[CANCER RESEARCH 39. 321 5-321 9, August1979]
0008-5472/79/O039-0000$02.OO
Possible Mechanisms of Action of Lithium on Augmentation of
in Vitro Spontaneous Myeloid Colony Formation1
Gary Spitzer,2 Dharmvir S. Verma, Barthel Barlogie, Miloslav A. Beran, and Karel A. Dicke
Deportment of Developmental Therapeutics, University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Houston, Texas 77030
ABSTRACT
to delineate these mechanisms in detail using human bone
marrow cells.
To understand the possible mechanisms of lithium carbon
ate-induced neutmophilia,the in vitro effect on human myeboid
MATERIALS AND METHODS
progenitor cells was examined. A significant increase in spon
taneous colony formation (15 of 24 experiments) was observed
These investigations were performed after approval by the
with the addition of lithium. Increased colony formation seldom local Human Investigations Committee. All patients donating
occurred when human placental conditioned media as a source their marrow were informed about the nature of the investiga
of colony-stimulating activity (CSA) was simultaneously added tion.
to the cultures. Further data suggest that lithium requires an
Acquisition of Marrow Specimens. Human marrow speci
adherent marrow cell population for this action and that in
mens were routinely obtained from patients with nonhemato
creases in CSA-containing cultures may be due to suboptimal logical cancers without bone marrow involvement on prior
CSA concentrations. Lithium was shown to release CSA from chemotherapy at the time of diagnostic bone marrow aspina
marrow cells and adherent cell population prepared from hu
tions. Marrow was aspirated from the posterior iliac spine.
man bone marrow. Lithium possibly increases spontaneous Approximately 1 ml of marrow was placed into a tissue culture
human myeboid colony development indirectly through CSA tube containing preservative-free hepanin (300 units in 2 ml of
release by adherent cells.
phosphate-buffered saline).
Marrow Cell Preparation Used in Various Experiments.
INTRODUCTION
Buffy coat cells were used for the experiments designed to
elicit the enhancement of spontaneous colony formation by
Various reports have described consistent elevation of gran
lithium and the abrogation of this effect by removal of adherent
ulocytes accompanying lithium administration in psychiatric
cells. Buffy coat cells were also used in those experiments
patients (12, 14, 18). In 1975, Gupta et a!. (8, 9) reported that showing the effect of lithium on HPCM-stimulated marrow cells.
lithium increased the leukocyte count in patients with Felty's HPCM was prepared as described previously(3).
syndrome. They also documented increases in CSA3 active
Ficoll-Hypaque interface cells were used in the experiments
against murine bone marrow cells in the urine of these patients. designed to show the release of CSA by lithium.
Recently, several authors have reported that lithium when
Preparation of Buffy Coat Cells. Marrow specimens were
administered to patients with various cancers may ameliorate centrifuged at 1200 x g for 10 mm in plastic culture tubes
chemotherapy-induced myebosuppression (4, 6, 19, 20, 22) (Falcon Plastics, Oxnard, Calif.; Model 3033). The buffy coat
and reduce the duration of granulocytopenic phase induced by was aspirated gently with a Pasteur pipet and subsequently
chemotherapy in acute myeboidleukemia (5). Lithium has also used for various experiments.
been used to elevate leukocytes, platelets, and hemoglobin
Preparation of Light-Density Cells. Marrow specimens were
levels in aplastic anemia with some success (1).
diluted in equal volumes of a-MEM with I 5% FCS and centni
Recently, Rothstein et a!. (15) have shown that the increase fuged at 400 x g for 35 mm after layering over a cushion of
in blood neutrophil count seen after lithium administration is Ficoll-Hypaque (density, 1.077 g/mb) contained in a conical
not merely due to demangination but is a result of enlargement plastic tube (Falcon Plastics; Model 3033) (2). The interface
of the total blood neutrophil mass and increased neutnophil cells were aspirated gently with a Pasteur pipet, washed with
production.
phosphate-buffered saline, resuspended in a-MEM, and used
Studies in mice have revealed that lithium enhances the CSA for the experiments mentioned later.
