[CANCER RESEARCH 42. 4730-4733,
0008-5472/82/0042-OOOOS02.00
November 1982]
Increased Accumulation of Vincristine and Adriamycin in Drug-resistant
P388 Tumor Cells following Incubation with Calcium Antagonists and
Calmodulin Inhibitors1
Takashi Tsuruo,2 Harumi lida, Shigeru Tsukagoshi, and Yoshio Sakurai
Cancer Chemotherapy
Center, Japanese Foundation for Cancer Research, Toshima-ku,
ABSTRACT
Some calcium antagonists and calmodulin inhibitors enhance
the intracellular levels of vincristine and Adriamycin in vincristine- and Adriamycin-resistant P388 leukemia cells by inhibiting
their outward transport. The high intracellular drug accumula
tion was directly related to the enhancement of the cytotoxicity
of the antitumor agents, and the vincristine and Adriamycin
resistance in these cells was circumvented.
The effect of some antitumor agents is related to the extent
of their penetration into and their accumulation and retention
within tumor cells (20). The acquired resistance of tumor cells
to some agents, a crucial problem in cancer chemotherapy, is
also related to intracellular drug accumulation and retention (1,
3, 6, 9,17.18,
21, 22, 24). For example, in VCR3- and ADMresistant tumor cell sublines, these agents can be shown to
enter the cell but are actively transported to the outside. This
results in a relatively low intracellular level of drug (3, 9, 17,
21, 22, 24) and thus to low cytotoxicity. Inhibition of drug efflux
without interfering with internalization may enhance the cyto
toxicity of antitumor agents and provide a mechanism to over
come this form of drug resistance in some tumor cells. We have
reported that verapamil, a calcium antagonist, inhibits VCR
efflux and enhances the cytotoxicity of VCR (24).
The present report concerns our finding that some calcium
antagonists and calmodulin inhibitors enhance the intracellular
levels of VCR and ADM in VCR- and ADM-resistant P388
leukemia cells which lead to circumventing drug resistance.
AND METHODS
Drugs. VCR and ADM formulated for clinical use were obtained from
Shionogi and Co., Ltd., Osaka. Japan, and Kyowa Hakko Kogyo Co.,
Ltd., Tokyo, Japan, respectively. [G-3H]VCR sulfate (6.3 Ci/mmol) was
purchased from The Radiochemical
Centre, Amersham, England.
[G-3H]ADM-HCI (76 mCi/mmol) was kindly contributed by Kyowa
Hakko Kogyo, Co., Ltd. Verapamil (5) and caroverine (10) are coronary
vasodilators with calcium antagonist action and were supplied by the
Eisai Co., Ltd., Tokyo, Japan, and Mitsubishi Chemical Industries Ltd.,
Tokyo, Japan, respectively. The other modifiers are calmodulin inhibi' This work was supported
by Grants-in Aid for Cancer Research from the
Ministry of Education, Science, and Culture (56010019) and from the Ministry of
Health and Welfare (54-5), Japan.
2 Recipient of an Award from Society for Promotion of Cancer Research,
Japan. To whom requests for reprints should be addressed.
3 The abbreviations used are: VCR. vincristine; ADM, Adriamycin;
P388/VCR
P388 leukemia cells resistant to VCR; P388/ADM, P388 leukemia cells resistant
to ADM; ICso, concentration of drug required for 50% inhibition of cell growth or
enzyme activity.
Received December 4, 1981 ; accepted August 5, 1982.
4730
tors; prenylamine is a coronary vasodilator (2), trifluoperazine and
clomipramine are antidepressants (15, 28), and No. 233 is a thrombin
inhibitor (12). These drugs were provided by Hoechst Japan Ltd.,
Yoshitomi Pharmaceutical Industry Ltd., Ciba-Geigy Japan, Ltd., and
Mitsubishi Chemical Industries Ltd., respectively, all located in Tokyo,
Japan. These drugs were called "modifier" in the text.
