Leuk #1
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.
Leuk#2
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.
Leuk #3
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.
Leuk #4
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.
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