[CANCER RESEARCH 36, 3798-3802, October 1976]

Action of the Vinca Alkaloids Vincristine, Vinblastine, and

Desacetyl Vinblastine Amide on Microtubules in Vitro1
Richard H. Himes2, Roderick N. Kersey, Irene Heller-Bettinger, and Fred E. Samson
Department of Biochemistry, University of Kansas, Lawrence, Kansas 66045 (A. H. H., R. N. K.J, and R. L. Smith Research Center, University of Kansas
Medical Center, Kansas City, Kansas 66103 (I. H-B., F. E. S.J

SUMMARY A newer Vinca alkaloid, VDS, has shown similar chemo

therapeutic behavior to VCR in tests against various expeni
The Vinca alkaloids differ in their chemothemapeutic ef mental cell lines (24). The structure of this compound is
fectiveness and their toxicities. To determine whether dif presented in Chart 1. Clinical trials are only in the Phase 1
fenencesare due to a differential effect on the assemblyof stage, although both neuropathy and marrow suppression
tubulin into microtubules, we examined the effects of yin may be significant side effects (4).
cnistine, vinblastine, and a newer alkaloid, desacetyl yin The question raised in this study was whether on not the
blastine amide, on the assembly of bovine brain tubulin in biological differences of these 3 alkaloids can be ascribed
Vitro. to differences in their reactivity with the microtubule pro
The three compounds block bovine tubulin polymeriza tein. The comparative effects of the 3 Vinca alkaloids on the
tion in vitro and almost equally effectively at a 1 j@IAconcen in vitro polymerization of tubulin and on MI formed in vitro
tration (tubulin, 6.5 @LM).At 10 @M, the three alkaloids also were determined. It was found that VCR, VLB, and VDS
interact with preformed micnotubules in vitro, causing spi showed only small differences in their ability to prevent
mal-like distortions of the microtubules. No effect of the tubulin polymerization. Furthermore, all 3 drugs caused
alkaloids on polymerization of another fibrous protein, ac distortion in the structure of preformed MI at identical
tin, was observed. Thus the differential actions of vinblas concentrations.
tine, vincnistine, and desacetyl vinblastine amide in vivo
seemto be basedon some biological processother than the MATERIALSAND METHODS
reaction with tubulin on the microtubules per Se.
Beef brain tubulin was purified by the polymerization
method of Shelanski et al. (23) as described previously (14).
INTRODUCTION
The extraction and reassembly buffer was 20 mM [2(N-
morpholinojethanesulfonic acid] 70 mM NaCI, 1 mM ethyl
The Vinca alkaloids are widely used in cancer chemother
eneglycol bis(f3-aminoethyl ether)-N ,N ‘-tetnaaceticacid,
apy. Microtubulamprotein, tubulin, has been implicated as a
and 0.5 mM MgCI2, pH 6.4. GIP (0.5 mM) was added for
possible target site for these compounds (29). Their oncoly
polymerization. The protein was purified through 2 polym
tic activity is probably due to the inhibition of formation and
enization cycles and was stoned at —80°
in the buffer con
possibly to the disruption of the mitotic spindle MI,3
taming 2 IA glycerol. Sodium dodecyl sulfate-gel electro
thereby arresting cell division at metaphase. Although the
phomesisshows the preparation to be about 90% tubulin. G
target molecule for both VCR and VLB appears to be tubu
actin was extracted from an acetone powder of rabbit mus
lin, their chemothemapeutic effectiveness for different types
cle by the procedure of Rees and Young (21) and was
of malignant cells varies greatly. Whereas VCR is quite
dialyzedat 4°overnightagainst0.5 mM AlP, 0.5 mM 2-
effective against Ridgway osteogenic sarcoma and CA755
mencaptoethanol, and 0.2 mM CaCI2 (pH 7.7) before use.
mammary carcinoma, VLB has no significant effectiveness
GIP was purchased from Sigma Chemical Company, St.
(24). VCR in combination with other non-Vinca drugs is
Louis, Mo. VLB, VCR, and VDS were gifts of the Eli Lilly
more effective against breast carcinoma, various lympho
mas, and lung small cell (oat cell), whereas VLB in this Company, Indianapolis, Ind.
The self-assembly of tubulin was followed by measuring
combination is more effective against choniocancinoma and
the increase in turbidity using a Gilford 2000 recording
embryonal carcinoma of the testes (11). The toxic side
spectnophotometer. Polymerization of G-actin was followed
effects of these drugs may result from their action on tubu
by viscosity measurements at 25 ±0.1°using a Cannon
lin and MT in normal cells. However, the major toxicity of
semimicmometen with a flow time for water of 61 .6 sec. For
the 2 drugs differs strikingly: the use of VCR is limited
electron microscopic examination, samples were negatively
chiefly by a neuropathy and of VLB by marrow suppression.
stainedwith2% unanylacetate.
1 Supported in part by USPHS Research Grant N5 1 1360 and a grant from
the Eli Lilly Co., Indianapolis, Ind. RESULTS
2 To whom requests for reprints should be addressed.