Cell Culture and Drug Treatment. P388/VCR and P388/ADM cells
(9, 24) were prepared and maintained in Roswell Park Memorial
Institute Medium 1640 supplemented with 10% fetal bovine serum
(Grand Island Biological Co., Grand Island, N. Y.), 20 /IM 2-mercaptoethanol, and kanamycin (100 M9/ml) (growth medium) (24). For drug
treatment experiments, tumor cells (2 x 10") were cultured at 37°for
INTRODUCTION
MATERIALS
Tokyo 170, Japan
5 hr in a Falcon No. 2054 culture tube containing 2 ml of growth
medium in a humidified atmosphere of 5% CO2. Then, they were
treated with graded drug concentrations (0.1 to 100 nw for VCR, 10 to
10" nM for ADM) in the absence or presence of the modifier, reincubated and counted with Coulter Counter 3 days after drug treatment
(23). Two tubes were used for each drug concentration. IC50 in the
presence or absence of modifiers was determined as described previ
ously (23, 24).
Cellular Uptake of ['HVvCR and [3H]ADM in the Presence of
Modifiers. Cellular uptake of the drugs was measured in growth me
dium. In order to compare the efficiency of modifiers, we used identical
nontoxic concentration of 6.6 JIM. In the presence of modifier at 6.6
/IM, P388/VCR and P388/ADM cells (2 X 10s) in Falcon No. 2054
culture tubes containing 1 ml of growth medium with 20 mM 4-(2hydroxyethyl)-1-piperazineethanesulfonic
acid buffer were incubated
with [3H]VCR (33 nw; specific activity, 6.3 Ci/mmol) and [3H]ADM (200
nw; specific activity, 76 mCi/mmol), respectively. After a 1-hr, 37°
incubation, intracellular VCR or ADM uptake was determined as de
scribed previously (24).
Extracellular Transport of [3H]VCR or [3H]ADM and Effect of
Modifiers. VCR- and ADM-resistant tumor cells actively transport VCR
and ADM outside the cells and usually maintain these drugs at very low
levels (3, 9,17,21,
22, 24). In order to achieve a sufficient intracellular
concentration of drugs, 2 experimental procedures were taken, (a)
Under the conditions described above, P388/VCR and P388/ADM
cells were initially loaded with [3H]VCR and [3H]ADM in growth medium
for 1 hr in the presence of modifiers (6.6 ¡IM)as described previously
(24); (b) P388/VCR cells were initially loaded with [3H]VCR in glucosefree growth medium supplemented with 10% dialyzed fetal bovine
serum (Grand Island Biological Co.) in the presence of 10 HIM sodium
azide for 30 min by a manner similar to that described previously (9,
21). Each cell suspension was centrifuged (80 x g; 10 min; 5°);
precipitated cells (2 x 105) were resuspended (more than 98% of the
cells excluded trypan blue) in 1 ml of growth medium containing 20
HIM 4-(2-hydroxyethyl)-l-piperazineethanesulfonic
acid buffer and in
cubated at 37° in the absence or the presence of modifiers (6.6 JIM).
At the indicated intervals, the intracellular [3H]VCR or [3H]ADM levels
were determined as described previously (24).
Inhibition of Calmodulin by Modifiers. The standard reaction mix
ture (0.5 ml) contained 40 ITIMTris-HCI (pH 7.5), 40 nriM imidazole HCI
(pH 7.5), 20 mM magnesium acetate, 20 ¿IMCaCI2, 1 HIM cyclic
adenosine 3':5' monophosphate, 0.01 unit of calmodulin-stimulated
bovine heart cyclic adenosine 3';5' monophosphate phosphodiester-
CANCER
RESEARCH
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VOL. 42
Calcium Modifiers on VCR and ADM Accumulation
ase (Sigma), 0.2 fig calmodulin (Sigma), and graded modifier concen
trations. Modifier and calmodulin (final volume, 0.4 ml) were preincubated for 5 min at 30° in the presence of buffer, magnesium acetate,
and calcium; reactions were started by adding 0.1 ml of the phosphodiesterase and cyclic adenosine 3':5' monophosphate mixture. After a
30-min incubation at 30°, phosphodiesterase
activity was determined
as described
previously (11, 27), and IC50 was estimated.
RESULTS AND DISCUSSION
The intracellular VCR and ADM levels in P388/VCR and
P388/ADM cells increased following 60-min incubation with
VCR or ADM in the presence of modifiers (Table 1). At a
nontoxic dose of 6.6 JUMof the modifiers, the cellular uptake of
VCR and ADM was enhanced 2- to 5-fold and approximately
2-fold, respectively. During 10- to 60-min incubation, the up
take of VCR or ADM was linear.
