Download Modulation of Cancer Chemotherapy by Green Tea`

Vol.
4, 153-156,
January
1998
Modulation
Yasuyuki
Sadao
of Cancer
Sadzuka,2
Tomomi
Chemotherapy
Sugiyama,
Sciences,
University
of Shizuoka,
Shizuoka
Japan
the
modulation
Biochemical
has played
in the
development
of cancer
rected
our attention
to the intake
investigated
the effects
the antitumor
combined
activity
ascites
of green
in the
green
tea
tumor
was
green
green
The
out the
by the
not
was
green
tea combination.
tea can
improve
and
been
cancer
the
therapy.
would
become
of
in
in normal
tis-
the enhance-
may
and
effective
chemotherapy,
extensively
of antitumor
e.g.,
treatments.
enhancement
not
antitumor
enough,
as the result
of a new
modulator,
addition,
cations
the use
and adds
mor
to improve
intake
activity
tumor
reduce
and
there
the
modulators
are
some
of patients
cases
side
The development
antitumor
agents,
activity
has been
iments,
designed
clinical
combination
widely used
The
is also
In
necessary.
activity
antituanti-
modulation
will
biochemical
in part by the
this fact.
1 This
work
was supported
in part
Research
and Education
Foundation.
requests
for reprints
Sciences,
University
Phone:
81-54-264-5610;
by a Grant-in-Aid
should
may
tea
tea
and
inhibits
the
previously.
tea is restricted
hinder
the mental
have a bad influence
action
cancer
green
on
therapy
patient’s
cancer
would
mental
be-
condition
tea as usual.
the effects
In
this
of drinking
study,
tea with DOX,3
therapy
(10-12),
and
were
we
green
tea
investigated
the
an antitumor
antibiotic
on tumor-bearing
mice.
caffeine,
which
agents
examined
AND
are
known
(13-16),
to en-
as green
tea
as well.
from
was
(Shizuoka,
The
highest
purity
and
be addressed,
of Shizuoka.
52-1
Fax: 81-54-264-5615.
from
from
was
Green
purchased
tea powder
The
other
drugs
chemicals
(Adriacin’),
Inc.
Tokyo
Kasei
from
was
was
(Tokyo,
Co.,
Japan).
Ltd.
(Tokyo,
Wako
Pure Chemical
a product
of Shizuoka
were
dissolved
used
in this
in sterile
study
isotonic
were
of
the
available.
Male
20-25
CDFJ
g,
were
and BDF1
strain
obtained
mice,
from
S weeks
Japan
of
SLC,
Inc.
(Hamamatsu,
Japan).
The animals
were housed
in a room maintamed
at 25 ± 1#{176}C
with 55 ± 5% relative
humidity
and were
free access
to regular
chow
Tokyo,
Japan)
and water.
Ltd.,
Tumors.
Ehrlich
ascites
mal) were i.p. transplanted
collected
on the 7th day
was kindly
for Cancer
pellets
carcinoma
(MF;
Oriental
(1
106
into the CDF1 mice.
after transplantation.
provided
X
Tokyo,
cells/ani-
The ascites
were
M5076
ovarian
by Dr. T. Tashiro
Research,
Co.,
(Japanese
Foun-
Japan).
Animal
Experiments.
Ehrlich
cells/animal)
were transplanted
ascites
onto
carcinoma
the
backs
(5
X
of CDF1
mice. DOX (2.0 mg/kg/day
the 10th, 12th, 14th, and
for 4 days) was i.p. administered
on
16th days after transplantation.
Green
tea powder
for 4 days)
(1.0
gfkg/day
and
theanine
and
caffeine
Shizuoka
at School
Yada,
10 mg/vial
Fermentation,
purchased
Animals.
age
injection,
Kyowa
Japan).
saline.
METHODS
DOX
Japan).
Caffeine
Industries,
Ltd.
io5
payment
of page charges.
This article
must therefore
be hereby
marked
advertisement
in accordance
with
18 U.S.C.
Section
1734 solely
to
To whom
been
green
(5-9),
investigated
a positive
of antitumor
(5),
purchased
given
enhances
the improved
Received
5/20/97; revised 9/5/97; accepted
10/10/97.
