JPS58210010A - Antitumor agent - Google Patents

Abstract

PURPOSE:An antitumor agent that contains 25-hydroxyvitamin D3-26,23-lactone, as an active ingredient, showing cytocidal effect against carcinocytes in vitro and making it possible to give it orally as well. CONSTITUTION:The objective antitumor agent contains 25-hydroxy-vitamin D3- 26,23-lactone as an active ingredient. The compound shows effects to inhibit the propagation or kill the tumor cells of K-562 cell originating from human leukemia and LICR-LON-HMy 2 cells originating from human myeloma in vitro and also shows antitumor effects in the tests where mice and rats are used as hosts. The dose is 0.1-10,000mug/day for adult, preferably 0.5-1,000mug/day for adult and it is given parenterally or orally. As a compound of the formula, is preferred 25R-hydroxyvitamin D3-26,23S-lactone.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 25-hydroxyvitamin I), -26,23
- Concerning antitumor agents containing lactones.

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 the body of shrimp, and as a result, we found that 25-hydroxyvitamin n1-26.2
3-lactone (hereinafter referred to as this substance or 25-(OH)-D
J-26,23-1actone)73
It was found that the drug had a cytocidal effect on cancer cells in vitro.

This substance has the following structure, for example.

-tacton* -1actone -1ac
tone258-(OH)-Dl-26,23R-1a
ct on.

The present inventors performed in vitro experiments on human leukemia-derived NI-562 and human bone marrow-derived LICR-LON-HMy.
When the antitumor effect of this substance was investigated using 2 cells, tumor cell growth suppressive effect or cell killing effect was observed. Furthermore, antitumor effects were observed in tests conducted using mice and rats as hosts.

This substance is 25R-COH)-Dl-26,23S -1
actone:25R-(OH)-DB-26,23
R-1acton@: 25B-(OH)-Ds-26
,238-1actone: 25S-(OH:)-
Da-26,23R-1actone or a mixture of two or more thereof may be used, but especially 2s R-(O
H) -DB-26,23S-1 actone is preferred. The antitumor agent of the present invention contains the above-mentioned substances as active ingredients, and is used in various formulations as shown below. The antitumor agent of the present invention is administered by a parenteral route such as intraperitoneally, 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, sorbic acid, sugar or derivatives thereof, alcohol, physiological saline, surfactants, antioxidants, etc. may be used in combination with this substance.

This substance may be present in unit dosage form from 0.00002 to 4 times 1
%, preferably 0.0002 to 1%. In addition, this substance has a daily dose of 0.1μ to 10,000 for adults.
Administer 0.5 to 1000x9 by smearing or decapitation.

Example 1 Ni-562 derived from human leukemia and containing 10% beef tallow
1n grown in suspension in RPMI 1640 medium supplemented with supernatant.
Experiments were performed using vltro cultures. Suspend each cell in a medium so that the number of cells is I x 10" / 1 nt, dispense 5 cells into a petri dish, and incubate at 37°C 5%.
The cells were cultured in an incubator with an air atmosphere containing carbon dioxide gas. 25
ft-(OH)-DB-26,238-1actone
ld dimethyl sulfoxide (hereinafter abbreviated as DMSO)
25R at a final concentration of 0M80 or 0.5% by volume.
-(OH)-DB-26,238-1aeton· was added to a petri dish at a predetermined concentration, and after 3 days of culture, it was stained with trivan blue and the total number of viable cells was counted on the needle side. The results are shown in Table 1.

Table 1 Growth inhibition rate shows the percentage when compared with the vehicle (0M80) administration group.

As above, 25R-(OH)-Dl-26,238
-1actone is -562 at a concentration of s00ng/-
showed a cell proliferation inhibition rate of 68%.

Example 2 An experiment was conducted using an ln vitro culture strain that is human myeloma-derived LICR-LON-HMy2 and grows in suspension in RPMI 164G medium supplemented with 10% tallow serum. Suspend each cell in a medium so that the number of cells is 1X10"/-, dispense the 5-cells into a petri dish, and
The cells were cultured in an incubator with an air atmosphere containing 5% carbon dioxide at ℃. 25R-(OH)-D, -26,23S-1act
One was dissolved in DM80 and added to the extraction concentration, and after 3 days of culture, the cells were stained with Trivan blue and the total number of living cells was counted. The results are shown in Table 2.

Table 2 Growth inhibition rate shows the percentage when compared with the vehicle (DM80) administration group.

As above (,25R-(OH)-DB-26,23-1
Actone showed a 71% cell growth inhibition rate against LICR at a concentration of 9/ml.

Example 3 7 with 400W high pressure mercury lamp in argon bubbling
Triglyceride ester IKf of intermediate fatty acids was irradiated for 2 hours to eliminate impure reactive peroxides.
5R-(OH)-D, -26,238-1actone
Dissolve 5111p and add 25R-(O
H) Da 26.23S-1actone at 0.
The following shell components were heated and dissolved so as to contain 5 μm, and soft capsules were prepared in a conventional manner using a soft capsule making machine.

Shell formulation example Gelatin 10 parts by weight Glycerin 2 Anti-counterfeiting agent (ethylparaben) 0.05 tt Titanium White 0.2 Water 0.2 // (parts by weight in final form) Equal in 1 capsule Those containing 1μ, 2μq, or 5μ were respectively prepared.

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Claims (1)

[Claims] (1) 25-hydroxyvitamin D, -26,23-
An antitumor agent containing lactone as an active ingredient. 12125-hydroxyvitamin D, -26,23-lactone is 25R-hydroxyvitamin D, -26°23
The antitumor agent according to claim 1, which is an 8-lactone.