JPH0517353A - Carcinostatic action-enhancing agent - Google Patents

Abstract

PURPOSE:To provide an agent containing lonidamine or its salt as an active ingredient and useful for enhancing the carcinostatic activity of ifosphamide, etc., without increasing the side effects. CONSTITUTION:An agent for enhancing the carcinostatic activity of 7- ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy camptothecin or ifosphamide contains a compound of the formula or its salt which is a known compound having the carcinostatic activity. The compound of the formula is administered together with the above-mentioned anticancer agent or after or before the administration of the cancer agent orally or in the form of injections, and further in a dose of 20-600mg/m<2> (the surface area of a living body) for an adult or in a dose of 1-60mg/m<2> (the surface area of a living body) for an adult in the form of injections one of three times a day.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an antitumor agent. More specifically, 7-ethyl-10- [4 containing lonidamine or a pharmaceutically acceptable salt thereof as an active ingredient.
And (1-piperidino) -1-piperidino] carbonyloxycamptothecin or ifosfamide.

[0002]

2. Description of the Related Art Usually, it is difficult to treat cancer with a single anticancer agent, and therefore, a treatment in which a plurality of anticancer agents are combined, that is, a combination therapy is attempted. However, the combination of suitable drugs used in the combination therapy differs depending on the anticancer drug, and it cannot be said to be established yet, and it is in a state that an appropriate combination must be selected by trial and error. In general, carcinostatic agents have strong side effects, which act as dosage control factors. Therefore, in combination therapy, it is a major problem to find a combination of drugs that enhance the carcinostatic action without mutually enhancing side effects.

7-Ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin is a carcinostatic agent with a promising future (cancer and chemotherapy, Volume 14, No. 3, PART.II, 850-8
57, 1987), ifosfamide is an anticancer drug that has already been clinically used. However, even for these anticancer drugs, it is not possible to establish a combination therapy with a drug that enhances the anticancer action without increasing the side effects. , Gives great advances in cancer treatment.

Now, lonidamine is represented by the following formula

[0005]

[Chemical 1] Is a known compound having a carcinostatic action (Japanese Patent Publication No. 59-19939 and DRUG OF TODA).
Y, Volume 25, NO. 3, pp. 195-209, 1989
Year, see). And the combined effect of this compound and a certain anti-cancer agent has already been reported (Cancer Che
mothery and Pharmacolog
y, 25, pages 32-36, 1989).

However, lonidamine or a pharmaceutically acceptable salt thereof and 7-ethyl-10- [4- (1-
The effect of combination with piperidino) -1-piperidino] carbonyloxycamptothecin or ifosfamide is not known.

[0007]

DISCLOSURE OF THE INVENTION The present inventors have found that a drug effective in combination therapy for cancer, namely 7-ethyl-10
It was investigated to provide a drug that enhances the anticancer action of these anticancer agents without enhancing the side effects of-[4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin or ifosfamide.

[0008]

As a result of various studies, the present inventors have found that lonidamine or a pharmaceutically acceptable salt thereof and 7-ethyl-10- [4- (1-piperidino) -1-piperidino]. When used in combination with carbonyloxycamptothecin or ifosfamide, a synergistic potentiating effect of carcinostatic action is exhibited without adversely affecting side effects, that is, lonidamine or a pharmaceutically acceptable salt thereof is 7-ethyl-10- [4- (1-piperidino) -1
The present invention has been completed by discovering that it becomes a useful drug for enhancing the carcinostatic action of -piperidino] carbonyloxycamptothecin or ifosamide.

Examples of the pharmaceutically acceptable salt of lonidamine include alkali metal salts such as sodium salt and potassium salt, and salts with basic amino acids such as lysine salt and arginine salt. These salts can be produced by reacting lonidamine with a desired base by a conventional method.

The drug of the present invention containing lonidamine or a pharmaceutically acceptable salt thereof as an active ingredient is used for various oral preparations such as tablets, capsules, granules and powders, and for parenteral administration such as injections. Various formulations of

Preparations for oral administration such as tablets, capsules, granules and powders contain lonidamine as a usual pharmaceutical additive, for example, excipients such as lactose, synthetic aluminum silicate, glucose, mannitol, crystalline cellulose and starch. , Carboxymethylcellulose, disintegrating agents such as sodium alginate, magnesium stearate, lubricants such as talc or a binder such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc. You can

The injectable preparation is prepared by, for example, dissolving or suspending lonidamine or a pharmaceutically acceptable salt of lonidamine in water and adding mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, mannose and the like. Add a tonicity agent,
If necessary, a stabilizer such as sodium sulfite and albumin and a preservative such as benzyl alcohol can be further added to produce the product by a conventional method. From the viewpoint of solubility, it is preferable to use a pharmaceutically acceptable salt of lonidamine as the injection.