The costs of publication
of this article were defrayed
Pharmaceutical
422, Japan.
has
of the oral administration
of green
we have performed
animal
exper-
to consider
of theanine
the
sarcoma
2
Green
or black
that
that
treatment.
components
dation
indicate
has
by drinking
of green
in clinical
effects
hance
and
needed.
the number
of mcdiSimultaneously,
the
of life of patients
of
its
the
of
enhances
this type
burden.
induce
examination
of food or beverage
as modulator
(biochemical
modulation),
then
activity
by
the patient’s
tea
and
better
during
Theanine
in
the
of modulators
increases
to the patient’s
burden.
the quality
of the activity
modulation.
of antitumor
has been
(3, 4), are confirmed
when
effects,
which
the side effects
If the
the enhancements
of biochemical
reduces
study
and
modulation
5-fluorouracil
However,
of
are
dying
tea (Ca-
that
patients.
biochemical
(1-4),
drugs,
been
coffee,
expect
To examine
the effects
tea on cancer
chemotherapy,
Chemicals.
In cancer
tea,
we could
effects
increase
never
green
If green
chemotherapy,
more
chemotherapy
of life of clinical
on
come
concen-
have
MATERIALS
effects
is high.
for clinical
patients.
These
restrictions
stability
of the patients
and/or occasionally
INTRODUCTION
clinical
green
beverages
evaluations
drinking
admin-
combination
Furthermore,
encourage
the quality
studied
to Japanese
common
China
for a long time. Some
reported
to have useful effects
chemotherapy
Frequently,
oral
the
observed
cancer
on Ehr-
ment of antitumor
activity of doxorubicm
induced by green
tea was observed
in M5076 ovarian sarcoma,
which has low
sensitivity
to doxorubicin.
These results suggest that drinking
our attention
of the
in these
tea
the inhibitory
In contrast,
concentration
after
on
The doxorubicin
increased
doxorubicin.
and
We carried
2.5-fold
di-
beverages
mice.
growth.
role
have
tea components
and
tumor-bearing
tea enhanced
with
doxorubicin
sues
of doxorubicin.
on tumor
We
of common
tea and
of doxorubicin
carcinoma
of doxorubicin
an important
chemotherapy.
of green
treatment
tration
one
interest
153
Research
carcinogenesis
and is known
to be effective
for the chemoprevention
of cancer
(8, 9). However,
the effects
of green tea on
ABSTRACT
istration
directed
sinensis),
popular
in Japan
components
have
Cancer
Tea’
We have
mellia
of Pharmaceutical
lich
by Green
and
Hirota
School
422,
Clinical
of
Shizuoka
3
The
abbreviation
used
is: DOX,
doxorubicin.
Downloaded from clincancerres.aacrjournals.org on May 14, 2017. © 1998 American Association for Cancer
Research.
154
Green Tea
Enhances
Cancer
Chemotherapy
120
100
100
80
80
,.
E
60
60
.
C)
a)
40
-S
0
E
0
20
F-
20
0
0
Control
p.
DOX
0
o.
i.
p.
+
Caffeine
DOX
.
DOX #{247}
Green
Tea
DOX
Theanine
+
DOX
.
DOX
p.
Green
+
Tea
DOX
+
p.
i.
0.
DOX
Theanine
Caffeine
+
Fig. I Effects
of green tea and tea components
on the changes
in tumor
weight
(Ehrlich)
induced
by DOX.
Each column
is the mean of eight
mice expressed
as percentage
of control
level;
bars,
SD. Significant
differences
from the level of the DOX-alone
group are indicated
by: a)
P < 0.001;
b) P < 0.01; and c) P < 0.05.
Fig. 2 Effects of test drug on the DOX concentration
in the tumors of
mice.
Each
point
is the mean
of eight
mice;
bars,
SD. Significant
difference
from the level of the DOX-alone
group
is indicated
by: a)
P < 0.001.
(100
DOX
mg/kg/day
13th,
15th,
days)
of tea
mice
were
tissues
for
and
killed
of 10 mM
or
on
the
18th
and
the
the
the
1 lth,
mg/kg/day
for
same
solid
day.