3 The abbreviations used are: IAT, microtubules; VCR, vincristine; VLB,

vlnblastine; VDS, desacetylvmnblastmneamide (vindesine). Inhibition of the self-assembly reaction by the 3 ymca
Received May 10, 1976; accepted July 9, 1976. alkaloids is shown in Chart 2. In these experiments, the

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 Action of Vinca Alkaloids on MT

was then examined. It has previously been shown by others

that both in vivo and in vitro VLB causes MT to form pama
crystals and spiral structures (1, 5, 8, 9, 15, 25). The latter
appear to be intermediates between MT and the crystals
(25). When the compounds were added after the formation
of MI, a small but reproducible decrease in the absombance
did occur (Chart 3). The extent of this decrease was almost
identical whether the final concentration of the drug was 1,
10, or 100 @M. However, some differences were observed
when these solutions were negatively stained and examined
with the electron microscope. MI treated with a 1 @IA con
R1
centration of the compounds were largely unaffected but a
OEsacETYL V@NBLAST@E
few spiral-like structures were observed. A proliferation of
AMIDE these spirals occurred in the presence of the higher con
desAcvLBAS VVJBCASTINE VINCRISTINE
R, ‘CONH2 R, :COOCH3 R, =COOCH3
centrations and few MT were present (Fig. 1). No differ
R2 OH R2 : R2 OCOCH3 ences in the abilities of VLB, VCR, or VDS to produce the
R3:CH3 R3 CH3 R@ : CHO
spirals were noted.
Chart 1. Chemical structures of VLB, VCR, and VDS. All 3 ymca alkaloids apparently have the property to cause
the unraveling of the MT. This apparently occurs by the
separation of pairs of protofilaments longitudinally, fol
lowed by a coiling of these pairs (25). The spiral structures
are stable to low temperature and to CaCl2, 2 microtubule
depolymenizing agents. This was indicated by the fact that
the absonbance was unchanged after these treatments.
When self-assembled tubulin was treated with 1 @M concen
trations of any of the alkaloids followed by the addition of 1
mM CaCI2 or by cooling to 0° (Chart 3), the absombance
decreased almost to 0. When the same experiment was
done using 10 @IA of the compounds, the absonbance
changed little. As a confirmation, samples were negatively
stained and observed with the electron microscope. Spirals
Unhibitor],,ALM
were abundant in samples that were incubated at 0°or with
Chart 2. Inhibition of polymerization by the ymca compounds. Tubulin 3 mM CaCI2after treatment with 10 @IA drug (Fig. 1). Indeed,
(0.8 mg/mI; 6.5 p@M) was incubated with the concentrations of the inhibitors
shown for 2 mm at 37@in 0.5 ml of reassembly buffer. GTP (5 @.tl of a 50 mM concentrations of as high as 8 mM CaCI2did not disrupt the
solution) was added and the absorbance at 500 nm was measured. The final structures but did appear to cause them to aggregate. The
absorbance value is plotted as a function of the concentration of inhibitor.
spiral structures, like MI, are sensitive to increases in ionic
compounds were preincubated with tubulin for 2 mm before
polymerization was initiated. However, it was found that
shorter on longer periods of preincubation did not change
the effectiveness of the alkaloids in preventing self-assem
bly. The results demonstrate that there is little difference in
the potency of the drugs in this in vitro system. Examination
of the data shows VCR to be slightly more effective than the
other 2 drugs. All 3 compounds block polymerization al
most completely at a concentration of 1 @IA when 6.5 @IA
tubulin was used. (This concentration of tubulin is calcu
lated assuming 90% of the protein to be tubulin.) These
results were confirmed by electron microscopic examina
tion. At concentrations slightly above 1 @M, no MT were
observed. Ultracentmifuge studies showed that at the molar
ratio of Vinca alkaloid to tubulin of 0.1 , large changes in the
size of the sedimenting speciesoccurred . The tubulin prep
arations contain a 6 and 30 5 species in roughly equal
proportions (see “Discussion―).In the presence of the Vinca
alkaloids, the amount of 6 and 30 5 decreases dramatically
and a new species with a sedimentation constant of >45 5 Minutes
appears. The in vitro assembly of porcine brain tubulin
prepared in the absence of glycerol (3) displayed a sensitiv Chart 3. Effect of VCR on MT. Tubulin (1.0 mg/mI; 8 @.tM)
was polymerized
in 0.5 ml of reassembly buffer containing 0.5 m@ GTP at 37―.
1st arrow, 5 p1 of
ity to VLB identical to that shown in Chart 2. either a 100 @M or 1 mM VCR solution was added; 2nd arrow, the sample was
Interaction of the 3 ymca alkaloids with MT formed in vitro cooled to O@ for 5 mm and then the absorbance was measured again.