The intracellular accumulation of VCR or ADM in the pres
ence of the modifiers in growth medium or in the presence of
sodium azide in glucose-free growth medium was rapidly re
duced upon reincubation in the absence of modifiers. This
outward efflux of the preloaded drugs was inhibited when the
cells were reincubated with the modifiers (Chart 1). We suggest
that the increased intracellular accumulation of VCR or ADM is
at least partly due to the inhibition of extracellular (outflow)
transport of the antitumor agents.
The increased intracellular levels of VCR and ADM were
directly related to the marked enhancement of drug cytotoxicity
(Table 2). It is important to note that, under the present exper
imental conditions, the modifiers were not directly cytotoxic to
the tumor cells. Trifluoperazine exhibited a relatively small
effect as compared to the other modifiers. This was due to the
fact that its concentration was low due to cytotoxicity. IC50 of
VCR against parent P388 cells was approximately 1.4 nM. Our
data demonstrate that in vitro resistance to VCR was circum
vented when P388/VCR cells were simultaneously exposed to
VCR and a nontoxic dose of modifiers (Table 2). The cytotox
icity mediated by ADM was also enhanced by these modifiers.
ICso of ADM against parent P388 cells was 21 nM. ADM
resistance was partially overcome in P388/ADM cells because
they are highly resistant (Table 2). The cytotoxicity of VCR and
ADM was also enhanced in P388 cells. The degree of en
hancement, however, was lower as compared to P388/VCR
and P388/ADM cells.
All of the modifiers, when used at the same concentration,
Chart 1. Effect of calcium antagonists and calmodulin inhibitors on the extra
cellular transport of [3H]VCR or [3H]ADM. P388/VCR (A) or P388/ADM (B) cells
(each 2 x 10Vml medium) were incubated in growth medium for 1 hr with
[3H]VCR (33 nM; specific activity, 6.3 Ci/mmol) or [3H]ADM (200 nM; specific
activity. 76 mCi/mmol), respectively, in the presence of 6.6 ¡IMof modifier as
described in "Materials and Methods." In C. P388/VCR cells were incubated in
glucose-free growth medium supplemented with 10% dialyzed fetal bovine serum
with 10 rriM sodium azide for 10 min, and [3H]VCR was added and incubated
further for 30 min. Then, each cell suspension was centrifugea, and precipitated
cells were resuspended and incubated at 37°in growth medium in the absence
or the presence of modifiers (6.6 /IM). At the indicated intervals, the intracellular
[3H]VCR or [3H]ADM levels were determined in duplicate as described previously
(24). Release of [3H]VCR (Ai, [3H]ADM (B), or [3H]VCR (C) in the presence of
verapamil (O
O), caroverine (•),prenylamine (A), trifluoperazine (A), clomipramine O, and No. 233 (•).O
O, drug release in fresh medium in the
absence of modifier. In A and 8, drug release in the absence of each modifier
was similar (not shown) when the release was expressed in terms of percentage
of the initial intracellular level listed in Table 1;
in A and B, drug release
in the absence of verapamil (the values of other modifiers did not vary more than
5% from
). Points, means of duplicate experiments.
Table 2
Enhancement of VCR and ADM cytotoxicity by calcium antagonists and
calmodulin inhibitors
P388/VCR or P388/ADM cells were cultured for 5 hr, and then they were
treated with graded drug concentrations of VCR or ADM in the absence or
presence of the indicated modifier concentrations, reincubated, and counted 3
days after drug treatment.
(nm) of VCR in
cellsWithout
P388/VCR
tration
modifier900
ModifierVerapamilCaroverinePrenylamineTrifluoperazineClomipramineNo.
OIM)3.3 modifier26 modifier1.0
Increased intracellular
described previously (24). Values are the mean of duplicate determinations.
