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Antimicrobial Agents and Chemotherapy, January 1999, p. 67-72, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Therapeutic Effect of Clarithromycin on a
Transplanted Tumor in Rats
Kazuhiko
Sassa,1
Yutaka
Mizushima,1,2,*
Takashi
Fujishita,1
Rokuo
Oosaki,1 and
Masashi
Kobayashi1
First Department of Internal Medicine, Toyama
Medical and Pharmaceutical University, Toyama
930-0152,1 and
Department of Geriatrics,
Hirosaki University, School of Medicine, Hirosaki
036-8562,2 Japan
Received 18 May 1998/Returned for modification 9 July 1998/Accepted 20 October 1998
 |
ABSTRACT |
The therapeutic antitumor effect of clarithromycin (CAM) was
examined with the 13762NF mammary adenocarcinoma and F-344 rat system.
When CAM treatment at a dosage of 2 mg/kg of body weight orally for 21 days was commenced after inoculation of the tumor, no significant
decrease in death rate was observed, although the loss in body weight
was less than that in the untreated group. When tumor-bearing (TB) rats
were treated with CAM in combination with carboplatin or
cyclophosphamide, a significant decrease in the death rate was
obtained, although neither treatment alone proved to be effective. A
beneficial effect was also observed when CAM treatment was combined
with surgical treatment. CAM showed no direct cytotoxicity to this
tumor in vitro according to the MTT
(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay.
Spleen cells obtained from TB rats receiving CAM treatment showed a
stronger tumor-neutralizing activity than those from rats which had not
received CAM treatment (Winn assay). Enhanced induction of cytotoxic
cells to allogeneic tumor was also observed in rats immunized with
allogeneic tumor cells together with CAM treatment (51Cr
release assay). The 13762NF tumor produces transforming growth factor-
(TGF-), tumor necrosis factor alpha, and matrix
metalloproteinase-9, and treatment of tumor cells with CAM in vitro for
24 h significantly inhibited the expression of the genes coding
for these proteins (reverse transcription-PCR). Levels of expression of
the TGF- and interleukin-6 genes of spleen cells obtained from
CAM-treated TB rats were both significantly lower than those of spleen
cells from CAM-untreated TB rats. This study suggests that CAM has
biological response modifier activities resulting in a beneficial
therapeutic antitumor effect and might be useful for the treatment of
human cancers.
| |
INTRODUCTION |
Recently, the biological response
modifier (BRM) activities of antimicrobial agents have become a matter
of growing concern in the medical field (5, 7, 21). In
Japan, Kudoh et al. (15) first reported in 1987 that
low-dose long-term treatment with erythromycin (EM) was effective for
diffuse panbronchiolitis. Pseudomonas aeruginosa is not
sensitive to EM in vitro, so activities other than an antimicrobial one
were indicated. Because of this fact, many investigators have taken
interest in the BRM activities of macrolides, and so far, a variety of
macrolide activities have been reported: e.g., reduction of bronchial
hyperresponsiveness in asthmatics (17); inhibition of
neutrophil chemotaxis or neutrophil-derived elastolyte-like
(9) or NADPH oxidase activity (27);
modulation of production various cytokines, such as interleukin-1
(IL-1) (10, 13, 26), IL-2 (13), IL-6
(2), IL-8 (21), and tumor necrosis factor alpha
(TNF-
) (13); inhibition of biofilm formation
(18); and other miscellaneous activities (1, 11, 19). Besides the activities mentioned above, Mikasa et al.
(16) have recently reported that long-term treatment with
clarithromycin (CAM) was effective for non-small cell lung cancer in
which surgical resection was not indicated. Together with results in
humans, Mikasa's group has also demonstrated antitumor activity of EM in vivo in mouse tumor systems (6), and antiangiogenesis
activity of CAM has been found in vitro (22). If macrolide
treatment is found to be truly effective for patients with advanced
stages of cancer, it would be greatly beneficial in the management of such patients. Thus, to confirm the beneficial effect of CAM reportedly found in patients with lung cancer, we carried out some animal studies
with a rat tumor. We report here that CAM has BRM activities which may
be of great benefit to patients with cancer.
| |
MATERIALS AND METHODS |
Animals.