4
(pH
7.8);
ovarian
sarcoma
planted
onto
the backs
4 days)
was
i.p.
days
after
the
x
(1
of BDF1
administered
theanine
and
(P
tumors
then
DOX
was
(w/v)
106 cells/animal)
14th,
Green
18th,
powder
mg/kg/day
mg/kg/day
16th,
(100
20th
were
p.o.
weighed.
bearing
Mice.
jection
of DOX
with the control
with
DOX
0.05)
and
of
Green
Activity
Tea
and
of DOX
Tea
Components
in Ehrlich
Ascites
on
the
Carcinoma
growth.
enhanced
antitumor
difference
from
istration
ity
of
treatment
tumor
The
by
DOX
to 37%
the DOX
of theanine
DOX
of DOX
weight
alone
and
group,
caffeine
(P
2.1-fold
<
concentrations
and
green
tea
of control
P
enhanced
0.01)
and
in the tumors
<
significantly
level
0.001).
the
(significant
Oral
1.9-fold,
<
0.001).
caffeine
Similarly,
increased
the
oral
DOX
administration
concentration
of
by
in Fig.
theanine
2.2-fold
2.
Table
DOX
1 . Green
concentrations
tea,
theanine,
in the heart
and
caffeine
and liver
(P
are shown
in combination
of
in the heart
Theamne
on the
Ovarian
Sarcoma
the tumor
of control
of green
to 37%
2.5-fold
evidence
and
Antitumor
Tumor-
weight
3. The incompared
combined
to 55%
(P
<
level.
tea was
of the control
level
the DOX
inhibitory
provides
activity
were
tumor
was
indicated
to
be
green
tea or tea components
with
alone
group.
of DOX
with
regarded
as the
activity,
induced
ous
reports
(13,
direct
14),
cause
by green
we
the
tea acts
have
of
as
effect
DOX
by
DOX
i.p.
Thus,
proof the
and
oral
theanine
biochemical
of
green
as the
in
combination
of
the
compared
with
enhancement
that
the DOX
in the tumor
of
tea or tea components.
confirmed
tea
concentration
concentration
the
as
tea
in the tumor,
The
increased
<
mor
DOX.
concentration
and
was
green
effective
tissues.
significantly
tea causes
the
of green tea is
by the
with
that
components.
the DOX
increment
that
observed
or caffeine
and in normal
This
DOX
and significantly
effect
on tumor
may expect
that green
Similarly,
the enhancement
it is suggested
was
with
Tumor
growth
of DOX
alone
green
effect
the possibility
of DOX
and
tissue,
that drinking
agents. This
We
of theanine
depends
on these
We determined
the
in
combined
by 25% compared
with the control
of green tea remarkably
reduced
the
modulator.
chemotherapy.
caffeine
targeted
0.001).
The
reduced
(P < 0.01)
administration
modulators,
Green
tea combined
with DOX increased
the DOX concentration in the tumor by 1.7-fold
compared
to the DOX-alone
group
(P
significantly
37%
a biochemical
motes cancer
and
activ-
respectively.
are shown
concentrations
Tumor
weights
are shown
in Fig.
alone did not reduce the tumor weight
level, whereas
green tea and theanine
administration
admin-
antitumor
and
M5076
This result indicates
activity
of antitumor
g).
the
in
decreased
the tumor weight
level, whereas
the addition
new
combined
and
combination
treatment
on Ehrlich
solid tumor-bearing
mice.
was inhibited
by DOX,
and the administration
Tumor-bearing
Mice.
Tumor
weights
after
treatment
are
shown
in Fig. 1 . The injection
of DOX alone reduced
the tumor
weight
by 25% compared
with the control
level (0.675
± 0.108
The
Tea
DOX
tumor
weight
enhanced
by
RESULTS
reduced
of Green
of
Oral
on the 15th, 17th, 19th, and 21st day. The mice
on the 22nd day, and solid tumors
were rapidly
Effects
the DOX
the
DISCUSSION
administered
were killed
Antitumor
in the heart
particular,
0.05).