Cellular accumulation of
VCR in P388/VCR cells
(pmol/106 cells)
Modifier
Cellular accumulation of
ADM in P388/ADM cells
(pmol/106 cells)
VerapamilCaroverinePrenylamineTrifluoperazineClomipramineNo. (2.4)24.2(1.7)32.3
(3.5)1.16(5.0)1
(12)
(13)120(7.5)
71
0.311.3(84)(18.5)
900900
106.6
2422
0.851.0 (28)(22)
900900900900
110
(8.2)82
102.2
222222240.94.9 (24)(4.5)
(11)
(13)260
69
2.32.01.17.94.7
(9.6)(12)
900900
(3.5)
(4.5)250
200
(22)(3.0)
900900
(3.6)
(4.1)660
220
900
900With
(1.4)
350 (2.6)
280 (3.2)
106.610
2424
20ICso
(5.1)
2424With
0.21(26)"
(114)ICso
233Concen
Numbers in parentheses, decrease (x-fold) in the ICx>value as compared to
that obtained in the absence of modifier.
caused about the same degree of accumulation (Table 1) and
of enhancement of cytotoxicity of
VCR and ADM (Table 2). However, the calcium antagonists
verapamil and caroverine showed rather weak inhibitory activity
against calmodulin (Table 3) as determined by in vitro enzyme
levels. These results appear to indicate that the effectiveness
of all of the modifiers in circumventing VCR and ADM resistance
roughly the same degree
(2.3)27.6(2.0)23.9(1.7)16.6(1.2)13.8
(4.5)0.37(1.6)0.2333.6
.04
233Control1.12(4.8)a0.66(2.9)0.80
Numbers in parentheses, increase (x-fold) in the intracellular amount of the
antitumor agents as compared to the control (without modifier).
NOVEMBER
modifier75
2624
6.66.6
3.36.6
Table 1
VCR and ADM accumulation by calcium antagonists and
calmodulin inhibitors
P388/VCR and P388/ADM cells were incubated with [3H]VCR or [3H]ADM in
the presence of 6.6 ¡IMmodifiers as described in " Materials and Methods. ' After
a 1-hr, 37° incubation, intracellular VCR or ADM uptake was determined as
(nM) of ADM in
cellsWithout
P388/ADM
1982
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4731
T. Tsuruo et al.
Table 3
Effect of calcium antagonists and calmodulin inhibitors on calmodulinstimu/ated brain phosphodiesterase
Modifier and calmodulin were preincubated for 5 min at 30°. and reactions
were started by adding phosphodiesterase
and cyclic adenosine 3':5' monophosphate mixture as described in "Materials and Methods." After 30 min of
incubation at 30°, phosphodiesterase
activity was determined as described
previously (11, 27), and IC5o was estimated.
Modifier
Verapamil
Caroverine
Prenylamine
Trifluoperazine
Clomipramine
No. 233
ICs
490
580
40
36
107
12
In any event, the elucidation of the structural and functional
interactions between the ¡ntracellular calcium environment and
calmodulin and the drug transport functions of the cell mem
brane could be quite important to cancer chemotherapy (25,
26). At present, we can only speculate upon the possibility of
identifying clinically effective calcium antagonists and calmo
dulin inhibitors to achieve promotion of drug responsiveness.
ACKNOWLEDGMENTS
We thank Dr. I. J. Fidler for his critical reading of the manuscript.
indebted to M. Shimizu for preparing the typescript.
We are
REFERENCES
at cellular levels is not directly related to their effectiveness as
calmodulin inhibitors which was estimated in in vitro enzyme
levels.
The actual mechanisms involved in the inhibition of drug
efflux remain to be determined; however, we speculate several
possible mechanisms to explain our results. First, the efflux of
antitumor agents from cells may be controlled, possibly by
calcium and calmodulin (calcium-calmodulin
complex). Cal
cium antagonists might lead to a poor formation of calciumcalmodulin complex by lowering the intracellular calcium con
centration, and calmodulin inhibitors could directly inhibit cal
cium-calmodulin complex. In both cases, the efflux of the drug
might be adversely affected. A possible explanation for the
superior effectiveness of calcium antagonists is that the modi
fication of intracellular calcium environment by calcium antag
onists might lead to a prominent inhibition of the formation of
calcium-calmodulin complex, since it is well known that intra
cellular calcium concentration is usually maintained at very low
levels when compared to the extracellular concentration (19).
Like calcium antagonists, calmodulin is also involved in cellular
calcium transport (7, 8,13,14). We have not directly measured
calcium fluxes, calcium levels, or calmodulin levels; however,
we believe that the cellular calcium environment may play an
important role in the manifestation of the observed phenome
non.