Male F-344 rats were purchased from the SLC Co.
Ltd., Shizuoka, Japan. The experimental rats were 12 to 14 weeks old,
weighed 230 to 250 g, and were kept in a clean room. The
experimental designs used in this study were approved by the ethical
committee of Toyama Medical and Pharmaceutical University.
Tumor.
The 13762NF (subclone MTLn3) mammary adenocarcinoma
(20), originating from an F-344 rat, was kindly given by
G. L. Nicolson and was maintained in vitro and in vivo. The E4
mammary adenocarcinoma cell line, originating from an SD rat, was
obtained from the Japanese Cancer Research Resources Bank (Tokyo,
Japan). Cultured cells were maintained in RPMI 1640 medium containing
10% fetal calf serum.
Anticancer drugs and CAM.
Cyclophosphamide (CY) was
administered at 60 mg/kg intravenously (i.v.) through the tail vein,
and carboplatin (CBDCA) was given at 50 mg/kg of body weight
intraperitoneally (i.p.). Clarithromycin (CAM) (Abbot Co., Ltd., North
Chicago, Ill.) was dissolved in tap water and administered orally (p.o.
[per os]) once a day by means of a gastric tube. The molecular
formula of CAM is C38H69NO13, and
the molecular weight is 747.96.
Experimental therapy.
13762NF tumor cells (2 × 106) were inoculated subcutaneously (s.c.) into the right
flank of the F-344 rat on day 0. Tumor size (millimeters) was expressed
as (short diameter + long diameter)/2. Animals without a tumor or
animals with a regressing tumor on day 50 after tumor inoculation were
judged to be cured. In most experiments, all animals judged to be cured
survived for more than 90 days.
Tumor-neutralizing assay.
A modified version of the Winn
assay (34) was carried out. The mixture of spleen cells
(80 × 106) and tumor cells (1 × 106) was inoculated s.c. into syngeneic rats which had been
irradiated (2.5 Gy) 24 h before inoculation. The
tumor-neutralizing activity of the spleen cells was evaluated by
measuring the tumor weight at appropriate points after inoculation.
51Cr release assay.
A mixture of
51Cr-labeled tumor cells (2 × 105) and
spleen cells (5 × 106 to 10 × 106)
was centrifuged at 500 rpm for 5 min, and then the cells were incubated
in a culture medium at 37°C in a 5% CO2 atmosphere for 5 h. The amount of release at the end of the incubation period was
measured, and the percentage of cytolysis was calculated by the formula
% cytolysis = [(test release 
spontaneous
release)/(maximum release spontaneous release)] × 100.
MTT assay.
The MTT
(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay
was performed according to the method used in our previous report
(23). Briefly, tumor cells (1 × 103 to
4 × 103) were seeded in 96-well flat-bottom plates
(Falcon 3072) and cultured in the presence or absence of a drug for 3 days, and 20 µl of MTT (5 mg/ml) was added to each well 4 h
before termination of incubation. Following this, the medium in the
wells was removed, 200 µl of dimethyl sulfoxide was added, and
activity was then measured by a spectrophotometer at 560 nm.
Expression of the TGF-, IL-6, TNF-, and MMP-9 genes.
Expression of genes was measured by the reverse
transcription-polymerase chain reaction (RT-PCR) method. Total RNA was
isolated from the spleen cells or tumor cells by the ISOGEN method
(3) and was reverse transcribed with random hexamers by
using an RNA-PCR kit (Takara, Tokyo, Japan). cDNA was amplified by the
PCR method, and the PCR products were separated on 1.5% agarose gels
and stained with ethidium bromide. The primers used for the
amplification of the transforming growth factor- (TGF-) gene,
IL-6 gene, TNF- gene, or matrix metalloproteinase-9 (MMP-9) gene
were as follows: TGF- gene, 5'-GCCCTGGACACCTATTGC-3' and
5'-GCTGCACTTGCAGGAGCGCAC-3'; IL-6 gene,
5'-ATGTAGCCGCCCCACACAGA-3' and
5'-CATCCATCTTTTTCAGCCAT-3'; TNF- gene,
5'-CAAGGAGGAGTTCCCAA-3' and 5'-GAATCTGTAGTGCCTCAGGC-3'; and MMP-9 gene, 5'-GGTCCCCCCACTGCTGGCCCTTCTACGGCC-3'
and 5'-GTCCTCAGGGCACTGGAGGATGTCATAGGT-3'. As an
internal control, a set of primers for the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene (5'-CAAAAGGGTCATCTCTG-3' and
5'-CCTGCTTCACCACCTTCTTG-3') were added to each sample. The
degree of gene expression was expressed as a ratio of TGF- (IL-6,
TNF-, or MMP-9) to GAPDH as determined with a densitometer.