Lonidamine or its pharmaceutically acceptable
The agent of the present invention containing a salt as an active ingredient is 7-ethyl-10.
-[4- (1-Piperidino) -1-piperidino] carbo
Simultaneous with Nyloxycamptothecin or Ifosfamide
Before or after administration of these anti-cancer agents
Orally or by injection. The dosage depends on the patient
Although it depends on the condition, age, body surface area, etc.,
For oral administration, 2 times as lonidamine per dose
0 to 600 mg / m 2 (body surface area) by injection
In the case of administration, 1 to 60 mg as lonidamine per dose
/ M 2 (body surface area), administered 1-3 times daily
It

[0014]

Lonidamine or a pharmaceutically acceptable salt thereof is 7-ethyl-10- [4- (1-piperidino)).
It synergistically enhances the carcinostatic action of -1-piperidino] carbonyloxycamptothecin or ifosfamide, and is not only low in toxicity per se, but also does not enhance the side effects of these carcinostatic agents.

For example, 7-ethyl-10- [4- (1-
When piperidino) -1-piperidino] carbonyloxycamptothecin or ifosfamide is used in combination with lonidamine in an amount that does not show a carcinostatic effect when administered alone, the carcinostatic effect is enhanced without increasing side effects (see Test Examples 1 and 2 below). ). Therefore, the agent of the present invention is 7-ethyl-
10- [4- (1-Piperidino) -1-piperidino] carbonyloxycamptothecin or ifosfamide is useful for treating cancer as an antitumor agent.

Test example The effects of the present invention will be described in detail below with reference to test examples.

Test Example 1 7-Ethyl-10- [4- (1
-Piperidino) -1-piperidino] carbonyloxycamptothecin antitumor effect enhancing effect a) Test material Mouse: BALB / c nude mouse (6 weeks old, 1 group 6)
Tumor: MX-1 (Nude mouse transplantable human breast cancer) Test compound: Lonidamine and 7-ethyl-10- [4
-(1-Piperidino) -1-piperidino] carbonyloxycamptothecin b) Test Method MX-1 was cut into pieces of about 3 mm square with a scalpel and subcutaneously transplanted to the back of one side of nude mice using a trocar needle.

From the 10th day after transplantation, the major axis (Lmm) and the minor axis (Wmm) of the tumor were measured, and the tumor weight (L x W ²
The mice were divided into four groups (the first group to the fourth group) when the value calculated by / 2) reached 100 to 300 mg.

The first group of mice contained 30 mg of 7-ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin dissolved in physiological saline.
/ Kg was intraperitoneally administered to the mouse, and immediately thereafter, lonidamine suspended in 0.5% carboxymethylcellulose was intraperitoneally administered to the mouse at a rate of 50 mg / kg. Thereafter, 50 mg / kg of lonidamine was intraperitoneally administered once a day for 19 times daily, and after 4 days, 30 mg / kg of 7-ethyl-10- [4- (1-piperidino) -1-piperidino]. Carbonyloxycamptothecin was administered once intraperitoneally. The first lonidamine and 7-ethyl-10- [4- (1-piperidino) -1-
The major axis and the minor axis of the tumor were measured three times a week after the administration of piperidino] carbonyloxycamptothecin to calculate the tumor weight, and the ratio (relative tumor weight) to the tumor weight before the first administration of lonidamine was obtained.

For the second group of mice, 0.
Lonidamine alone suspended in 5% carboxymethylcellulose was administered, and mice in Group 3 were treated with 7-ethyl-10- [4- (1-piperidino) -1-piperidino dissolved in physiological saline as described above. ] Only carbonyloxycamptothecin was administered, to the mice in the fourth group (non-administration group), 0.5% carboxymethylcellulose alone was administered instead of lonidamine dissolved in 0.5% carboxymethylcellulose, and the relative tumor weights were measured. I asked.

Further, in order to determine the side effect of the test compound administered by the change in body weight, the body weight of the mice in each group was measured daily, and the change in body weight after the initial administration of lonidamine was calculated as%. Displayed in. c) Test results Changes in relative tumor weight (average value within each group) of mice in each group are shown in FIG. As shown in FIG. 1, a carcinostatic effect was not observed by single administration of lonidamine (see the broken line L), but when it was used in combination with 7-ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin. (Refer to the broken line L + X), a more remarkable anti-cancer effect was observed than when 7-ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin was administered alone (Refer to the broken line X).

The change in body weight (average value in each group) is shown in FIG.
As shown in FIG. 2, the administration of lonidamine alone did not suppress body weight (see polygonal line L), and it was determined that lonidamine had low toxicity. And lonidamine and 7-ethyl-10- [4
7-Ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxy indicates the change in body weight when combined with-(1-piperidino) -1-piperidino] carbonyloxycamptothecin (see polygonal line L + X). Since no difference was observed with that of camptothecin alone (see the broken line X), lonidamine contained 7-ethyl-10.
It was not determined to increase the toxicity of-[4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin.

Test Example 2 Anti-tumor action enhancing effect of ifosfamide a) Test materials The mice and tumors used are the same as in Test Example 1.