Secondly, it might be possible that the energy-dependent
drug exodus system in the membrane might be perturbed by
the modifiers or by the change in calcium environment. The
hydrophobic nature of calmodulin inhibitors or calcium antag
onists might be related to the inhibition of energy-dependent
drug exodus system, thereby potentiating the toxicity of VCR
and ADM. Additionally, diMarco (4) reported that the calciumsequestering agent EDTA caused a marked increase of ADM
uptake in tumor cells. He speculated about 2 possibilities: (a)
sustained Ca2* deficiency induces damage to the cell mem
1. Biedler, J. L., and Riehm, H. Cellular resistance to actinomycin D in Chinese
hamster cells in vitro: cross-resistance, radioautographic, and cytogenetic
studies. Cancer Res.. 30: 1174-1184,
1970.
2. Braasch, W.. and Fleck, D. Die Beeinflussung von Coronardurchblutung
und
Sauerstoff-Versorgung
des Herzmuskels durch W-{3'-Phenyl-propyl-{2')-]1.1-diphenyl-propyK3)-amin.
Arzneim. Forsch. 11: 336-339, 1961.
3. Däne,K. Active outward transport of daunomycin in resistant Ehrlich ascites
tumor cells. Biochim. Biophys. Acta, 323. 466-483, 1973.
4. diMarco, A. Mechanism of action and mechanism of resistance to antineoplastic agents that bind to DMA. Antibiot. Chemother.. 23. 216-227, 1978.
5. Fleckenstein, A. Specific pharmacology of calcium in myocardium, cardiac
pacemakers, and vascular smooth muscle. Annu. Rev. Pharmacol. Toxicol.,
17: 149-166, 1977.
6. Goldstein, M. N., Hamm, K., and Amrod, E. Incorporation of tritiated acti
nomycin D into drug-sensitive and drug-resistant HeLa cells. Science (Wash.
D. C.). 151: 1555-1556,
1966.
7. Heaker, H., and Racker, E. Purification and reconstitution of the Ca2*ATPase from plasma membranes of pig erythrocytes. J. Biol. Chem., 254.
6598-6602,
1979.
8. Hinds, T. R., Larsen. F. L., and Vincenzi, F. F. Plasma membrane Ca2*
9.
10.
11.
12.
13.
14.
15.
16.
brane and to the mechanism of drug extrusion; (b) calcium
deficiency may affect Ca2+-H+ exchange on the membrane,
17.
which is related to the extrusion of anthracyclines. At the
present time, these possibilities regarding the perturbation of
the energy-dependent
drug exodus system cannot be over
looked.
Thirdly, the affinity of VCR for intracellular targets may be
altered by calcium antagonist-induced changes in the calcium
environment or by calmodulin inhibitors. The function of microtubules, the target of VCR, is known to be changed by calcium
and calmodulin (16, 29, 30). Because the effects we observed
with VCR were more pronounced than those with ADM (Table
2), this possibility must be considered at the present.
18.
4732
19.
20.
21.
22.
23.
transport: stimulation by soluble proteins. Biochem. Biophys. Res. Commun.,
8?. 455-461, 1978.
Inaba, M., Kobayashi, H., Sakurai, Y., and Johnson, R. K. Active efflux of
daunomycin and Adriamycin in sensitive and resistant sublines of P388
leukemia. Cancer Res., 39. 2200-2203,
1979.
Ishida, Y., Ozaki, H., and Shibata, S. Vasorelaxant action of caroverine
fumarate (a quinoxaline derivative), a calcium-blocking agent. Br. J. Phar
macol.. 77. 343-348. 1980.
Jarrett, H. W., and Kyte, J. Human erythrocyte calmodulin. Further chemical
characterization and the site of its interaction with the membrane. J. Biol.
Chem.. 254. 8237-8244,
1979.
Kikumoto, R., Tamao, Y., Ohkubo, K., Tezuka, T.. and Tonomura, S. Throm
bin inhibitors. 2. Amide derivatives of W- substituted L-arginine. J. Med.
Chem.. 23. 830-836, 1980.
Larsen, F. L., and Vincenzi, f. F. Calcium transport across the plasma
membrane: stimulation by calmodulin. Science (Wash. D. C.), 204:
306-309, 1979.
Lepeuch, C. J., Haiech, J., and Démaille, J. G. Concerted regulation of
cardiac sarcoplasmic reticulum calcium transport by cyclic adenosine monophosphate-dependent
and calcium-calmodulin-dependent
phosphorylations. Biochemistry, 18: 5150-5157.