<
mg/kg/day
for 4 days)
reduced
concentration
In
for
and
and
and
(10
tea
(2.0
trans-
for 4 days)
removed
theanine
DOX
the
were
mice.
and DOX
Activity
extracted
the DOX
tumor-bearing
Effects
in 10 volumes
mice.
on
transplantation.
of
The
by chboroform:methanol
(4: 1 , v/v). The DOX concentration
was
determined
with
fluorescence
spectrophotometer
(excitation
wavelength,
470 nm; emission
wavelength,
585 nm).
M5076
did not increase
liver
weighed.
homogenized
buffer
on
(10
on
day,
and
were
phosphate
administered
injections
performed
removed
samples
p.o.
i.p.
were
rapidly
tissue
was
days,
components
were
The
4 days)
17th
antitu-
In previtheanine
Downloaded from clincancerres.aacrjournals.org on May 14, 2017. © 1998 American Association for Cancer
Research.
and
Clinical
Table
Doxorubicin
1
con centration
Group
Each
a
(ng/g
tissue)”
Heart
alone
+ green
tea
+ theanine
+ caffeine
value
464
376
224
456
I 12
± 144
702
618
658
716
±
±
69h
±
±
232
±
166
P
from
the
.
C)
± 65
,T
60
a)
a)
22
±
mice.
level
of the
DOX
alone
40
E
group:
F-
0.05.
<
b)
80
0
difference
155
100
Liver
152
± SD of eight
is the mean
b Significant
Research
in the heart and liver of mice
DOX
DOX
DOX
DOX
DOX
Cancer
20
0
caffeine
then
inhibit
the DOX
increase
causing
the
the
enhanced
the
antitumor
increased
increment
in normal
in
by green
The
vivo.
dependent
concentration
on
in the
components
in green
of DOX as well.
concentration
tea,
was
theanine,
of DOX
due
in the
tumor
centration
to specifically
trations
in
reduced
by the combination
suggest
that
the point
normal
only.
green
tea
of drug
Cardiac
reported
heart
tissues
(12,
associated
reduce
hand,
the
side
18).
severe
by the
heart
Because
green
catechins
effect
tea
has
19-21),
(5,
of a decrease
and
in the past
side
study
effects
can
beneficial
effects
of antitumor
in consideration
an
ideal
combination
that
data
apy.
In
green
is
antioxidative
expect
peroxide
level
modulation
that
in the
were
not per-
the antitumor
effects
green
tea described
in this
the antitumor
of drinking
in the
Thus, we can expect
toxicity
induced
by
modulator
green
and
of both
whereas
Because
of DOX
because
activity
and side
tea is a common
tea
with
effects
chemotherapy
is
easy to try for humans
in clinical
treatment.
We expect
that
cancer
chemotherapy
with the addition
of green tea will induce
a positive
effect.
Furthermore,
tea,
we examined
which
has
M5076
tumor
DOX
effects
sensitivity
growth
alone.
theanine,
55%
low
to investigate
these
with
of control
DOX
level.
the
broad
on M5076
to DOX.
was
In contrast,
not observed
Thus,
The
results
of green
sarcoma
inhibitory
effect
of green
the tumor
against
to Ehrlich
which
DOX
ascites
was
not
carcinoma.
effective,
On the M5076
an antitumor
green
a meal.
Green
chemotherapy.
favors
a patient’s
efficiency
the
appears
demonstrated
physiological
of
effects
in clinical
drinking
as
influences
on cancer
beverage
attitude
and
a
treatment
green tea
of a favorite
encourages
the
and that this efficacy
of life in cancer
important
to
effects
intake
index,
the quality
chemother-
positive
mental
of the chemotheraputic
discovery
in the field
is
chemotherapy.
of study
of bio-
modulation.
The
fact
moprevention
may
this
study
the
future.
drink
have
that
positive
in improving
This
will
think
of
suggest
the side
as well. For patients
it is easy to suggest
tea may
We
was
to reduce
tea has
results
on cancer
tea
and
tumors
green
but
also
We
green
tea is useful
news
be helpful
hope
that
clinicians
to these
only
the
for clinical
to promote
tea, according
more
not
for encouraging
be good
may
be
that
the
patients.
cancer
che-
of chemoThe
eradication
encourage
results,
for
efficacy
their
results
of
of cancer
in
patients
to
so that cancer
therapy
successful.