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A. H. Himesetal.

strength. An intermediate NaCI concentration (0.25 IA), Table 1

which is known to depolymenize MT (14), did cause the Lack
polymerizationMuscle
of effect of VLB, VCR,and VDSon G-actin
disassembly of the spirals. ATP,0.5 G-actin (36 @.tM) was incubated in 0.5 ml of 0.5 mM
Since it has been shown that VLB can precipitate actin as theVinca
[email protected], and 0.2 mM CaCI2(pH 7.7) with
wasthen
alkaloids for 2 mm at 25°.KCI (10 @dof a 4 M solution)
well as tubulin (30), we examined the possible effects of the controlsof
added. After 25 mm the viscosity was measured.Two
ymca alkaloids on the conversion of G-actin to F-actin using alkaloids,both
G-actin incubated in the buffer alone and with Vinca
rabbit muscle actin. As the results in Table 1 demonstrate, periodused.Vinca
without KCl,showedno increasein viscosity in the time
these compounds, at fairly high concentrations, exhibited
no inhibitory effect on the polymerization of G-actin. Actin (@.tM)None
alkaloids Concentration
filaments formed in the presence of the compounds appear 1.41VCR
to be normal by electron microscopy. 1.40VCR 0.86
1.53VDS 86
1.44VLB 117
DISCUSSION 1.38VLB 9.8
98 1.38
The results presented here demonstrate that the ymca
alkaloids VLB, VCR, and VDS inhibit the self-assembly of
amounts of 6 and 30 5 material. Because of differences
brain tubulin with near equal effectiveness. VCR may be in molecular weight, the molar concentration of the 30 S
about 50% more effective than VCR and VDS (Chart 2).@Ihis component is substantially lower than that of the total
is consistent with the findings that the 3 compounds inhibit
tubulin present. If the inhibition of polymerization involves
axoplasmic transport with almost equal effectiveness (17)
the addition of the Vinca compounds to the ends of the
and that there is little difference in the apparent binding
aggregates on unfolded rings (7, 12), then a concentration
constants of VLB, VCR, and desacetylvinblastine to brain
substantially lower than that of the total tubulin would be
tubulin (13, 19, 31). To our knowledge the binding of VDS inhibitory. For example, if the molecular weight of the
has not been reported. The literature contains a rather wide
aggregateis in the order of 1 x 10',at a totalprotein
mangeof reported affinity constants for the binding of VLB concentration of 1 mg/mI, the molar concentration of the
depending on the source of the tubulin. Apparently 2 moles
aggregateswould be 0.5 @tIA.
of VLB are bound per mole of tubulin dimer with affinity The concentrations of drugs required for the inhibition of
constants of2.3 x 10@
M1 (13),3 to 5 x 10@
IA' (31),and 6 x assembly of bovine brain tubulin are much higher than
106 M' (19), fortubulin from calf brain, chick embryo brain,
those reported for chick embryo brain tubulin (28). In the
and porcine brain, respectively. The reasons for these dif
latter case, 50% inhibition of the rate of assembly was
femencesare not known. However, it should be pointed out achieved using a tubulin to VLB ratio of 1O@. The difference
that we find the concentrations of VLB necessary to cause
between these results and ours could be due to a number of