1979.
Levin, R. M., and Weiss, B. Selective binding of antipsychotics and other
psychoactive agents to the calcium-dependent activator of cyclic nucleotide
phosphodiesterase. J. Pharmacol. Exp. Ther.. 208. 454-459, 1979.
Marcum, J. M., Dedman, J. R., Brinkley, B. R., and Means, A. R. Control of
microtubule assembly-disassembly by calcium dependent regulator protein.
Proc. Nati. Acad. Sei. U. S. A., 75. 3771-3775.
1978.
Nishimura, T.. Suzuki. H., Muto. K., and Tanaka. N. Mechanism of Adria
mycin resistance in a subline of mouse lymphoblastoma L5178Y cells. J.
Antibiot. (Tokyo), 32. 518-522, 1979.
Peterson, C., and Trouet, A. Transport and storage of daunorubicin and
doxorubicin in cultured fibroblasts. Cancer Res.. 38. 4645-4649,
1978.
Schatzmann, H. V., and Vincenzi, F. F. Calcium movements across the
membrane of human red cells. J. Physiol. (Lond.), 201: 369-395, 1969.
Sirotnak, F. M.. Chello, P. L., and Brockman, R. W. Potential for exploitation
of transport systems in anti-cancer drug design. Methods Cancer Res., /6.
381-447, 1979.
Skovsgaard, T. Mechanisms of resistance to daunorubicin in Ehrlich ascites
tumor cells. Cancer Res., 38. 1785-1791,
1978.
Skovsgaard, T. Mechanisms of cross-resistance
between vincristine and
daunorubicin in Ehrlich ascites tumor cells. Cancer Res., 38. 4722-4727,
1978.
Tsuruo, T., lida, H., Tsukagoshi, S., and Sakurai, Y. Comparison of cytotoxic
effect and cellular uptake of 1-/f-D-arabinofuranosylcytosine
and its W4-acyl
derivatives, using cultured KB cells. Cancer Res., 39: 1063-1070,
1979.
CANCER
RESEARCH
VOL. 42
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1982 American Association for Cancer Research.
Calcium Modifiers on VCR and ADM Accumulation
24. Tsuruo. T., lida, H., Tsukagoshi, S., and Sakurai, Y. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced
cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res., II
1967-1972,
1981.
25. Tsuruo, T., lida, H., Tsukagoshi, S., and Sakurai, Y. Prevention of vinblastine
induced cytotoxicity by ruthenium red. Biochem. Pharmacol., 30. 213-216,
1981.
26. Tsuruo, T., lida, H., Tsukagoshi, S., and Sakurai, Y. Enhancement of
vinblastine-induced
cytotoxicity by lysolecithin and phosphatidylinositol.
Cancer Lett., 13: 133-137, 1981.
27. Volpi, M., Sha'afi, R. J., Epstein, P. M. Andrenyak, D. M., and Feinstein, M.
NOVEMBER
1982
B. Local anesthetics, mepacrine, and propranolol are antagonists of calmodulin. Proc. Nati. Acad. Sei. U. S. A., 78: 795-799, 1981.
28. Weiss. B., and Levin, R. M. Mechanism for selectively inhibiting the activation
of cyclic nucleotide phosphodiesterase and adenylcyclase by antipsychotic
agents. Adv. Cyclic Nucleotide Res., 9. 285-303, 1978.
29. Welsh, M. J., Dedman, J. R., Brinkley, B. R., and Means, A. R. Calciumdependent regulator protein: localization in mitotic apparatus of eukaryotic
cells. Proc. Nati. Acad. Sei. U. S. A., 75. 1867-1871.
1978.
30. Welsh, M. J., Dedman, J. R., Brinkley, B. R., and Means, A. R. Tubulin and
calmodulin. Effects of microtubule and microfilament inhibitors on localiza
tion in the mitotic apparatus. J. Cell Biol., 87. 624-634, 1979.
4733
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Increased Accumulation of Vincristine and Adriamycin in
Drug-resistant P388 Tumor Cells following Incubation with
Calcium Antagonists and Calmodulin Inhibitors
Takashi Tsuruo, Harumi Iida, Shigeru Tsukagoshi, et al.
Cancer Res 1982;42:4730-4733.
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