JPS5925325A - Remedy for cancer - Google Patents

Abstract

PURPOSE:To provide an agent for improving the antitumor activity of 5-fluorouracils, by using a pentose phosphoric acid ester and/or purine nucleotides as active components. CONSTITUTION:The agent contains the compounds selected from pentose phosphoric acid esters such as ribose-1-phosphate, and purine nucleotides such as adenosine-5'-triphosphate, guanosine-5'-triphosphate, etc. The amount of the above compound is >=0.5mol, preferably 0.5-5mol per 1mol of 5-fluorouracil. Preferably, both compounds are compounded together before hand, and administered at the same time. The addition of the compound is effective to suppress the proliferation of cultured cancer cells, elongate the life of animal affected with ascites carcinoma, and suppress the proliferation of scirrhous cancer.

Description

[Detailed description of the invention] The present invention relates to a pain therapeutic agent.

Recently, various excellent antitumor drugs have been developed for use in chemotherapy for severe malignant tumors.
C was introduced, and its results are improving year by year. However, at present, the effects of chemotherapy are only temporary in most cases, and the effects are not necessarily satisfactory for completely suppressing tumor growth and ensuring long-term survival for patients. Currently, 5-fluorocracil (hereinafter abbreviated as 5-FU) and other antibiotics are the mainstream anti-J tumor agents that are frequently used clinically, and in the future, various 5-fluorocracils (hereinafter abbreviated as 5-FU) and other antibiotics are the mainstream. -FUs are also expected to be developed. Each antitumor agent containing a compound having a 5-FU skeleton as an active ingredient has advantages and disadvantages. For example, 5-FU has a strong effect, but its blueness and side effects are also extremely large, and therefore, in actual treatment, side effects are unavoidable at the same time as the effects appear. Furthermore, 1-(2-tetrahydrofuryl)-5-fluorocuracil has relatively little toxicity and side effects, but its antitumor effect is said to be somewhat inferior. 5- Even better from these realities
The development of FUs is expected.

On the other hand, the administration method of the conventionally used anti-II tumor agent,
Research is underway to enhance the antitumor effect by improving the dosage form. For example, attempts have been made to increase efficacy and reduce side effects by combining conventionally used antitumor agents with various other antitumor agents or drugs that do not have antitumor effects. It has been done many times. Among these studies, there are the following reports. Mukherjee et al. [Journal of Biological Chemistry Vol. 235, p. 433 (196
0] reported that the decomposition of useful 5-FU could be prevented by the addition of thymine. Gott et al. [Cancer Research Vol. 29, pp. 80-7 (1969)
], the addition of wild boar and glucose significantly increased the effect of 5-FU on Ehrlich ascites cancer cells, but Kelashiru et al. [Cancer Research Vol. It has been reported that cancerability was not increased. In addition, Quindhakser et al. [Journal of Pharmaceutical Sciences Vol. 61, p. 1669 (1972)] suggested that coadministration of thioxyclidine would result in a ``2'' increase in 5-FUO analgesia.In fact, This method is described by Shadow et al. [Journal Op Pharmaceutical Sciences° Vol. 62, p.
] It was reported that the effect of 5-FU was enhanced by
[5 years)] also reported that severe toxicity occurred. After that, Fujii et al. [Cancer Vol. 69, p. 763 (1978)]
[Ikenaka et al., Cancer Vol. 353 pages (1979)].

5-F U (compounds with z skeleton have 5-
FU-deoxylipose monophosphate and 5-FU
5-FU is converted into K, which is said to exert antitumor effects. Therefore, effective metabolites from 5-FU can be used in large numbers in pain cells or in living organisms with cancer. If produced, it is expected that 5-FUO will become a stronger anticancer drug.

In view of the current situation of IVi, researchers have been conducting intensive research to obtain antitumor agents that can enhance the antitumor effects of 5-FUs. As a result, only when 5-FUs were combined with several substances that had no anti-inflammatory effect,
He discovered that it was possible to achieve the purpose of T/L, and completed the development of a trigger.

That is, at least one compound selected from the group consisting of pentose lithic acid esters and purine nucleotides. R2 is the same or different and represents a water ice atom or a tetrahydrofuryl group.
Pertains to.

According to Kienori 4VC, the antitumor effect-enhancing effect itself cannot be tolerated, but the anti-flour tumor effect is intolerable, but this and 5-FU 1
The anti-1m Yang effect Zhu can be increased by using it in combination.

When the anti-1141 tumor drug of R. Kinen is used, the concentration of effective metabolites from 5-FU in the till tract increases and anticancer properties are enhanced in experimental animals, so it is also excellent in mi therapy for human tumors. It is expected that this will have a positive effect.

In the present invention, typical examples of pentose phosphates include ribose-1-phosphate, thioxyribose-1-phosphate, etc., and typical examples of purine nucleotides include adenosine-5-triphosphate, etc. Examples include guanosine-5-triphosphate, inosine-5-triphosphate, adenosine-5-monophosphate, and the like.

Misfire r! In the 11 antitumor agents, the blending ratio of 5-fluorocracils and pentose phosphates and/or purine nucleotides varies depending on the compound used, but it is generally It is preferable to use 0.5 mol or more, preferably 0.5 to 5 mol, of the latter to 1 mol of the former.

