JPS58210011A - Antitumor agent - Google Patents

Abstract

PURPOSE:An antitumor agent that contains 1alpha,25-dihydroxyvitamin D3-26,23-lactone as an active ingredient, thus showing cytocidal effect against carcinocytes in vitro and making it possible to give it orally as well. CONSTITUTION:The objective antitumor agent contains, as an active ingredient, 1alpha,25-dihydroxyvitamin D3-26,23-lactone. This compound shows, in vitro, the action of inhibiting cell propagation or cytocidal effect against K-562 cells originating from human leukemia or LICR-LON-HMy 2 originating from human myeloma. The dose to an adult is 0.1-10,000, preferably 0.5-1,000 micrograms/ day and it is given parenterally or orally. As a compound of the formula, is preferred 1alpha,25R-dihydroxyvitamin D3-26,23S-lactone.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 1α,25-dihydroxyvitamin-D,-2
Regarding antitumor agents containing 6,23-lactone:

do.

Currently used antineoplastic agents include alkylating agents, antimetabolites, antibiotics, plant alkaloids, and immunotherapeutic agents.
Many of the drugs that exhibit cell-killing effects also have strong side effects.

The present inventors have been conducting research on substances in living organisms, and have found that 1α, 2B, f (-dihydroxyvitamin-1), -26,23-lactone (hereinafter referred to as this substance or l
α, 25-(OH), -D, -26,23-1ac
It has been found that the compound (abbreviated as "tone") exhibits a cytocidal effect on cancer cells in vitro.

This substance has the following structure, for example Avch.

Bioch@m, Biopluym,,! ! Mu,
387 (1980) H,F, Dsluca.

-26,23-1actone -26,238
-1actone-26, 2338-1aato
-26,23R-1 actone-26,23R-1
actone The present inventors tested human leukemia-derived NI-562 and human myeloma-derived LICR-LON-HM in vitro.
When the antitumor effect of this substance was investigated using y2 cells, tumor cell proliferation suppressive or cell killing effects were observed. Furthermore, antitumor effects were observed in tests conducted using mice and rats as hosts.

This substance is 1α, 25 R-(OH)! -DB 26,
238-1actorm;1α, 258-(OH)1-
DB-26, 23S-1aatone”, 1α.

25R-(OH)a D, -26,23R1acton
e: 1α, 25s-(OH)1-DB-26,2
3R-1actone or a mixture of two or more thereof may be used, especially 1α, 25R-(OH)! −
DB-26,238-1acton@ is preferred. The anti-inflammatory agent of the present invention contains the above-mentioned substances as active ingredients and can be used in various formulations as shown in the following.

The antitumor agent of the present invention is administered parenterally via the intraperitoneal route, but has the characteristic that it can be administered orally.

Preparations containing this substance as an active ingredient are used in dosage forms such as tablets, powders, granules, suppositories, capsules, alcoholic solutions, oily solutions, and aqueous suspensions. As the oily solvent, triglyceride esters of intermediate fatty acids, corn oil, cottonseed oil, peanut oil, fish liver oil, oily esters, etc. are used. Also preferred are cacao oil and glycerin. Other ingredients such as lactose, starch, Merck, magnesium stearate, sorbic acid, salts of sorbic acid, sugars or derivatives thereof, alcohol, physiological saline, surfactants, antioxidants, etc. may be used in combination with this substance.

The substance may be contained in a unit dosage form from 0.00002 to 4% by weight, preferably from 0.0002 to 1% by weight. In addition, this substance has a daily fi0.1μ~1θ00 for adults.
Administer at 0μ, preferably from 0.5 to 1000μ.

Example 1 -562 is derived from human leukemia and grows in suspension in RPMI 1640 medium supplemented with 10% tallow serum.
Experiments were performed using vitro cultured strains. Suspend each cell in a medium so that the number of cells is 1X10''/mg,
5 tnl of the mixture was dispensed into a petri dish and cultured at 37° C. in an incubator with an air permeation containing 5% carbon dioxide gas. 1αr 25
R-(OH)2-D, -26,23S-1acto
ne was dissolved in dimethyl sulfoxide (hereinafter abbreviated as DMSO), and the final concentration of DMSO was 0.5% by volume and 1α.

25R-(OH)■Dl-26,23S-1acton
Add e to the petri dish to a predetermined concentration, and culture 3.
Days later, the cells were stained with Trivan blue and the total number of viable cells was counted.

The results are shown in Table 1.

Table 1 Growth inhibition rate shows the percentage when compared with the vehicle (DM80) administration group.

As above, engineering α, 25 R-(OH), -D, -2
6,238-1 actona showed a cell proliferation inhibition rate of 759 g against -562 at a plausibility of 50 n9/ml.

Example 2 An experiment was conducted using an in vitro culture strain of human miniroma-derived LICR-LON-HMy2, which grows in suspension in RPMI 1640 medium supplemented with 10% tallow serum. Each Liao JI! The suspension was suspended in a medium so that the number of liters was lXl0'/d, and 5 portions thereof were dispensed into petri dishes and cultured at 37°C in an incubator containing 5% carbon dioxide. 1 (1, 25R-(OH), -ri, -26,
2351aclon. was dissolved in DMS OK and added to the titration concentration, and after 3 days of culture, it was stained with Trivan blue and the total number of viable cells was counted. The results are shown in Table 2.

Table 2 shows the growth inhibition rate compared to the 4 groups treated with vehicle (DMi90).

As mentioned above, lα, 25 R-(OH)i D! 2
6,23 S-1 actone showed a 58% cell proliferation inhibition rate against LICR at a concentration of song/+i.

Example 3 7 with 400W high pressure mercury lamp in argon fist bubbling
2 hours: 1α, 25 R-(O)(), -26,23S to triglyceride ester IK9 of intermediate fatty acid which was injected to eliminate impure reactive peroxides.
-1actona 5 m9'z dissolved, 1α, 25R-(OH)z-DB-26,23S in 1 capsule
The following shell components were heated and dissolved so as to contain 5 μ9 of -1actone, and soft capsules were prepared using a soft capsule making machine in a conventional manner.

Shell formulation example Gelatin 10M parts Glycerin 2 Preservatives (ethylparaben) 0.05# Titanium white 0.2 Capsules containing 1μ, 2μ, or 5μq were prepared in the same manner.

Procedural amendment August 17, 1981 Kazuo Wakasugi, Commissioner of the Patent Office 1, Indication of case 1981 Patent Application No. 92320 2
゛'”0 Name Anti-tumor agent 3 Relationship to the case of the person making the amendment Patent applicant name (1) 0) Kureha Chemical Industry Co., Ltd. 8, Contents of the amendment Page 2, lines 8 to 9 of the specification of the present application ni r Avch
, Biochem, Biopluys, 387 (1980) H, F, Deluca J, KrArch, Biochem.

Biophya, 204.387 (1980) H
, F, and DeLuca J.

Claims (2)

[Claims] (1) 1α,25-dihydroxyvitan-D, -2
An anti-11Φ tumor agent containing 6,23-lactone as an active ingredient. (2) 1α,25-dihydroxyvitamin-D, -2
6,23-lactone is 1α, 25R-dihydroxy-D
, -26,238-lactone, the antitumor agent according to claim 1.