JPH0120128B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a toxicity reducing agent for an antitumor agent, which contains a carboxylic acid derivative or a salt thereof as an active ingredient and reduces the toxicity of a 5-fluorouracil derivative. 5-Fluorouracil was synthesized by Dushinsky in 1957, and since its antitumor activity was reported by Heidelberger et al., it has been the most widely used anticancer drug in clinical practice, with a wide anticancer spectrum, especially in the glandular It is characterized by its excellent effects on cancer. However, 5-fluorouracil has significant toxicity and side effects, and side effects appear at the same time as the onset of efficacy. Therefore, in actual treatment, the medication must be discontinued before the cancer can be cured with 5-fluorouracil. There are many cases where this is not possible. Recently, since 5-fluorouracil is a representative compound of nucleic acid antimetabolites, research and development of less toxic compounds using 5-fluorouracil as the basic skeleton have been carried out in various fields, and several excellent compounds have been developed. A report has been made. Many of these are masked types of 5-fluorouracil, and 5-fluorouracil gradually increases in vivo.
5-Fluorouracil is converted into fluorouracil, so it has great significance in that it reduces direct side effects on the digestive system etc. when administered orally, but the strong toxicity derived from 5-fluorouracil converted in vivo is The problem that remains recognized and remains is how to attenuate the side effects of 5-fluorouracil. As a result of intensive research on the toxicity reducing effect of 5-fluorouracil of various compounds, the present inventors found that
The present inventors have discovered that specific carboxylic acid derivatives and salts thereof have excellent toxicity-reducing effects, leading to the completion of the present invention. That is, the present invention is based on the general formula (R ₁ is an amino group, a formyl group, a carboxyl group,
_5- The present invention relates to an agent for reducing the toxicity of an antitumor agent, which is characterized by reducing the toxicity of fluorouracil derivatives. Among the carboxylic acid derivatives represented by the general formula () and their salts in the present invention, those mainly used include ureidopropionic acid, β-alanine, sodium malonate, sodium formylacetate, sodium oxaloacetate, glutamic acid, and aspartic acid. , cysteine and aminooxyacetic acid, and particularly preferred are β-alanine, sodium malonate, sodium formylacetate and aminooxyacetic acid. All of these compounds are known compounds, and have no or almost no antitumor effect or toxicity, and can significantly reduce the toxicity without reducing the antitumor effect of 5-fluorouracil derivatives, and further reduce the tolerable dose of 5-fluorouracil derivatives. 5-fluorouracil derivative, and exhibits an antitumor effect greater than that achieved by administering a 5-fluorouracil derivative alone. Representative compounds among the 5-fluorouracil derivatives whose toxicity is reduced according to the present invention are as follows. Γ5-fluorouracil Γ1-(2-tetrahydrofuryl)-5-fluorouracil Γ1,3-bis(2-tetrahydrofuryl)-5
-Fluorouracil Γ1-n-hexylcarbamoyl-5-fluorouracil Γ1-ethoxymethyl-5-fluorouracil Γ3-(2-tetrahydrofuryl)-5-fluorouracil Γ5-fluorouracil-O-β-D-glucuronide Γ5'-deoxy-5- Fluorouridine Γethyl 6-n-butoxy-5-fluorohexahydro-2,4-dioxopyrimidine-5-
Carboxylate Γ2',5'-dideoxy-5-fluorouridine Compounds other than those mentioned above may be used as long as they are converted to 5-fluorouracil in the body. The carboxylic acid derivatives and salts thereof of the present invention may be used alone or in combination of two or more. Although the ratio of the 5-fluorouracil derivative and the carboxylic acid derivative to be used cannot be determined unconditionally depending on the combination of each compound, it is generally preferable to use about 1 to 50 times, by weight, the latter to one part of the former. The toxicity reducing agent containing the carboxylic acid derivative or its salt of the present invention can be administered at the same time as, or before or after, the administration of the 5-fluorouracil derivative. It can also be administered in advance by blending with a 5-fluorouracil derivative. The dosage form can be selected depending on the therapeutic purpose, and examples include oral preparations such as tablets, capsules, and granules, and parenteral preparations such as injections and suppositories. When forming such a dosage unit form, carriers conventionally known in the art are used, and they are manufactured according to methods commonly used in the art. The amount of carboxylic acid derivative or its salt used is 5-
The amount of 5-fluorouracil derivatives used varies depending on the symptoms, age, and weight, but the amount of 5-fluorouracil derivatives used is usually the daily dose for adults.
200 to 1000 mg/body is appropriate, and the carboxylic acid derivative or its salt is considered to be preferably 0.2 g to 50 g/body, and can be administered once or in divided doses. Next, typical formulations of the toxicity-reducing agent for the anti-tumor agent of the present invention and the toxicity-reducing anti-tumor agent containing the agent and a 5-fluorouracil derivative are listed. Prescription Example 1 β-Alanine 2000 mg Distilled water for injection Appropriate amount 10 ml per ampoule Prepare an injection with the above mixing ratio. Formulation Example 2 Ureidopropionic acid 100mg Sodium malonate 100mg Crystalline cellulose 38mg Sodium starch glycolate 50mg Magnesium stearate 2mg Hydroxypropyl methylcellulose 10mg 300mg per tablet Prepare tablets at the above mixing ratio. Formulation Example 3 5-Fluorouracil 25mg Sodium formylacetate 175mg Lactose 20mg Cornstarch 35mg Crystalline cellulose 43mg Magnesium stearate 2mg Per capsule 300mg Capsules are prepared at the above blending ratio. Formulation Example 4 1-(2-tetrahydrofuryl)-5-fluorouracil 100mg Sodium malonate 200mg Lactose 500mg Cornstarch 185mg Hydroxypropyl methylcellulose 10mg Magnesium stearate 2mg Talc 3mg Per package 1000mg Granules are prepared at the above blending ratio. Formulation example 5 1,3-bis(2-tetrahydrofuryl)-5-
Fluorouracil 50mg Cysteine 1000mg Witepsol H-15 1750mg 1 unit 2800mg Suppositories are prepared with the above blending ratio. Next, the results of acute toxicity tests and antitumor tests are shown. (1) Acute toxicity test Experiments were conducted using female Hartley guinea pigs weighing 250 to 300 g under an 18-hour fast. All specimens were dissolved or suspended in water and forcibly administered orally using an oral probe. The dosages of carboxylic acid derivatives and their salts were fixed at 100, 500, and 2500 mg/Kg, and the dosage of 5-fluorouracil was varied at a ratio of 1.2, so that the amount of administered liquid was 1 ml/100 g body weight. It was prepared as follows. The LD ₅₀ value was calculated by calculating the number of deaths 48 hours after administration and using the Up and Down method. The results are shown in Table 1.