production by lung tissue (9, 10). Using human peripheral
Culture Procedure. The culture procedure has been de
leukocyte undenlayers, lithium has been shown to increase scnibed before except for using HPCM as a source of CSA
colony formation in in vitro agar culture system (21 ). However, instead of peripheral blood beukocytes(19). Briefly, the marrow
thus far, exact mechanism(s) involved have not been cleanly preparations were cultured in equal volumes of double-strength
elucidated. Herein, we report in vitro experiments performed a-MEM with 30% FCS and 0.6% agar (Bacto-agam;Difco Lab
oratories, Detroit, Mich.) giving a final concentration of 0.3%
,Supported
inpart
byGrants
CA 11520,CA 14528,
andCA 19856from agar with single-strength a-MEM and 15% FCS. For all cub
NIH, Bethesda,Md.
tunes, 0.1 ml HPCM was used as a source of colony-stimulating
2 To whom request for reprints should be addressed, at Developmental Ther
factor in underlayers of 0.5% agan and a-MEM with 15% FCS.
apeutics, University of Texas System Cancer Center, M. D. Anderson Hospital
The same batch of HPCM was used throughout the study. All
and Tumor Institute, 6723 Bertner Avenue, Houston, Texas 77030.
3 The abbreviations
used
are:
CSA,
colony-stimulating
activity;
HPCM,
human
cultures were plated in triplicate for 7 days in a fully humidified
placental conditioned medium; a-MEM, modified Eagle's medium; FCS, fetal calf
atmosphere of 7% CO2 and air at 37°.
serum; CFU-C, human myeloid progenitor cell.
Received November 21 , 1978; accepted May 15, 1979.
Culture Scoring. Cultures were scored on Day 7 using an
AUGUST 1979
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3215
G. Spitzer et a!.
achievedanalyzed
lithium in the presence of HPCM oventhat
Olympus dissecting microscope at X25 to 40. They wereulationwith
HPCMalone. Because of this unexpected finding, we
nextcolonyfor total number of colonies (pen plate). The finalwith
the effect of lithium on spontaneous colony forma
incidence was the mean of the colony incidence fromexamined
each
ofRemoval
plate for that particular observation in the study.tion.Twelve
experiments were performed at a cell number
of Adherent Cells. Removalof adherent cell pop 5 X 105/plate, a dose which routinely induces
spontaneousulation
withml was achieved by incubating 2 x 106 buffy coat cells/icolonyformation;
10 incorporated lithium in culture plates
of a-MEM and 15% FCS, total volume of 2 ml in 35-mmandwithout
HPCM, and 2 examined spontaneous colony for
Falcon Petmidishes (Falcon Plastics; Model 3001 ) for 3 hr.mationalone.
theNonadhement
In other experiments, we also examined
cells for culture were obtained as describedeffect
at other cell doses on usually both stimulated
of
below.
experimentsPreparation
andlithium
unstimulated colony formation. A total of 2
experimentssigned
wasperformed with a cell dose of 1 X 1O5/dish, 9
of Conditioned Media. In the experiments de
andcellsto examine the release of CSA, light-density marrowwereperformed
with a cell dose of 2.5 X 105/dish,
were obtained by Ficoll-Hypaque gradient centnifugationbecauseof
were(density,
the limitation of cell numbers, 5 experiments
1.077 g/mb) as described above.performedwith
cells/dish.To
7.5 X 1O@
prepare the conditioned media, 2 x 106 interface cellsChart1
, A and B, are representative of experiments exam
from
a Ficoll-Hypaque gradient were incubated per 1 ml of a-ining
theeffect of lithium on both spontaneous colony
formationMEM
theseTo
and 15% FCS (total volumeof 2 ml; total cells 4 x 106).and
that induced with HPCM. As can be seen from
spontaneousinterface
induced variable enhancement of
obtain adherent cell-conditioned media, 2 x 106/mI ofgraphs,lithium
bydescribed
For example, the experiment represented
cells were subjected to adherence procedure ascolonyformation.
formationwere
1Ashows enhancement of spontaneous colony
above (4 x 106 cells/dish), and nonadhenent cellsChart
0.05.MEM.