Statistical analysis.
Data are shown as means ± standard errors, and statistical significance was evaluated by the
Student's t test or Fisher's exact probability test. A
P value of <0.05 was judged to be significant.
| |
RESULTS |
Effect of treatment with CAM alone on the growth of the 13762NF
tumor in F-344 rats.
In order to know the effect of CAM treatment
alone on the growth of a transplanted 13762NF tumor in F-344 rats, the
following protocol was carried out. First, different doses of CAM were
administered p.o. once a day for 21 days from day 8 to day 28. As shown
in experiment 1 of Table 1, no
significant differences in survival rate on day 50 were observed for
all doses employed (0.5 to 32 mg/kg). Second, timing of administration
was examined at a CAM dosage of 2 mg/kg. As shown in experiment 2 of
Table 1, the survival rate on day 50 increased from 0% to 33% when
CAM was commenced on day 1 and to 42% when CAM was commenced 5 days
before inoculation of the tumor cells. Cured rats rejected
reinoculation of the identical tumor (5 × 106 cells
s.c.) (data not shown).
When tumor cells were inoculated s.c. into rats, animals lost weight
gradually starting a week later. However, in the group receiving CAM
treatment (2 mg/kg p.o. from days 8 to 28), the degree of loss was
significantly smaller than that for the untreated group, although there
was no significant difference in tumor sizes between the two groups
(Fig. 1).
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FIG. 1.
Changes in body weight (BW) after tumor inoculation.
Tumor cells (2 × 106) were administered s.c. on day
0. CAM (2 mg/kg) was administered p.o. for 21 days from day 8 to day
28. The summarized results of four independent experiments are shown.
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|
Effect of combined treatments with a chemotherapeutic agent and CAM
or surgery and CAM on the growth of the 13762NF tumor in rats.
The
therapeutic effect of CAM alone was not found to be strong enough, so
we examined the combined effect of a chemotherapeutic agent and CAM on
the growth of the 13762NF tumor in rats (Table 2). When 60 mg of CY or 50 mg of CBDCA
per kg of body weight was combined with CAM, the survival rate
significantly increased. We then examined the combined effect of
surgical resection and CAM on the death rate. In experiment 1, surgical
resection was performed on day 18 and CAM was administered for 21 days
from day 23 to day 43. For the surgery-alone group, 3 animals died because of a local recurrence, and 13 of 17 (76%) died because of
metastases to the lung (Table 3).
Conversely, in the surgery and CAM group, one animal died from surgery,
and only 6 of 19 (32%) died because of metastases (P < 0.05). In experiment 2, surgery was carried out at an earlier date
(on day 15) to reduce the local recurrence rate, and CAM was
administered for 14 days from day 1 to day 14. In the surgery-alone
group, 4 animals died because of local recurrence, and 6 of 13 (46%)
died because of metastases. Conversely, in the surgery and CAM group, 1 animal died because of surgery, and none of the 16 (0%) died because of metastases (P < 0.05).
Studies of mechanisms of the therapeutic effect of CAM treatment.
(i) Direct cytotoxicity to tumor cells in vitro.
Whether CAM shows
any direct cytotoxicity to 13762NF cells was examined in vitro with the
MTT assay. No significant cytotoxicity was observed with 0.5 to 50 µg
(0.67 to 67 µM) of CAM per ml. CBDCA (1 to 100 µg/ml [2.67 to 267 µM]) as a positive control showed a significant cytotoxicity to this
tumor (data not shown).
(ii) Antitumor cellular immunity.
Antitumor cellular immunity
of the hosts was examined by the in vivo tumor-neutralizing assay by
using spleen cells. As shown in Table 4,
only spleen cells obtained from tumor-bearing (TB) rats which had
received CAM treatment showed detectable tumor-neutralizing activity.