50% inhibition of the assembly of 6.5 @M beef brain and
factors. One factor would be the use of tubulin from differ
porcine brain tubulin to be identical (about 0.6 pM). This ent sources. Another is the fact that results obtained from
would imply similar affinities of VLB for tubulin from these 2
rate studies cannot be compared directly with those ob
sources. tamed using extent of reaction. Finally, if the mechanism of
One aspect of these results deserves further comment.
inhibition suggested above is valid, the presence of differ
We find that the concentration of Vinca alkaloids necessary
ent size aggregates in the tubulin preparation would help
to cause complete inhibition of polymerization is substan
explain the different sensitivities to the alkaloids.
tially less than the total amount of tubulin present. That is,
It has been proposed that VLB disrupts MI in vivo by
when the protein concentration is calculated on a molar
blocking the polymerization reaction resulting eventually in
basis, using 110,000 as the molecular weight, the presence
the disappearance of MI (31). The claim has also been
of 1 mole of Vinca alkaloid for every7 moles of tubulin dimer
made that the Vinca alkaloids do not have a high affinity for
causes essentially complete inhibition (Chart 2). This is
MI per se (31). To the contrary, the results presented here
difficult to understand simply on the basis of a reaction
show that all 3 Vinca alkaloids do cause structural changes
between tubulin dimem and the alkaloid (dimem + 2 VLB
in the preformed MI at fairly low concentrations. Although
dimem•2 VLB). The apparent disparity can be explained
a drug to proteinmolar ratioof about 1 was requiredfor
by considering the composition of tubulin preparations ob
maximum production of the spinal protofilaments, some
tamed by the method used in this study. These preparations
effect was seen at a ratio of about 0.1. It may be inferred
contain tubulin as the 6 S dimen and an aggregated form
(“rings―).
The aggregate is necessaryfonthe polymerization from these observations that the Vinca alkaloids havethera
peutic effects by interacting with preformed MI in nondivid
to take place and probably servesas an initiation site (2, 7,
ing tumor cells as well as preventing mitotic spindle MI
10, 12, 20, 27). The aggregates, usually in the form of a
from forming in dividing cells. Similarly, some of their clini
ring, contain tubulin and a small amount of other proteins
cal toxicity may be related to damage done to preformed
(6, 16, 22, 26). In our preparations we usually find equal
MI, such as innerveaxons.
4 After submission of this manuscript, an article by Owellen et a!. (18) Although the clinically observed differences between
appeared which describes the inhibition of tubulin assembly in crude porcine VCR, VLB, and VDS probably cannot be ascribed to their
brain homogenate by a variety of Vinca alkaloids. These workers found the
relative effectiveness of VCR and VLB to be similar to what we report, small differences in reactivity with tubulin, some pmelimi
although they found VDS to be a little more effective than VCR. nary results in our laboratory indicate that their actions on

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 Action of Vinca Alkaloids on MT

