Antitumor agent

Details Antitumor agent Antitumor agent

1979-08-16

1982-03-16

Demers, Arthur P.

Drug, bio-affecting and body treating compositions

Nonspecific immunoeffector, per se ; or nonspecific...

Bacterium or component thereof or substance produced by said...

2603455, 542426, C07D31170

Patent

active

043201415

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to an antitumor agent containing as the active ingredient an .alpha.-tocopherol vitamin A acid ester. Further, this invention relates to novel compound, .alpha.-tocopherol-13-cis-vitamin A acid ester.


BACKGROUND ART

Vitamin A acid has already been known to possess antitumor activity and recognized as being effective for prophylaxis of development or therapy of experimental tumor developed on epithelial cells. However, the vitamin A acid is quite strongly toxic and due to this properties, vitamin A acid has not been brought into practice up to now as an antitumor agent.


DISCLOSURE OF INVENTION

As a result of our extensive researches with a view to overcoming defects according to prior arts, we found that .alpha.-tocopherol vitamin A acid ester (chemical nomenclature: tocopheryl retinoate) possesses the antitumor activity and shows very low toxicity.
The term .alpha.-tocopherol as used in this invention indicates dl-.alpha.-tocopherol or d-.alpha.-tocopherol and the term vitamin A acid indicates one in the all trans-form or 13-cis-form. Vitamin A acid ester of 13-cis-form is a novel compound and a process for the preparation thereof is explained below. Such process includes a process which comprises subjecting both 13-cis-vitamin A acid and .alpha.-tocopherol used as the starting materials to ester linkage or a process which comprises converting all trans-form vitamin A acid ester into 13-cis-form ester by isomerization. The process comprising formation of ester linkage may be carried out according to a known ester formation reaction, for example, the process described in Japanese Pat. No. 26632/1974. As the process for the isomerization, there can be applied a known photoisomerization process for carotenoids.
Acute toxicity in mice of .alpha.-tocopherol vitamin A acid ester which is the active ingredient of the antitumor agent of this invention is particularly low as shown below, even when any route of administration such as oral route, intraperitoneal route or intravenous injection is applied.


______________________________________ LD.sub.50 Values in Mice Oral Intraperitoneal Intravenous administration administration injection ______________________________________ .alpha.-Tocopherol- more than more than more than trans-vitamin A 10g/kg 10g/kg 1g/kg acid ester .alpha.-Tocopherol- more than more than more than 13-cis-vitamin A 10g/kg 10g/kg 1g/kg acid ester Vitamin A acid 780mg/kg 150mg/kg 92mg/kg ______________________________________
Physiological activities of the .alpha.-tocopherol vitamin A acid ester used in the present invention as the active ingredient are shown below.
(1) Prophylactic effect on development of tumor
To groups of 10 ICR mice, was applied 0.2% acetone solution of a cancerigenic agent, dimethylbenzanthracene (abbreviated hereinafter as DMBA) by coating said solution on the depilated back of the mice once a day for two weeks. From one week after the final administration of DMBA, an acetone solution of. 0.06% croton oil and a lotion containing an acetone solution of 0.06% croton oil and the active ingredient according to the present invention were coated successively on the back once a day for 4 months.
The lotion used above was prepared according to the following process:
A desired amount of .alpha.-tocopherol vitamin A acid ester was dissolved in 10 g of ethyl alcohol together with 0.5 g of polyoxymethylene sorbitan monolaurate and 6 g of glycerin and purified water were added thereto to make up the total 100 g. The solution thus obtained was stirred thoroughly to give lotion.
Test results obtained are shown below in table.


______________________________________ Admini- Number of animals stration in which tumor was Treatment route developed ______________________________________ Control 0 0.3% Lotion of .alpha.- percutaneous 0 tocopherol-trans- vitamin A acid ester 0.3% Lotion of .alpha.- " 0 tocopherol-13-cis- vitamin A acid ester Cro

REFERENCES:
patent: 2231125 (1941-02-01), Karrer
patent: 3151127 (1964-09-01), Spaivel
patent: 3878202 (1975-04-01), Fukawa et al.
Komatsu et al., Chem. Abstracts, 89 (1978), #100352.
The Merck Index, 7th edition, Merck and Co., N.J. p. 1097.

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