In the present invention, 5-FU and pentose phosphate esters or purine nucleotides can be administered separately, but it is preferable to mix them in advance and administer them at the same time. As the dosage unit form of the antitumor agent according to the present invention, various forms can be selected depending on the therapeutic purpose,
For example, the oral side of tablets, capsules, granules, etc., injections,
Examples include parenteral preparations such as planing. In forming the dosage unit form, carriers conventionally known in the art are used, and the preparation is carried out according to methods commonly used in the art. The amount of 5-FU to be incorporated into these various dosage unit forms varies depending on the types of 5-FU and pentose phosphates or purine nucleotides, but cannot be particularly limited. , generally about 10 to 200 Da for oral preparations, and about 50-1 for parenteral preparations.
000~ is desirable. The daily dose is also 5-FU.
Although it cannot be specifically limited, the usual clinical dose is approximately 20 to 1200 Q per day for oral preparations as 5-FU.
, about 50 to 2,000 for injections, and about 50 to 1 for planing.
It is desirable to set it to 2000#.

Next, we investigated the growth-inhibiting effect of unexploded 1J1 anti-1 river tumor i1 on cultured cancer cells, the survival effect of animals with ascites cancer, and the suppressive effect on the proliferation of fixed tumor cells using the following 0° (1) culture. Determination of the growth inhibitory effect on 11fi cells Ehrlich cancer cells of in vitro subcultured cancer cells
1210 leukemia cells were cultured at 1x1 in Eagle's medium containing 10% calf serum (TNL).
05 cells, 15×10411 for LL210 cells,'
i! was inoculated. To this culture solution, 5-
F U To IJ Hose-1=phosphoric acid, thioxyribose-1-phosphoric acid'! , or atonosine-5'-IJ phosphoric acid and cultured at 37°C for 148 hours] Jerpur of Nogeological Chemistry Vol. 193, p. 265 (1951) J In accordance with this, it was set at 111. The amount of cell proliferation in the control group was reduced to 10
Table 1 shows the amount of cells in the drug administration group when the concentration was 0%. Note that 5-FU was used at a concentration that exhibited an approximately 50% growth-inhibiting effect on each cell.

(2) Measurement of antitumor effect (a) Survival prolonging effect on ascites tumor Ehrlich ascites tumor cells, which are serially transplanted tumors, 5×-1
06 mice were intraperitoneally inoculated into male ddY macus (6 animals per group) weighing approximately 20 g. 24 hours after tumor cell inoculation, 5-FU and coal sugar phosphates such as lipose-1-phosphate, deoxylipose-1-phosphate, adenosine-5-triphosphate, guanosine-5'- An antitumor agent containing purine nucleotides such as triphosphoric acid was dissolved in physiological saline and sterilized in the amounts shown in Table 2.

The drug was administered intraperitoneally once a day for 7 consecutive days. The average number of days of survival (T/C) f: of drug administration group T and control group C was determined by observing the number of days from tumor cell inoculation until tumor death in mice. These results are shown in Table 2.

(1)) Proliferation inhibitory effect on solid tumors 2 × lo7 cells of Ehrlich tumor cells or sarcoma +80 tumor cells, which are serially transplanted tumors, were transplanted into male ddY cells weighing iJ 20 y.
Anti-AI was applied to the axilla of mice (8 mice per group): Jj, tetrahydrofuryl)-5-fluorocracyl and ribose-1-phosphoric acid,
Thioxyribose-1-phosphate, ゛ or atenosis 5
Table 3 shows 11 (11) shown in Table 3.
The drug was administered intraperitoneally 11 times for 7 consecutive days. 1 Severely injured cell inoculation 1
After 0 days, the tumor was removed and its iTi: ilj f j
The average of drug administration group T and control group C+)Ii
The ratio CT/C) of tumor severity I11 was determined. These results are shown in Table 3.

The inequality sign in Table 1 and Table 2 means that there is a macus that survives 60 or more times.

From Table 3 onwards, the following can be seen from Tables 1, 2 and 3. That is, when 5-FUK7i carbohydrate phosphate esters or purine nucleotides are combined, the cell proliferation inhibitory effect on cultured cancer cells is greater than when 5-FU is used alone. Regarding antitumor effects, the addition of sugar phosphate esters or purine nucleotides to 5-FU produced significant antitumor effects, including prolonging the survival of mice with ascites tumors and inhibiting the growth of solid JII' tumors. Enhancement of the effect was observed. Furthermore, the growth-inhibiting effect on solid tumors is also enhanced when purine nucleotides are combined with 1-(2-tetrahydrofuryl)-5-fluorocracil, a derivative of 5-X; The antitumor effect of all 5-FU compounds known to be converted to FU is mutually enhanced by combination with purine nucleotides or 1-11-carbohydrate phosphates. I understand.

(herein)

Claims (1)

[Claims] (1) At least seven compounds selected from pentasaccharide phosphate esters and purine nucleotides containing gold and enhancing the anti-+7.ljjM effect. [IN1 Mountain, November <2 is the same or different and represents a wood atom or a tetrahydrofuryl group] 5
-fluorocracyl (and (b) selected from pentose phosphate esters and purine nucleotides #, i'h,
An anti-tumor drug containing at least 11 ur of the compound. (3) Claims containing 0.5 mol or more of at least one compound selected from pentose phosphates and purine nucleotides per 1 mol of 5-fluoro I'I cracils. The antitumor agent according to item 2.