The present invention provides an agent for alleviating side effects caused by use of an anti-tumor agent, which contains 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H-pyrimidi nedione (1) represented by formula (1):
##STR00001##
or a pharmaceutically acceptable salt thereof. The 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione or a pharmaceutically acceptable salt thereof exhibit an inflammatory-suppressing action in the digestive tract and advantageously alleviate diarrhea and loss of body weight concomitant with administration of a chemical for treating cancer without suppressing the anti-tumor effect. Thus, the compounds of the present invention are of great value as agents for alleviating side effects caused by use of an anti-tumor agent, which enable not only the chemotherapy to be continuedly carried out, but also the body exhaustion to be effectively prevented.
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1. A method for alleviating side effects caused by use of an anti-tumor agent selected from the group consisting of an alkylating agent, a plant-derived compound, an antibiotic, or a platinum containing agent comprising administering 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione represented by formula (1):
##STR00003##
or a pharmaceutically acceptable salt thereof to a patient to whom an the anti-tumor agent has been administered.
2. A method according to
0. 3. A method according to
4. A method according to
0. 5. The method of claim 4, wherein the anti-tumor agent is irinotecan hydrochloride.
0. 6. The method of claim 4, wherein the anti-tumor agent is cisplatin.
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This application is a
TABLE 1
Compounds
No. of
Body weight
Suppression
(dose, mg/kg)
animals
change (g)
ratio (%)
Control
8
29.3 ± 3.7
5-FU(20)
8
15.6 ± 3.6**
46.7
5-FU(20) +
8
23.3 ± 4.8*##
20.7
Compound 1(100)
CDDP(1.0)
8
11.9 ± 5.4**
59.4
CDDP(1.0) +
8
17.3 ± 5.7**#
41.1
Compound 1 (100)
Suppression of body weight increase was confirmed in the rats in the anti-tumor-agent-administration alone groups, in which 5-FU in an amount of 20 mg/kg/day or CDDP in an amount of 1.0 mg/kg/day was administered to each rat for 4 consecutive days. It became apparent that suppression of body weight increase due to the anti-tumor agent was alleviated when Compound 1 was administered in an amount of 100 mg/kg/day in combination with the anti-tumor agent. Moreover, it was confirmed that the occurrence of diarrhea as observed in the combination-administration groups was lower than that of diarrhea as observed in the anti-tumor-agent-administration alone groups.
(a) Preparation of Test Solution—I:
Irinotecan hydrochloride (hereinafter referred to as “CPT-11”; KAMPTO Injection 100 mg/5 ml; product of Yakult Co., Ltd.) was diluted with saline so as to obtain a 6 mg/ml solution for administration at 60 mg/kg/day.
(b) Preparation of Test Solution—II:
Compound 1 was suspended in a 0.5% hydroxypropylmethyl cellulose solution (hereinafter referred to as “0.5% HPMC”) so as to obtain a 3 mg/ml suspension, and the suspension was stirred by use of a stirrer for about 20 minutes at room temperature. The suspension was subjected to ultrasound treatment for 5 minutes while being cooled with ice, to thereby obtain a test solution containing Compound 1 for administration at 30 mg/kg/day.
(c) Test:
Five-week-old Donryu male rats were divided into a control group and treatment groups so that the average body weights of the groups and the standard deviations (S.D.) of the groups were made to be as close to one another as possible. To each rat of the anti-tumor-agent treatment alone groups, the CPT-11 solution was intravenously administered once a day for five consecutive days at a daily dose of 1.0 ml per 100 g of body weight. Simultaneously, a 0.5% HPMC solution was orally administered once a day for five consecutive days at a daily dose of 1.0 ml per 100 g of body weight. To each rat of the combination-administration treatment groups, the CPT-11 solution was intravenously administered once a day for five consecutive days at a daily dose of 1.0 ml per 100 g of body weight. Simultaneously, to each rat of the combination-administration groups, the solution of Compound 1 was orally administered once a day for five consecutive days at a daily dose of 1.0 ml per 100 g of body weight. To each rat of the control group, saline was intravenously administered for five consecutive days at a daily dose of 1.0 ml per 100 g of body weight. Simultaneously, a 0.5% HPMC solution was orally administered for five consecutive days at a daily dose of 1.0 ml per 100 g of body weight. Prior to each administration, the stool and anal fecal matter of each rat were observed in order to check the occurrence of diarrhea. The number of rats which had diarrhea at least once during the test period were counted as “diarrhea-rats”. The accumulated occurrence of diarrhea was calculated by use of the following equation:
accumulated occurrence of diarrhea (%)=(the number of rats which had diarrhea/the total number of rats)×100
As shown in
(a) Preparation of Test Solution—I:
CDDP was suspended in saline so as to obtain a 0.6 mg/ml suspension, and the suspension was stirred by use of a stirrer for about 20 minutes at room temperature. The suspension was subjected to sonication for 5 minutes while being cooled with ice to thereby obtain a test solution containing CDDP for administration at 6.0 mg/kg/day.