There were no significant differences between the TB plus CAM and TB
groups or between the non-TB plus CAM and non-TB groups.
(iii) Effect of CAM on expression of the TGF-, IL-6, TNF-,
and MMP-9 genes.
The tumor used in this study has been proved to
produce TGF- and MMP-9 (25), which are well known to have
a variety of activities concerning immunosuppression or metastasis
(29, 30, 33). To know the effect of CAM on the production of
TGF-, MMP-9, or TNF- from the tumor cells, we examined the
expression of the genes coding for these proteins by the RT-PCR method.
Tumor cells incubated with CAM in vitro for 24 h were used for the
experiment. Expression of the TGF-, MMP-9, and TNF- genes was
significantly inhibited by the treatment with CAM at low concentrations
(Fig. 2). Inhibition of MMP-9 activity
could be confirmed by zymography (8) using 7.5%
polyacrylamide gels with 1.5 mg of type IV collagen-derived gelatin per
ml embedded in them (data not shown).
We then examined the expression of the TGF-
gene of spleen cells
obtained from TB rats. CAM (2 mg/kg p.o.) treatment was
commenced on
day 8 after tumor inoculation, and spleens were removed
on days 18 (10 days of CAM treatment) and 28 (20 days of CAM treatment).
The level of
expression of the TGF-
gene on days 18 and 28 was
lower in the
CAM-treated TB group than that in the CAM-untreated
TB group, but a
statistical difference was only observed for the
20-day CAM treatment
group (Fig.
3A). As shown in Fig.
1, CAM
treatment prevented TB rats from losing body weight. Therefore,
we also
examined the effect of in vivo treatment with CAM on the
expression of
the IL-6 gene of spleen cells by RT-PCR. As shown
in Fig.
3B, the level
of expression of the IL-6 gene of spleen
cells on days 18 and 28 was
significantly lower in the CAM-treated
TB group than in the untreated
TB group. The levels of IL-6 in
serum in TB rats were all below the
detection level of the kit
(data not shown).
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FIG. 3.
Effect of in vivo treatment with CAM on expression of
the TGF- (A) and IL-6 (B) genes of spleen cells. Tumor cells were
administered s.c. on day 0. CAM (2 mg/kg) was administered p.o. on days
8 to 17 and on days 8 to 27. Spleens were removed on day 8 or 28 for
the assay. An asterisk indicates statistical significance versus the
untreated samples. NS, not significant.
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|
(iv) Effect of CAM on the induction of cytotoxic cells to the
allogeneic tumor.
The effect of CAM treatment on the induction of
cytotoxic cells to allogeneic (SD rat) E4 tumor was examined by the
51Cr release assay. F-344 rats were immunized with viable
E4 tumor cells twice on days 0 (3 × 107 cells s.c.)
and 9 (3 × 107 cells i.p.), followed by CAM treatment
(2 mg/kg p.o.) on days 1 to 14. The assay was performed twice on days
12 and 15 (Table 5). Under this
condition, only spleen cells obtained from rats which had been
immunized with E4 cells followed by CAM treatment showed a detectable
cytotoxicity to E4 tumor cells.
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TABLE 5.
Cytotoxic activity of spleen cells obtained from rats
immunized with allogeneic E4 tumor cells followed by CAM
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| |
DISCUSSION |
We have shown in this study that CAM has BRM activities resulting
in a beneficial therapeutic effect on a transplanted tumor in rats. A
sufficiently good therapeutic effect could not be obtained by CAM
treatment alone, but was observed when CAM was combined with
chemotherapy or surgery. Concerning the therapeutic antitumor effect of
macrolides, Hamada et al. (6) first reported that EM was
effective for prolonging the survival time in Ehrlich ascites carcinoma-ddY and P388 leukemia-CDF1 mouse systems. Our
results and their results seem to support the finding by Mikasa et al. (16) that long-term treatment with CAM prolonged the
survival of patients with advanced non-small cell lung cancer. A
particularly interesting finding was that CAM treatment could reduce
the death rate due to metastasis (Table 3). CAM treatment was found to be effective when it was administered either before or after surgery. At the time surgical resection of a primary tumor was undertaken, the
micrometastases mainly to the lung had already occurred in our system.
