liposomal 1,25 D-3 was associated with an induction of differentiation sice treated HL60 cells showed a monocytic morphology, increased expression of CD14 and decreased expression of CD33. When peripheral blood leukaemic cells from M4 and M5 acute myeloid leukaemia (AML) patients were admixed with liposomal compounds an antiproliferative effect was sent in all five cases, including the two cases where free compounds led to enhanced growth. Liposomal delivery of 1,25 (OH)(2) vitamin D-3 may offer a novel approach to treatment of myelomonocytic leukaemia.
A pilot study of all-trans retinoic acid in
patients with Philadelphia chromosome-positive
chronic myelogenous leukemia.
Cortes J Kantarjian H OBrien S Beran M Estey E Keating M Talpaz M
Leukemia 1997 JUL;11(7):929-932
Kantarjian H, Univ Texas, MD Anderson Canc Ctr, Dept Hematol, 1515 Holcombe Blvd, Box 61, Houston,TX 77030 USA
Retinoids have significant antiproliferative effect against chronic myelogenous leukemia (CML) cells in vitro. We conducted a pilot study to investigate the clinical effect of all-trans retinoic acid (ATRA) in patients with CML. Thirteen patients with Philadelphia chromosome (Ph)- positive CML in late chronic phase (n = 7), accelerated phase (n = 5), or blastic phase (n = 1) were treated. All had been previously treated and 12 (92%) had disease refractory to interferon-alpha therapy. They received ATRA 175 mg/m(2) orally in two divided doses daily until disease progression. The median duration of therapy was 56 days (range 11 to 190). Only one patient in late chronic phase had a transient decrease in WBC counts; all other patients in late chronic phase showed no response to therapy. Four of the five patients in accelerated phase showed evidence of antileukemia effect manifested by a decrease in bone marrow and/or peripheral blood blasts, promyelocyte and/or basophil percentages. In all cases the response was transient. The patient in blastic phase had no evidence of antileukemic effect. The treatment was well tolerated with the major side-effects being headache, nausea, dry skin, and dry mucosal membranes. One patient required dose reductions due to toxicity. We conclude that in this population of patients with extensively treated, advanced stage, Ph-positive CML, ATRA alone is ineffective for long-term therapy. The antileukemia effect seen in some patients warrants further investigation of retinoids in other schedules and in combinations in patients with CML.
Interaction of vitamin D derivatives
and granulocyte-macrophage colony-stimulating
factor in leukaemic cell differentiation.
James SY; Williams MA; Kelsey SM; Newland AC; Colston KW
Leukemia (ENGLAND) Jul 1997, 11 (7) p1017-25,
Division of Gastroenterology, Endocrinology and Metabolism, St George's Hospital Medical School, London, UK.
The ability of the physiologically active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and two novel vitamin D analogues, EB1089 and KH1060 to induce the differentiation of the U937 and HL-60 leukaemic cell lines was evaluated, alone or in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF). Studies revealed that following 96 h treatment, the vitamin D derivatives inhibited the proliferation, and induced the differentiation of U937 and HL-60 cells in a dose-dependent manner, as determined by cell counts and nitroblue tetrazolium (NBT) reduction assays, respectively. EB1089 and KH1060 were found to be more effective than 1,25(OH)2D3 in exhibiting their antiproliferative and differentiative effects. In contrast, induction of leukaemic cell differentiation with 1 ng/ml GM-CSF after 96 h was less effective when compared with the vitamin D derivatives used individually. Fluorescence activated cell scanning (FACS) analyses indicated that the vitamin D derivatives readily induced the expression of the monocyte-associated cell surface antigen, CD14, and also the beta2-integrins, CD11b and CD18 in both cell lines after 48 h and 96 h treatment. The ability of EB1089 and KH1060 to induce these antigens was achieved with greater efficacy relative to the native hormone. When U937 and HL-60 cell cultures were cotreated for 48 h with the vitamin D compounds and GM-CSF and analysed by FACS, enhanced effects on CD14 and CD11b induction were observed compared to those of the compounds alone. These co-operative effects may occur as a consequence of molecular events which involve the transcription by vitamin D receptors (VDR) of genes required for the responsiveness of immature cells to factors such as GM-CSF, and place these and other related vitamin D analogues as potential therapeutic agents in the treatment of leukaemia.
Gamma-interferon-induced resistance to
1,25-(OH)(2)D-3 in human monocytes
and macrophages: A mechanism for the
hypercalcemia of various granulomatoses.
Dusso AS Kamimura S Gallieni M Zhong M Negrea L Shapiro S Slatopolsky E
J Clin Endocrinol Metab 1997 JUL;82(7):2222-2232
Dusso AS, Washington Univ, Sch Med, Dept Internal Med,
Div Renal, 660 S Euclid Ave, Box 8126, St Louis,MO 63110 USA
The hypercalcemia of various granulomatoses is caused by endogenous 1,25-dihydroxyvitamin D [1,25-(OH)2(D3)] overproduction by disease-activated macrophages. The inability of 1,25(OH)(2)D-3 to suppress its synthesis in macrophages contrasts with the tight control of its production in macrophage precursors, peripheral blood monocytes (PBM). We examined whether 1,25(OH)(2)D-3 resistance develops as PBM differentiate to macrophages or with macrophage activation. Normal human pulmonary alveolar macrophages (PAM) are less sensitive to 1,25(OH)(2)D-3 than PBM, despite similar vitamin D receptor content; however, both PBM and PAM respond to exogenous 1,25-(OH)(2)D-3 by inhibiting 1,25(OH)(2)D-3 synthesis and inducing 1,25(OH)(2)D-3 degradation through enhancement of 24-hydroxylase mRNA levels and activity. The human monocytic cell Line THP-1 mimics PAM in 1,25(OH)(2)D-3 synthesis and sensitivity to exogenous 1,25(OH)(2)D-3. We utilized THP-1 cells to examine the response to 1,25(OH)(2)D-3 with macrophage activation. Activation of THP-1 cells with gamma-interferon (gamma- IFN) enhances 1,25(OH)(2)D-3 synthesis 30-fold, blocks 1,25-(OH)(2)D-3 suppression of its synthesis, and reduces by 42.2% 1,25-(OH)(2)D-3 induction of its degradation. The antagonistic effects of gamma-IFN are not merely restricted to enzymatic activities. In THP-1 cells and in normal PBM, gamma-IFN inhibits 1,25-(OH)(2)D-3 induction of 24-hydroxylase mRNA levels without reducing mRNA stability, suggesting gamma-IFN inhibition of 1,25(OH)(2)D- 3 transactivating function. These results explain 1,25(OH)(2)D-3 overproduction in granulomatoses and demonstrate potent inhibition by gamma-IFN of 1,25(OH)(2)D- 3 action in immune cells.