Test compounds: lonidamine and ifosfamide b) Test method 7-ethyl-10-in group 1 and group 3 mice.
The same as in Test Example 1 except that ifosfamide was administered once each on the first day of the test (dose 400 mg / kg) instead of administering [4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin twice each. . c) Test results Changes in relative tumor weight of mice in each group (mean value in each group) are shown in FIG. As shown in FIG. 3, the antitumor effect was not observed by the single administration of lonidamine (see the broken line L), but when it was used in combination with ifosfamide (see the broken line L + Y), it was more remarkable than when the ifosfamide was administered alone (see the broken line Y). Anticancer effect was recognized.

The change in body weight (average value within each group) is shown in FIG.
As shown in FIG. 4, the change in body weight when lonidamine and ifosfamide were used in combination (see polygonal line L + Y) was almost the same as that when ifosfamide was administered alone (see polygonal line Y). Therefore, lonidamine enhances the toxicity of ifosfamide. It was decided not to do.

[0026]

EXAMPLES Hereinafter, formulation examples of the drug of the present invention will be described and explained.

Example 1 Tablets 100 parts by weight of lonidamine, 30 parts by weight of lactose, 20 parts by weight of crystalline cellulose, 5 parts by weight of hydroxypropylmethylcellulose, and 20 parts by weight of carboxymethylcellulose were added to 150 parts by weight of water and kneaded, followed by kneading. The mixture was crushed and dried. 5 parts by weight of magnesium stearate was added to the obtained dried product and mixed to obtain a granule. The granules were compression-molded with a tableting machine into tablets having a diameter of 8 mm and a weight of 180 mg to give tablets each containing 100 mg of lonidamine.

Example 2 Injectable solution A mixture of 0.5 parts by weight of lonidamine L-arginine salt and 5 parts by weight of sorbitol was added with distilled water for injection and dissolved.
The amount was adjusted to 00 parts by weight, and this aqueous solution was filtered with a membrane filter. The filtrate was filled with 5 ml of each ampoule purged with nitrogen, sealed, and sterilized at 120 ° C. for 15 minutes to obtain an injection containing 25 mg of L-arginine salt of lonidamine in one ampoule.

[Brief description of drawings]

FIG. 1 shows that mice were treated with lonidamine and 7-ethyl-.
It is a figure explaining the carcinostatic effect when it uses together with 10- [4- (1-piperidino) -1-piperidino] carbonyloxy camptothecin. The polygonal line (L + X) is lonidamine and 7-ethyl-10- [4- (1-piperidino) -1.
-Piperidino] carbonyloxycamptothecin in combination, the change in relative tumor weight is shown by broken line L, the change in relative tumor weight by administration of lonidamine alone, and the broken line X is shown in 7-ethyl-10- [4- (1- Piperidino) -1
-Piperidino] carbonyloxycamptothecin alone, the change in relative tumor weight, and line C
Shows changes in relative tumor weight when no drug was administered at all.

FIG. 2 shows lonidamine and 7-ethyl-in mice.
It is a figure explaining a body weight change at the time of using together with 10- [4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin. The polygonal line (L + X) is lonidamine and 7-ethyl-10- [4- (1-piperidino) -1.
-Piperidino] carbonyloxycamptothecin in combination with weight change, broken line L represents the change in body weight with lonidamine alone, and broken line X represents 7-ethyl-10
-[4- (1-Piperidino) -1-piperidino] carbonyloxycamptothecin alone shows the change in body weight, and line C shows the change in body weight when no drug was administered.

[Fig. 3] Fig. 3 is a view for explaining the anti-cancer effect of using lonidamine and ifosfamide in combination in mice. Line (L + Y) shows changes in relative tumor weight when lonidamine and ifosfamide were used together, line L shows changes in relative tumor weight when lonidamine alone was administered, and line Y represents relative tumor weight when ifosfamide was administered alone. The change in weight is shown, and the polygonal line C shows the change in relative tumor weight ratio when no drug was administered.

FIG. 4 is a diagram illustrating changes in body weight when lonidamine and ifosfamide are used in combination in mice. Line (L + Y) shows the change in weight when lonidamine and ifosfamide were used together, line L shows the change in weight when lonidamine alone was administered, line Y shows the change in weight when ifosfamide was administered alone, and line C shows the change in weight. The changes in body weight when no drug was administered are shown.

Continued front page    (72) Inventor Munetaka Matsui             Osaka Prefecture Osaka City Miyakojima Ward 1-2-1 Tobuchicho 2-             No. 408 (72) Inventor Masakuni Ozaki             14 Nishinoshomonguchi-cho, Kichijoin, Minami-ku, Kyoto             Inside Shinshin Pharmaceutical Co., Ltd.

Claims (3)

[Claims] 1. 7-Ethyl-10- [4- (1) containing lonidamine or a pharmaceutically acceptable salt thereof as an active ingredient.
-Piperidino) -1-piperidino] carbonyloxycamptothecin or ifosfamide antitumor agent. 2. 7-Ethyl-10- [4- (1) containing lonidamine or a pharmaceutically acceptable salt thereof as an active ingredient.
-Piperidino) -1-piperidino] carbonyloxycamptothecin antitumor agent. 3. An anti-tumor effect enhancer of ifosfamide containing lonidamine or a pharmaceutically acceptable salt thereof as an active ingredient.