highertarget cell numbers (5 and 7.5 X 1O@
cells), p <
nemoved by 2 vigorous washings of Petni dishes with a-at
byincubated
in spontaneous colony formation induced
Subsequently, the Petni dishes with adherent cells wereThisdifference
thefor
was abrogated when HPCM was added to
(each dish containing 2 ml of a-MEM with 15% FCS)lithium,however,
dishes.at
varying periods in a fully humidified atmosphere of 7% CO2culture
experimentspared
37°.Conditioned media from nonadherent cells were pre
Chart2A shows the cumulative data of the
thising by centrifuging the aspirated nonadherent cells, remov
performed with HPCM and lithium. As can be seen from
variable.in
theeffect of lithium on CSA-stimulated plates is
the supemnatant,nesuspending the cells to a volume of 2 mlchart,
theplastic
2Bis the cumulative data from experiments in which
a-MEM and 15% FCS, and reseeding into a new 35-mmChart
Petni dish.effect
oflithium on spontaneous colony formation was exam
Conditioned media were harvested at specific times andmed.Enhancement
aprepared
of spontaneous colony formation was
7through by centrifuging at 2000 rpm for 10 mm and passingcommonphenomenon.
In 6 of 9 experiments at 2.5 X 1O@,
a Millipone filter (0.45 sm). Conditioned media wereof
lithiumstored
12 at 5 x 10@,and 2 of 5 at 7.5 x 1O@cells,
at —20°
until assayed on 0.5 x 1O@nonadherent, light
moredensity
increased spontaneous cloning efficiency by 50% on
(<1 .077 g/mb), human marrow cells from a single(58%
experiments). Moreover, some of these increases
of
donor.
theAgents
greaten than 100% (Chart 2B). In 2 experiments,
were bythe
Used. Lithiumcarbonate (Lot 763970; Fisher Sci
80
entific Co., Pittsburgh, Pa.) was dissolved in a-MEM in a
stocksolution
B
of1
of lithium (1000 mEq/liter). A lithium concentration
mEq/Iitem was used in those experiments designed to ex
amine spontaneous colony formation and the effect of sponta
300
This•concentration
neous colony formation after removal of adherent cells.
(-)
concentrationsachieved
is equivalent to serum lithium
carbonate.,Lithium
in humans with p.o. lithium
4.0,@‘.AmEq/Iiten
carbonate was used at concentrations of 0.5 to
220
.@100
in experiments examining CSA release. Endotoxin
a,
(Escherichia co!i 055:B5;
Yconcentrations
Difco Laboratories)
was used at,‘@‘E
ag/mI.@“Statistics.
of 100
experiments“with
Differences between the results of
and without lithium were examined by using a Student's
2-sample t test.,‘2@'
,,‘;/‘RESULTS60Lithium
withoutHPCM.
Effects on Human Marrow Cells: with and
To explorethe effect of lithiumon in vitroculturegrowth
of
human myebold progenitor cells, lithium was used at a
@)7.5
concentration of 1 mEq/biter with varying cell numbers (1 toI
ofhuman
x 105/dish) obtained from buffy coat preparations
bone marrow. Simultaneous experiments were pen
formed
9experiments
using HPCM alone and HPCM and lithium. A total of
of this design showed no definite pattern of stim
.
@
3216
.
.
.
z
I40
0
2 5
50
75
25
•
50
75
Number of Marrow Cells per Dish
( 0
Chart 1. Lithium enhancement of spontaneous colony formation. Bone mar
row cells were cultured with HPCM without lithium carbonate (Li) and with lithium
carbonate (A). Marrow was also cultured without HPCM and without lithium (0)
and with lithium (•)
to see the effect on spontaneous colony formation. Bars,
S.D. Lithium causes enhancement of spontaneous colony formation but no
significant difference in cultures containing HPCM.
CANCERRESEARCHVOL. 39
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Lithium-Mechanism
A
[B
30
(13900%i
, ieOO%)
0
a)
@
non.adherent
with lithium
20
(control)
cells
A. - .A non•adherent
(control)
only
cells
C.)
LL
0
.5 “00
.0
a)
0'
C
C
0
a,
E
.:@
—i:
::
I@.
:.
:
.
.
75
25
10
z
I—
@e
@
unseparated
U.