MI in nerve fibers do differ (J. A. Donoso, unpublished 6. Dentler, W. L., Granett, S., and Rosenbaum, J. L. Ultrastructure Locali
zation of the High Molecular Weight Proteins Associated with in Vitro —
data). That is, when isolated vagus nerves are incubated assembled Brain Microtubules. J. Cell Biol., 65: 237-241 , 1975.
with Vmncaalkaloids (5 x 10@ IA), VCR affects the MI in 7. Erickson, H. P. Assembly of Microtubules from Preformed, Ring-shaped
unmyelinated axons primarily, whereas VLB affects the MT Protofilaments and 6-S Tubulin. J. Supramol. Struct., 2: 393-411 , 1974.
8. Erickson, H. P. Negatively Stained Vinblastine Aggregates. Ann. N. Y.
in myelinated and unmyelinated axons equally. This is in Acad. Sci., 253: 51-52, 1975.
contrast to the greater neumotoxicity of VCR over VLB clini 9. Fujiwara, K., and Tilney, L. G. Substructural Analysis of the Microtubule
cally. and Its Polymorphic Forms. Ann. N. Y. Acad. Sci., 253: 27-50, 1975.
10. Gaskin, F., Cantor, C. R., and Shelanski, IA. L. Biochemical Studies on
This work indicates that the different oncological and the in Vitro Assembly and Disassembly of Microtubules. Ann. N. Y. Aced.
biological actions of the 3 ymca alkaloids are not accounted Sci., 253: 133-146, 1975.
11. Johnson, I. S. Plant Alkaloids. In: J. F. Holland and E. Frei (eds.), Cancer
for in their interactions with tubulin on MT as such. This is Medicine, pp. 840-850. Philadelphia: Lea & Febiger, 1973.
not to deny that the effect of these compounds on tubulin 12. Kirschner, IA. C., Sutter, IA., Weingarten, IA., and Littman, D. The Role of
and MT is not therapeutically important, rather, it raises the Rings in the Assembly of Microtubules in Vitro. Ann. N. Y. Acad. Sci.,
253: 90-106, 1975.
possibility of other additional molecular bases for some of 13. Lee, J. C., Harrison, D., and Timasheff, S. N. Interaction of Vinblastine
their therapeutic effects. For example, it has been shown with Calf Brain Microtubule Protein. J. Blol. Chem., 250: 9276-9282,
(30)thatVLB, in high concentrations, can precipitate a 1975.
14. Lee, Y. C., Samson, F. E., Jr., Houston, L. L., and Himes, A. H. The in
lange number of other acidic proteins, such as actin. Possi Vitro Polymerization of Tubulin from Beef Brain. J. Neurobiol., 5: 317-
ble interactions with this particular fibrous protein were 330, 1974.
15. Marantz, A., and Shelanski, IA. L. Structure of Microtubular Crystals
examined because actin is widespread and abundant in Induced by Vinblastine in Vitro. J. Cell Biol., 44: 234-238, 1970.
nerve tissue, thereby suggesting another possible area of 16. Murphy, D. B., and Borisy, G. G. Association of High-Molecular-Weight
involvement that could account for the clinical neuropathy. Proteins with IAicrotubules and Their Role in IAicrotubule Assembly in
Vitro. Proc. NatI. Acad. Scm.u. S. A. 72: 2696-2700, 1975.
However, no effect by any of the 3 compounds on actin 17. Ochs, S., and Worth, A. Comparison of the Block of Fast Axoplasmic
polymerization in vitro could be found. Although the polym Transport in Mammalian Nerve by Vincristine, Vinblastine, and Desacetyl
enization in vitro and the normal appearance of the actin Vinblastine Amide Sulfate (DVA). Proc. Am. Assoc. Cancer Res., 16: 70,
1975.
filaments in the presence of the Vinca alkaloids do not 18. Owellen, A. J., Hartke, C. A., Dickerson, A. IA., and Haines, F. 0.
muleout the possibility that actin is involved in the different Inhibition of Tubulin-Microtubule Polymerization by Drugs of the Vinca
biological actions of these compounds, they do argue Alkaloid Class. Cancer Res., 36: 1499-1502, 1976.
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against it. Vincristine, Vinblastine and Colchicine to Tubulin. Biochem. Biophys.
The results suggest that the differential actions of VLB, Res. Commun. 47: 685-691, 1972.
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ACKNOWLEDGMENTS 768, 1973.
24. Sweeney, IA.J., Cullinan, G. J., Poore, G. A., and Gerzon, K. Experimen
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with the Vinca alkaloids. Aes., 15: 37, 1974.
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R. H. Himes et a!.

Fig. 1. Electron micrographs of MT formed in vitro treated with Wnca alkaloids. MT were formed as described in Chart 3 and then treated with VLB for 5
mm. A, 1 @.tMVLB; B, 10 @tM VLB; C, 10 @MVLB, then 3 mM CaCl2for 5 mm; 0, 10 @.tM VLB, then cooled to 0@for 5 mm. Samples were stained with 2% uranyl
acetate. x 100,000.

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Action of the Vinca Alkaloids Vincristine, Vinblastine, and
Desacetyl Vinblastine Amide on Microtubules in Vitro
Richard H. Himes, Roderick N. Kersey, Irene Heller-Bettinger, et al.

Cancer Res 1976;36:3798-3802.

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