I. Konishi,
T.,
and
Dezuki,
Y.
Biochemical
modulation.
CRC
Crit.
of
2. Hidalgo,
0. F., Gonzalez,
F., Gil, A., Campbell,
W., Barrajon,
E. and
Lacave,
A. J. I 20 hours simultaneous
infusion
of cisplatin
and fluorouracil in metastatic
breast
cancer.
Am. J. Clin.
Oncol.,
12: 397-401,
1989.
weight
as
to
that green
tumor,
effect
that
These
without
similar
tea against
effect
green
activity
tea,
expect
Rev.,
tea enhanced
the antitumor
activity
of DOX
against
M5076
tumor,
indicating
that the effects
of green tea as a modulator
are
not specific
found
important
biochemical
modulator
with antitumor
agents,
with
by green
tumors.
drinking
green
may
on
tea, as well
demonstrate
study,
of
we
REFERENCES
(22),
by the administration
decreased
these
usefulness
ovarian
the combination
significantly
We
addition
Therefore,
effects
the antitumor
DOX.
the
DOX.
or drug-resistant
this
therapy
beverage,
of
tea has a very
chemical
it has
with
dose
of antitumor
green
from
peroxide
could
observed
the
useful
biochemical
on both
agents.
was
enhancement
were
These
some
we
in the lipid
of a drug,
be
DOX
elevating
bow sensitivity
concen-
of DOX
of lipid
as well as the DOX concentration.
Many studies
about biochemical
formed
con-
effects
DOX.
effects
side
elevation
+
Fig. 3 Effects
of green
tea and theanine
on the changes
in tumor
weight
(M5076)
induced
by DOX.
Each column
is the mean
of eight
mice expressed
as percentage
of control
level;
bars,
SD. Significant
differences
from the level of the DOX-alone
group are indicated
by: a)
P < 0.01; and b) P < 0.05.
enhance
is very
e.g.,
because
DOX
DOX
side
tea with
green tea reduces
the lipid peroxide
level.
that drinking
green tea reduces
the cardiac
DOX
the
with
of green
may
toxicity
17,
other
Tea
not
distribution.
to be caused
components,
the
DOX
Theanine
i-
or caffeine.
increasing
On
DOX
Green
thereby
in
mainly
DOX
DOX
and
vitro
tumor,
tea and theanine
decreased
the DOX concentration
in the
Thus,
green
tea was shown
to enhance
the antitumor
activity
the
the
activity
in DOX
tissues
cells
in
it is possible
that other
on the antitumor
effect
In contrast,
Green
heart.
Ehrlich
tea is considered
that
tumor.
However,
tea have efficacy
observed
of
by green
components
from
concentration
enhancement
effect
these
efflux
DOX
of
1: 88-97,
1992.
3. Bertino,
J. R., Sawicki,
W. L., Lindquist,
C. A.,
Schedule
dependent
antitumor
effects
of methotrexate
cil. Cancer
Res., 37: 327-328,
1977.
4. Bud,
Rinvkin,
G. 1., Fleming,
R. M.,
S. E. 5-Fluorouracil
and Gupta,
V. S.
and 5-fluoroura-
Bukowski,
R. M., McCracken,
J. D., and
and folinic
acid
in the treatment
of
Downloaded from clincancerres.aacrjournals.org on May 14, 2017. © 1998 American Association for Cancer
Research.
156
Green Tea Enhances
advanced
Oncology
Cancer
Chemotherapy
14. Sadzuka,
Y., Sugiyama,
T., Miyagishima,
A., Nozawa,
Y., and
Hirota, S. The effects of theanine, as a novel biochemical
modulator,
on
the antitumor activity of Adriamycin.
Cancer Lets., 105: 203-209,
1996.
coborectal
cancer: a randomized
comparison.
A Southwest
Group Study. J. Clin. Oncob., 5: 272-277,
1987.
S. Graham,
H.
N. Green
tea
composition,
and
polyphenol
chemistry.
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Modulation of cancer chemotherapy by green tea.
Y Sadzuka, T Sugiyama and S Hirota
Clin Cancer Res 1998;4:153-156.
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