(b) Preparation of Test Solution—II:
Compound 1 was suspended in 0.5% HPMC so as to obtain a 3 mg/ml suspension, 10 mg/ml suspension, and 30 mg/ml suspension, respectively, and each suspension was stirred by use of a stirrer for about 20 minutes at room temperature. Each suspension was subjected to sonication for 5 minutes while being cooled with ice to thereby obtain test solutions containing Compound 1 for administration at 30 mg/kg/day, 100 mg/kg/day, and 300 mg/kg/day, respectively.
(c) Test:
Five-week-old Donryu male rats were divided into a control group and treatment groups so that the average body weights of the groups and the standard deviations (S.D.) of the groups were made to be as close to one another as possible. Yoshida sarcoma (2×104 cells/0.1 ml/rat) was subcutaneously transplanted on the back of each rat, and administration was started the day following the day of transplant. To each rat of the CDDP treatment alone groups, the CDDP solution of 6.0 mg/kg was intravenously administered on the first administration day, and a 0.5% HPMC solution was orally administered for seven consecutive days at a daily dose of 1.0 ml per 100 g of body weight. In a similar manner, to each rat of the combination-administration treatment groups, the aforementioned CDDP solution at 6.0 mg/kg was intravenously administered on the first administration day, and a solution of Compound 1 (30 mg/kg/day, 100 mg/kg/day, or 300 mg/kg/day) was orally administered once a day for seven consecutive days at a daily dose of 1.0 ml per 100 g of body weight. To each rat of the control group, saline was intravenously administered on the first administration day in a dose of 1.0 ml per 100 g of body weight. Simultaneously, a 0.5% HPMC solution was orally administered once a day for five consecutive days at a daily dose of 1.0 ml per 100 g of body weight. In order to observe the action of Compound 1 per se, Compound-1-administration alone groups were provided for administration at 30 mg/kg/day, 100 mg/kg/day, and 300 mg/kg/day, respectively.
The rats were weighed on the day of transplantation (day 0) and the day following the day of final administration (day 8), and the suppression ratio of body weight increase was calculated by use of the following equation.
Ratio of suppression of body weight increase (%)=(1−body weight changes of one treatment group/body weight changes of the control group)×100
The weight of the tumor was measured by weighing rats sacrificed on the day following the day of the final administration, and the tumor shrinkage ratio was calculated by use of the following formula.
Ratio of tumor shrinkage (%)=(1−tumor weight changes of one treatment group/tumor weight changes of the control group)×100
The results are shown in Table 2.
TABLE 2
Inhi-
Body
Weight
bition
weight
change
Compounds
No. of
Tumor
ratio
change
ratio
(dose, mg/kg)
animals
weight (g)
(%)
(g)
(%)
Control
8
0.666 ± 0.244
25.9 ± 9.2
CDDP(6.0) +
8
0.162 ± 0.155
75.7
−19.4 ± 8.6
174.9
0.5% DPW
CDDP(6.0) +
8
0.167 ± 0.147
74.9
−2.7 ± 12.8
110.4
Compound 1
(30)
CDDP(6.0) +
7
0.139 ± 0.130
79.1
−9.1 ± 18.9
135.1
Compound 1
(100)
CDDP(6.0) +
8
0.158 ± 0.122
76.3
−7.4 ± 16.3
128.6
Compound 1
(300)
Saline +
7
0.787 ± 0.307
−18.1
29.3 ± 10.2
−13.1
Compound 1
(30)
Saline +
8
0.816 ± 0.329
−22.4
23.9 ± 6.6
7.7
Compound 1
(100)
Saline +
7
0.829 ± 0.281
−24.5
28.1 ± 6.0
−8.5
Compound 1
(300)
Significant inhibition of tumor weight and body weight to the control group has been proven when CDDP alone was administered at a dose of 6 mg/kg. When Compound 1 was administered for seven consecutive days, suppression of body weight was alleviated without affecting the anti-tumor action.
(a) Preparation of Test Solution—I:
5-Trifluoromethyl-2′-deoxyuridine (hereinafter abbreviated as FTD) was suspended in a 0.5% HPMC solution so as to obtain a 20 mg/ml suspension, and the suspension was stirred by use of a stirrer for about 20 minutes at room temperature. The suspension was subjected to sonication for 5 minutes under ice cooling, to thereby obtain a test solution containing HD for administration of 200 mg/kg/day.
(b) Preparation of Test Solution—II:
FTD was suspended in a 0.5% HPMC solution so as to obtain a 20 mg/ml suspension. To the suspension, Compound 1 was added so as to attain a concentration of 9.4 mg/ml. The resultant mixture was stirred by use of a stirrer for about 20 minutes at room temperature, and then subjected to sonication under ice cooling, to thereby obtain a test solution containing FTD and Compound 1 (mol ratio 1:0.5).