Control of micrometastasis is very important in the treatment of cancer
patients, and a BRM having such an activity has been greatly desired.
CAM may become a candidate for BRM to control micrometastasis.
What are the mechanisms for the beneficial therapeutic effect of CAM?
CAM showed no cytotoxicity to 13762NF tumor cells in vitro, so a direct
cytotoxic effect of CAM seems unlikely. We showed by the Winn assay
that the therapeutic antitumor effect of CAM might be partly due to the
enhanced antitumor immunity. CAM was found to have an activity which
inhibited the tumor cells and spleen cells from producing TGF-,
which has immunosuppressive activity (24, 25). When the
14C-labelled CAM (2 mg/kg) was administered once orally to
normal rats, concentrations in various tissues peaked 1 h after
administration. The peak concentrations of CAM were as follows: liver,
6.84 ± 1.18 µg/g; lung, 5.28 ± 0.29 µg/g; spleen,
3.11 ± 0.19 µg/g; and blood, 0.18 ± 0.01 µg/ml. We have
no data concerning the concentrations of CAM in tumor tissues when it
is administered repeatedly. However, concentrations of CAM employed for
the in vitro experiments of at least 0.5, 1.0, or 5.0 µg/ml would
reflect the in vivo situation. Therefore, we speculate that the
enhancement of antitumor immunity may be caused in part by the
inhibition of the immunosuppressive factor TGF-. In Hamadas' tumor
system (6), IL-4 levels in serum were found to be
significantly high in TB mice receiving EM, and the antitumor effect
was abolished by in vivo treatment with the anti-IL-4 antibody; in
their experiment, neither the anti-TNF- antibody nor the
anti-IFN-
antibody affected it. They speculated that enhanced
tumoricidal activity of macrophages induced by EM treatment via the
stimulation of IL-4 production might be responsible for the beneficial
therapeutic effect of EM. We have not yet examined this possibility in
our rat system. Concerning the inhibition of micrometastasis by CAM
treatment (Table 3), there are several possible mechanisms. Welch et
al. (28) have reported that TGF- has an activity that
stimulates the invasiveness and metastatic potential of tumor cells,
and Nakajima et al. (20) showed the close association
between the production of MMP-9 and the metastatic potential of tumor
cells. The 13762NF tumor we used in this study could produce a large
amount of MMP-9, and CAM could inhibit the production of MMP-9 as well
as TGF- from this tumor. Besides the possibilities mentioned above,
Sawaki et al. (22) have reported that CAM has an
antiangiogenesis activity in vitro via the inhibition of IL-8
production. This activity of CAM is very interesting, but we have not
yet studied this possibility.
It is of interest to note that CAM treatment reduced loss of body
weight in TB rats (Fig. 1). TNF- (4), IL-1, and IL-6 (12) have been reported as factors that induce cachexia.
Expression of the TNF- gene of tumor cells was shown to be inhibited
by in vitro treatment with CAM dose dependently (Fig. 2), and
expression of the IL-6 gene of spleen cells obtained from CAM-treated
TB rats was found to be significantly lower than that of spleen cells from untreated TB rats (Fig. 3B). We suppose that inhibition of the
production of cachexia-inducing factors may also contribute to some
extent to the therapeutic effect of CAM treatment.
As Mikasa et al. (16) have already reported, CAM treatment
was effective for non-small cell lung cancer. However, as they showed,
CAM was not effective for small cell lung cancer. There is no agent
that is effective for all types of cancer, so we should define for
which type of cancer the macrolide is specifically effective. EM and
CAM belong to 14-member ring macrolides, but there remains the question
of the 15- or 16-member ring macrolides. More study will be required to
define the applicability of macrolides as a BRM in cancer treatment.
| |
ACKNOWLEDGMENT |
We are grateful to Motowo Nakajima (Novartis Pharma Co. Ltd.,
Tokyo, Japan) for his kind advice.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Geriatrics, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan. Phone: 81-172-39-5345. Fax: 81-172-39-5346.
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Antimicrobial Agents and Chemotherapy, January 1999, p. 67-72, Vol. 43, No. 1
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Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