‘200
0
@
0@- .0
fr—4
C.)
‘300
a
C;)
.—. unseparated
withlithium
(I,
E
.2 ‘400
@
of Action on Mye!oid Colony Formation
0
10
25
50
50
75
Number of Morrow Cells per Dish ( xlO@)
Chart 2. Cumulative data of lithium effect en human marrow cells with and
without placental conditioned media. Lithium carbonate was added at a concen
tration of 1 mEq/liter to culture dishes with (A) and without (B) HPCM and a
variable number of cells per dish. The results are expressed as the percentage
of change in CFU-C with lithium compared to that of cultures without lithium.
Points at any cell dose, different marrow specimen. In most experiments contain
ing HPCM. the change is minimal, and some even show a decrease of CFU-C.
However,withoutHPCM lithiumusuallycausesa significantincreasein sponta
neous colony formation.
increase was 13,900 and 800%. However, in only 2 of 11
experiments at 1 x 1O@,5 of 15 at 2.5 x 10@,4 of 19 at 5.0
x 1O@,and 0 of 5 at 7.5 x 1O@cells, addition of lithium to the
cultures containing HPCM induced an increase of greater than
50% cloning efficiency
(22% of the experiments;
Chart 2A).
Some experiments with both lithium and HPCM show a de
crease of CFU-C's.
The Effect of Adherent Cell Removal on Spontaneous
Colony by Lithium. To determine if the lithium effect may be
mediated through an adherent cell population in the marrow
and not direct stimulation of CFU-C, adherent cell removal was
performed in another 3 experiments. Cells were cultured at cell
doses ranging from 2.5 to 7.5 x 105/dish.
Chart 3 is representative of these experiments. In all in
stances, the lithium enhancement of spontaneous colony for
mation is markedly reduced by the removal of adherent cells.
Therefore, it does appear that lithium requires adherent cells
for enhancement of spontaneous colony formation.
Lithium Effect on Human Marrow Colony Formation Stim
ulated with Varying Concentrations of HPCM and Its Modu
latlon by Removal of Adherent Cells. To determine if the
variable effect of lithium on colony formation in HPCM-contain
ing cultures may be due to suboptimal amounts of HPCM,
lithium (1 mEq/liten) was added to cultures containing 0.025
to 0.3 ml of HPCM. Colony formation was significantly in
creased in lithium-containing cultures at HPCM concentrations
of 0.025 ml (p < 0.05) and 0.05 ml (p < 0.025) as shown in
Chart 4A. This enhancing effect of lithium was abolished by
prior removal of adherent cells (Chart 4B).
Lithium Release of CSA from Light-Density Human Marrow
Cells. To determine if this action is through CSA release,
lithium at varying concentrations (0.5, 1.5, and 3 mEq/liter)
was incubated with bone marrow and compared to that ne
leased by 100 @tmg/ml of endotoxin and cells alone. The
release of CSA from both bone marrow cell suspensions from
which the nonadherent cells had not been removed and adhem
ent cells alone were examined at 24, 72, 96 hr, and 1 week.
Chart 5 is representative of 3 such experiments performed.
2.5
5.0
7.5
Number of Marrow Cells (x 105)
Chart 3. Effect of removal of adherent cells en lithium stimulation of sponta
neous colony formation. Bone marrow without adherent cells removed with lithium
and without lithium were cultured at varying cell concentrations. Without HPCM
as describedpreviously,lithiumincreasedspontaneouscolonyformation.Bone
marrow was also cultured after adherent cells had been removed with lithium and
without lithium. This procedure abrogated both spontaneous colony formation
and lithium-induced increases. Bars, S.D.
Lithium did enhance release of CSA from both bone marrow
adherent cells (Chart 5B) and bone marrow cell populations
from which nonadhenent cells were not removed (Chart 5A).
The maximal release in this experiment was at 96 hr of incu
bation, and after this time, there was a decrease in the activity.
CSA release was greater with higher concentrations of lithium
(3 mEq/liter) and from cell populations from which nonadhement
cells were not removed (Chart 5A). Low concentrations of
lithium (0.5 mEq/litem) were no more active than was CSA
activity obtained with incubation of cells alone.
