JPS58208223A - Antitumor agent - Google Patents

Abstract

PURPOSE:To provide an antitumor agent exhibiting cytocidal activity against cancer cells in vitro, by using 1alpha,24,25-trihydroxycholecalciferol as an active component. CONSTITUTION:1alpha,24,25-Trihydroxycholecalciferol of formula is used as an active component. The compound exhibits proliferation inhibiting effect and cytocidal effect in vitro to tumor cells such as K-562 cell derived from human leukemia, LICR-LON-HMy2 cell derived from human myeloma, etc. Furthermore, antitumor effect can be observed in the test using mouse and rat as the host. Dose: 0.1-10,000mug, preferably 0.5-1,000mug daily for adult by parenteral or oral administration.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an antitumor agent containing 1α, 24, 25-trihydroxycholecalciferol.

Currently used antineoplastic agents include alkylating agent 2 antimetabolites, antibiotics, plant alkaloid agents, and immunotherapeutic agents.
Many of the drugs that exhibit cell-killing effects also have strong side effects.

As a result of our research on biological substances (1α, 24.25-) lyhydroxycholecalciferol (hereinafter referred to as this substance), we found that 1α, 24.25-(OB
)m-D) has been found to exhibit a cytocidal effect on cancer cells in vitro.

This substance has the following structure, for example, JP-A-55-2
No. 2655 and Japanese Unexamined Patent Publication No. 55-22656K.

1α, 24.25-(OH), -D, 1α,
24R,25-(α()s-Da) We in
When the antitumor effect of this substance was investigated in vitro using human leukemia-derived Ni-562 cells, human myeloma-derived LICR-1, ON-HMy 2 cells, tumor cell growth suppressive or cell killing effects were observed. .

Furthermore, tests conducted using mice and rats as hosts showed that anti-I
II! A tumor effect was observed.

This substance is】α=24R-25-(OH)a-Da −
1α, 248,215-(0H)a-Ds or a mixture thereof. 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 include tablets, powders, granules,
It is used in dosage forms such as suppositories, capsules, alcoholic solutions, oily solutions, and aqueous suspensions. As the oily solvent, triglyceride 9 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, sugar or its derivative alcohol, physiological saline, surfactants, antioxidants, etc. may be used in combination with this substance.

The substance may contain 0.0QOO2 to 4% by weight, preferably 0.0002 to 1% by weight in a unit dosage form. In addition, this substance is for adults] 1 Todoro p0.14 ~ 10,000
4, preferably 0.5-1000 pIi.

Example 1 Human leukemia-derived 0K-562 incubator grown in suspension in RPMI 1640 medium supplemented with 1051 tallow serum.
vitr.

Experiments were conducted using cultured strains. Each cell number is 1x
Suspend in medium and soil so that the ratio is 10'/WlJ, and
- was dispensed into a petri dish and cultured in a 37C incubator with an air atmosphere containing 5% carbon dioxide gas.

1α, 24R,25=(OH)a-Da is dissolved in dimethyl sulfoxide (hereinafter abbreviated as IMsO), and DM
When the final concentration of SO is 0.5 volume, 1αl 24Rj 2
5-(α()a-Da) was added to a petri dish at a predetermined concentration, and after 3 days of culturing, it was stained with Torinoson Blue and the number of nematode cells was counted. The results are shown in Table 1.

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

As mentioned above, 1α, 24R-25-(OH)m-Da is 10n! At a concentration of il/M, it showed a cell growth inhibition rate of 79% against -562.

A similar experiment was carried out using 1α, 248, 25-(OH) Hatake-
The results were obtained as shown in Table 2'.

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

As above, l'', 248.25- (0H)a
-Da tj: -56 at a concentration of 500 nip/rat
2 showed a cell proliferation inhibition rate of 67%.

Example 2 Human myeloma-derived (D LICR-1, ON-HMy
Experiments were conducted using an in vitro culture strain that grows in suspension in RPMH640 medium supplemented with fetal serum.

Medium V so that the number of cells is lXl0'/-
cl! ! The mixture was made cloudy, and 05rR1 was dispensed into C'1'-V and cultured in a 37tl' incubator in an air atmosphere containing 5% carbon dioxide gas. 1α+ 24B+ 2*-(OH%-D
A was dissolved in DM80 and added to a predetermined concentration, and after 3 days of incubation, it was stained with trivan blue and the number of nematode cells was counted. The results are shown in Table 3.

Table 3 The growth inhibition rate shows superiority when compared with the vehicle (DMSO) administration group.

As mentioned above, lα, 24R, 25-(OH-containing, is 5
nli/Tnl (D concentration) showed a cell proliferation inhibition rate of 91% against LICR.

A similar experiment was conducted using 1α'+ 248125-(OH)8-DI, and the results shown in Table 4 were obtained.

Table 4 The growth inhibition rate shows superiority when compared with the vehicle (DMSO) administration group.

As mentioned above, 1(L24S,25-(OH)a-Da) exhibited a cell proliferation inhibition rate of 86% against LICR at a concentration of 500n51/M.

Example 3 Triglyceride esters of intermediate fatty acids were irradiated for 72 hours with a 400W high-pressure mercury lamp in alumino-zeta pulling to eliminate impure reactive peroxides.
(r-24R125-(OH)s-Da 5m1iF was dissolved and IJ24R*25-(O
H) The following shell components were heated and dissolved to contain a-Ds of 0.54, 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 Preservatives (ethylno, F-laben) 0.05 // Titanium white 0.2 parts by weight In the same way, capsules containing 11 IJl, 2 μy, or 5 parts were prepared, respectively. did.

Agent Yoshio Kawaguchi Procedural amendment dated August 7, 1982 1, case description 1981 Patent Application No. 90591 2
, Title of the invention: Anti-tumor agent 4, Agent: Yamada Building 7, 1-1-14 Shinjuku, Shinjuku-ku, Tokyo, Subject of amendment: Specification 11-8, Contents of amendment: The second page of the present specification is attached as an attached document. Tooshi correction.

There are various drugs such as alkylating agents, antimetabolites, antibiotics, plant alkaloids, and immunotherapeutics, among which ln
Many drugs that exhibit cell-killing effects in vitro also have strong side effects.

As a result of our conventional research on biological substances, we found that 1α,24.25-) lyhydroxyprecalciferol (hereinafter referred to as this substance or 1α,24.25-(OH
)s-D) exerts a cytocidal effect on cancer cells in vitro.9.

This substance has the following structure, for example, Tokkaicho 55-2
No. 2658 and Special No. 11mlt@55-22656.

Claims (3)

[Claims] (1) An antitumor agent containing 1α, 24.25-)licht-10xycholecalciferol as an active ingredient. (2) 1α, 24.25-) Lich P Roxy; The tumor agent according to claim 1, wherein the lecalciferol is 1α* 24R+ 20-trihydroxycholecalciferol. (3) The antitumor agent according to claim 1, wherein the 1α,24.25-trihydroxycholecalciferol is lα,248.25-trihydroxycholecalciferol.