(c) Preparation of Test Solution—III:
Compound 1 was suspended in a 0.5% HPMC solution so as to obtain a 10 mg/ml suspension, and the suspension was stirred by use of a stirrer for about 20 minutes at room temperature. The suspension was subjected to sonication for 5 minutes under ice cooling, to thereby obtain a test solution containing Compound 1 for administration of 100 mg/kg/day.
(d) Test:
Eight-week-old male ICR rats were divided into a control group and treatment groups so that the average body weights of the groups and the standard deviations (S.D.) of the groups were made to be as close to one another as possible. To each rat of the FTD treatment alone groups, the FTD solution of 200 mg/kg/day (1.0 ml) was orally administered once a day for eight consecutive days (per 100 g body weight of each rat). To each rat of combination-administration treatment groups, a mixture solution of FTD and Compound 1 was perorally administered once a day for eight consecutive days at a daily dose of 1.0 ml per 100 g of body weight. To each rat of the control group, a 0.5% HPMC solution was perorally administered for eight consecutive days. In order to observe the action of Compound 1 per se, Compound 1-administration alone groups were provided for administration of 100 mg/kg/day.
The rats were weighed at the previous day of the first administration (day 0) and the following day of the day of final administration (day 9), and the ratio of body weight ratio was calculated by use of the following equation. There sults are shown in Table 3.
Ratio of body weight change (%)=body weight changes/body weight before administration×100
Test results were statistically analyzed in accordance with the Dunnett method ((*; p<0.05) and (**; p<0.01)).
TABLE 3
Compounds
No. of
Body weight
weight change
(dose, mg/kg)
animals
change (g)
ratio (%)
Control
6
1.4 ± 0.9
3.9
FTD(200)
6
−1.6 ± 4.7**
−17.6
VID(200) +
6
0.3 ± 0.7
0.7
Compound 1 (94)
Compound 1 (100)
6
2.4 ± 1.1
6.8
Administration of solo FTD at a daily dose of 200 mg/kg for eight consecutive days resulted in a decrease ratio of the body weight at the following day of the final administration to that before administration of approximately 18%. The decrease in the body weight was protected by incorporating Compound 1 at a dose of 94 mg/kg/day.
After the aforementioned body weight measurement on the following day of final administration was completed, each rat was anesthetized with ether, and a region of the large intestine 3-6 cm from the anus and the whole jejunoileal portion, i.e., the small intestine from which the duodenum was removed, were collected. Immediately after the collected region were washed with saline, the portions were frozen to preserve at −80° C. Each sample preparation was diluted with a 0.05M phosphate buffer (pH 7.4) so as to attain a tissue concentration of approximately 10% (W/V), and the resultant mixture was homogenized, subjected to sonication, and subjected twice to freeze-thawing. The thus-treated matter was centrifuged at 12,000 g for 15 minutes, and the supernatant was collected to serve as a sample for cytokine measurement.
Cytokines, i.e., IL-1β and mouse IL-6 were measured by use of an ELISA kit for mouse (product of Endogen, Inc.), and the results are shown in Table 4.
Test results were statistically analyzed in accordance with the Dunnett method ((*; p<0.05) and (**; p<0.01)).
TABLE 4
(pg/mg protein)
Small
Compounds
intestine
Large intestine
(dose, mg/kg)
IL-6
IL-1β
IL-6
Control
16.2 ± 5.9
23.6 ± 10.0
11.1 ± 5.7
FTD(200)
95.5 ± 19.2**
77.3 ± 42.1**
118.0 ± 47.6**
FID(200) +
17.2 ± 11.9
14.0 ± 4.0
11.3 ± 4.6
Compound 1 (94)
Compound 1 (100)
19.8 ± 9.9
23.7 ± 4.6
10.7 ± 4.7
Administration of FTD at a daily dose of 200 mg/kg/day for eight consecutive days resulted in a high level of inflammatory cytokine IL-6 both in the small intestine and the large intestine as compared with the control group. In addition, the level of IL-1β was elevated in the large intestine. The increase in level of the inflammatory cytokines was inhibited by incorporating Compound 1 at a dose of 94 mg/kg, which is a nearly same level observed in the control group.
5-Chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione (1) or a pharmaceutically acceptable salt thereof exhibit a suppressing action against inflammations evoked in the digestive tract after administration of an anti-tumor agent, and advantageously alleviate diarrhea and loss of body weight concomitant with administration of a chemical for treating cancer without suppressing the anti-tumor effect. Thus, the compounds of the present invention are of great value as agents for alleviating side effects caused by use of an anti-tumor agent, which enable not only the chemotherapy to be continuedly carried out, but also the body exhaustion to be effectively prevented.
Suzuki, Norihiko, Fukushima, Masakazu, Yamamoto, Noriyuki
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