To further determine if CSA release from unfractionated,
light-density bone marrow cells was solely contributed to by
adherent cells, whole bone marrow was further fractionated
into nonadhement and adherent cells. CSA release was then
determined in all 3 fractions (unfractionated, nonadherent, and
adherent). As shown in Table 1, only at the highest lithium
concentration (4 mEq/liter), a marginal CSA activity was de
tected in the nonadherent fraction despite significant CSA
release in response to endotoxin. The nonadherent fraction
still had a residual 3% monocytes by morphology and latex
phagocytosis. However, much higher levels of CSA (23 to 46fold) were released by unfractionated or adherent cells in
response to lithium.
DISCUSSION
This manuscript is the first report of lithium-induced enhance
ment of spontaneous colony formation and lithium-induced
CSA release by human marrow cells. Lithium has been de
scnibed to release CSA from mouse lung (10) and a CSA from
human mononuclear cells active against munine bone marrow
(1 1). However, it has been shown that the GSA released from
human peripheral blood monocytes and lymphocytes are mul
tiple, and the CSA active on human bone marrow are of
different molecular weights and released at different time pe
nods than are those active on munine bone marrow (16).
Moreover,Morleyand Galbraith(13) did notconfirmthat lithium
enhanced CSA release from human peripheral blood mononu
AUGUST 1979
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3217
G. Spitzer et a!.
A
.
With
HPCM
Alone
0
a,
U)
@0
a)
a,
a.
. With
C-)
HPCM
Alone
0 With HPCM •
Lithaum
0
UC-,
@3O
@
ieO
20
.@
30
a.
20
C-)
;
10
UC-,
0.025
005
I
@o40
}
a
@
B.
C
a,
0 With HPCM.Lithium
I
10
I
U
I
0.1
0.2
0.3
0025
Concentration of Human Placental Conditioned
0.05
Medium
0.1
0.2
03
(ml per culture dish)
Chart 4. Effect of lithium on colony formation in cultures containing lithium and human placental conditioned media at varying concentrations. A, bone marrow was
cultured at increasing concentrations of HPCM with HPCM alone and with HPCM and lithium. Uthium signlficantiy increased colony formation at concentrations of
HPCM of 0.025 and 0.05 ml in the underlayers; B, when adherent cells were removed, lithium did net effect colony formation at low concentrations of HPCM. Bars,
S.D.
40
(0
a)
C.)
A
B
>“,
.@o
15
Chart 5. The effect of lithium on CSA release by
human marrow cells. A, nenadherent cells net re
moved; and B, adherent cells alone. Lithium effect
maximum release of CSA at 96 hr followed by decline
in the activity
by 7 days
of incubation
0,
10
endotexin
(100 1fg/ml); t@,lithium(3 mEq/liter); 0, lithIum 1.5
mEg/liter; •,lithium (0.5 mEq/Iiter); A, cells alone.
Bars, S.D. In this experiment, the CSA release from
adherent cells (B) is much less than that released
when nonadherent cells are not removed.
20
0@
E
z
0
24
72
96
168
Periodof incubation (hours)
clear cells. There are no reports that document lithium-induced
CSA release by human marrow cell populations or the release
of CSA active on human bone marrow. It has been suggested
that the colony-stimulating cell population in marrow may be of
more significance in vivo than are peripheral mononuclear
cells. We, therefore, decided to examine the possibility that
lithium may require a bone marrow-adherent cell population for
its mechanism of action and that the mechanism of action may
be through the release of CSA from that population.
When
bone marrow adherent cells are removed prior to culture with
lithium, themewas a marked reduction of both spontaneous
colony formation and lithium enhancement of spontaneous
colony formation. When lithium was incubated with light-density
(<1 .077 g/mb), human marrow cell suspensions and adherent
cell populations prepared from these suspensions, it was found
to release CSA active on human bone marrow. Furthermore,
the activity released from nonadhenent bone marrow cell sus
pensions was minimal, approximately 20 to 50 times less than
adherent or unfractionated cell suspensions, and even this little
3218
activity could be due to incomplete removal of adherent cells.