[Table] As is clear from Table 1, the carboxylic acid derivatives and salts thereof of the present invention have an excellent toxicity reducing effect, especially β-alanine, sodium malonate, sodium formylacetate, and aminooxyacetic acid. There are some notable ones. (2) Anti-tumor test 5 × 10 ⁵ murine polyplantable tumor L1210 cells
BDF ₁ was implanted intraperitoneally in male mice. The sample was dissolved or suspended in water and administered once to each group of 8 mice.
ml/100g body weight from the day after tumor transplantation.
The drug was orally administered once a day for 7 consecutive days. The dosage is 500mg/for carboxylic acid derivatives and their salts.
Fixed as Kg. Examples of 5-fluorouracil derivatives include 5-fluorouracil (5-FU), 1
-(2-tetrahydrofuryl)-5-fluorouracil (FT) and 1,3-bis(2-tetrahydrofuryl)-5-fluorouracil (FD)
-1), the dosage was varied for each compound, and the average survival days were determined for each dosage and expressed as an increase in survival rate. The rate of increase in survival prolongation is as follows: Rate of increase in life expectancy (%) = Average survival days of the sample administration group - Average survival days of the untreated control group / Average survival days of the untreated control group ×
Calculated as 100. Table 2 shows the maximum rate of increase in life extension of 5-fluorouracil derivatives when used in combination with 500 mg/Kg of carboxylic acid derivatives or their salts.

[Table] The results are shown in Table 2. By using carboxylic acid derivatives or their salts in combination, the optimal dosage of 5-fluorouracil derivatives increases,
Along with this, it was observed that the survival rate increased significantly. The effect was particularly remarkable for β-alanine, sodium malonate, sodium formylacetate, and aminooxyacetic acid.

Claims (1)

[Claims] 1. General formula (R ₁ is an amino group, a formyl group, a carboxyl group,
_5- A toxicity reducing agent for an antitumor agent, characterized by reducing the toxicity of a fluorouracil derivative.