There have been 2 previous reports (13, 21) of lithium
induced augmentation of human myeboid colony formation
either using cultures containing human peripheral blood cells
as an underlayemor a human mononuclear cell source of CSA.
This could suggest that lithium may have a direct effect on
CFU-C as well as an indirect action through release of CSA.
When we examined lithium effects in cultures incorporating
HPCM, we noticed a variable effect but significantenhance
ment was unusual. The concentrations of HPCM used in some
of our experiments may not have been those necessary to
achieve maximal colony numbers. Therefore, it is conceivable
that the target cells in those experiments in which lithium
enhanced colony formation despite the prestimulation with
HPCM may not have been maximally stimulated. We then
examined whether this variability could be due to suboptimal
stimulation by HPCM. Lithium did in fact only enhance colony
formation at low concentrations of HPCM, and this enhance
ment was abolished by removal of adherent cells. These results
CANCER RESEARCH VOL. 39
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Lithium-Mechanism of Action on Mye!oid Colony Formation
Table 1
ACKNOWLEDGMENTS
marrowunfractionated,
Lithium-induced CSA release from human bone
fractionsHuman
nonadherent,
and adherent cell
allowedtolight densitybonemarrowcells(<1.077 g/mI) were
period,nonadherent
adhere to plastic surfaces for 3 hr. At the end of this
in“Materials
cells were removedfrom someculturesas described
cultureswereand Methods―and seeded into new Petri dishes. All
thenlithium
restoredto a total volumeof 2 ml witha-MEMandsera,and
endotoxin(1
carbonatein concentrationsfrom 1 to 4 mEq/liter,
wereharvested
00 @mg/mb), or no additional
x1
reagents
were added. Media
after 7 days and measuredfor CSAactivity against0.5
O@light-density,
@ig/Cell
ml)Unfractienated
fraction
5Nonadherent
14Adherent
a Colonies,
>40
nonadherent
marrow.EndetoxinLithium
bone
(1
mEg/liter)
Uthium (2.0
mEq/liter)
Lithium (4
mEq/Iiter)
(100
0
0
0
0
lie ±3b
0
87 ±8
ios ± 4
0
89 ±12
125 ± 5
3 ± 0.6
69 ±10
79 ±
77 ±
83 ±19
cells.
b Mean ±S.D.
suggest that the variability observed in previous experiments
(HPCM pluslithium)mighthave been due to inadequateHPCM
concentrations used inadvertently. Previous publications of
enhanced colony formation with leukocyte undenlayens may
have been due to a similar mechanism, furthermore, the dis
appearance of this effect by removal of adherent cells suggests
the indirect mechanism of lithium action. The documentation of
CSA release from adherent cells and not from nonadhenent
cells may further suggest that the mechanism of indirect action
may be due to CSA release from adherent marrow cells.
Despite these findings, one should not conclude that CSA
release from an adherent marrow cell population is the only
possible mechanism of lithium action. Also, the variable ratio of
CSA release from unfractionatedand adherent cell fractions
from individual marrow specimens attest to the complexity of
CSA release by lithium and could be due to variable blood
contamination of marrow specimens or complex cell-to-cell
interactions. Further experiments are obviously indicated to
more cleanly dissect the cellular requirements for lithium-in
duced CSA release from whole-marrow and adherent marrow
cell populations.
Another interesting facet in these studies is the variable
instances of spontaneous colony formation from human bone
marrow which is not directly related to the CFU-C incidence. It
is possible that further analysis of the mechanism of action of
lithium on in vitro granubopoiesis may identify patients who may
not respond to lithium administration p.o. Further investigations
are under way to examine the effects of lithium on human
marrow which has been previously exposed to chemotherapy
to determine if these changes persist after the administration
of cytotoxic therapy.
The authors wish to thank Ann Creamer and Sherrie Smith for their expert
technical assistance and Lee Merniweather for her secretarial assistance in the
preparation of this manuscript.
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3219
Possible Mechanisms of Action of Lithium on Augmentation of
in Vitro Spontaneous Myeloid Colony Formation
Gary Spitzer, Dharmvir S. Verma, Barthel Barlogie, et al.
Cancer Res 1979;39:3215-3219.
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