JPS5938929B2 - anticancer drug - Google Patents

Description

[Detailed description of the invention] The present invention relates to a novel anticancer agent.

Recently, cancer has come to be cited as a major cause of death in humans, and therefore research and development of anticancer drugs is being actively carried out both in Japan and abroad.

As a result, many anticancer drugs have been discovered, and although some are in clinical use, cancer has not yet been completely controlled. The present inventors conducted various studies in order to invent an excellent anticancer drug, and as a result, they discovered an anticancer drug that has excellent effects and has almost no toxicity.

That is, the present invention relates to an anticancer agent containing squalene-2,3-epoxide or squalene and squalene as main ingredients.

The squalene used in the anticancer agent of the present invention can be obtained, for example, by extracting from the liver of sharks (lamina crocodiles, excluding rays) or by chemical synthesis, and includes squalene-2 and 3. - Epoxides can be obtained by oxidizing squalene.

One example is removing the liver from a shark, fractionally distilling the contents of the liver, treating it with a solvent (e.g. ethanol), and then fractionally distilling the liver, which has a boiling point of about 350°C (350°C).
0 mmHg) purified squalene is obtained. squalene-2
・To obtain 3-epoxide, this material is mixed with, for example, T,
D. Willett et al.'s method [T., Biol, Chem.
, 242, 4182 (1967)], and after purification, it is treated with an alkali. The Rf value on thin layer chromatography of epoxide is approximately O.4
(developing solvent benzene) and gives a characteristic peak m/e426 in the mass spectrum. The toxicity of this squalene and its epoxide is extremely low, and the acute toxicity in the latch is LD5o of 35y/9 or more when administered orally, and even if 8V/kg is orally administered to the latch every day for one continuous month, there is no pathology. No adverse effects were observed visually or histopathologically.

Such low toxicity is rarely seen with conventionally known anticancer drugs. The anticancer agent of the present invention is effective when administered orally or parenterally, but the effect is particularly remarkable when administered orally.

For oral administration, various forms of conventional oral preparations can be used, and for example, those encapsulated in soft gelatin capsules can be used. The unit dosage form for oral administration of the anticancer agent of the present invention is squalene-2.
3-epoxide or squalene 50-500
Examples include those in which ~ is encapsulated in capsules. The dosage varies depending on age and symptoms, but for example, 500 to 2,000 or more of the active ingredient is orally administered 1 to 3 times a day. The anticancer agent of the present invention can provide excellent anticancer effects when used alone or in combination with other anticancer agents or other treatments.

The therapeutic effect can be particularly enhanced when used in combination with surgical treatment such as cancer removal surgery or radiotherapy. Furthermore, one of the characteristics of the anticancer agent of the present invention is that it can prevent metastasis of cancer to the lungs, which cannot be treated with other anticancer agents. The anticancer agent of the present invention has a more remarkable anticancer effect than conventionally used anticancer agents, has extremely low toxicity, has no side effects even when used repeatedly, and has extremely high practical value. The anticancer effect of the anticancer agent of the present invention will be specifically shown below.

Example 1 1CR mice (female) were divided into groups of 6, and sarcoma 18
107 cancer cells of the ascites type were transplanted subcutaneously into the right sore of a mouse, and 24 hours later, squalene-2 and 3 were implanted.
-Epoxide, 1/50T119 per mouse
It was administered orally once a day for 10 days.

After 4 weeks, when comparing the tumor weight of mice in the untreated group with the tumor weight of mice treated with squalene-2,3-epoxide, the tumor growth rate in the treated group was inhibited by 49%. It was done.

At the same time, add 50% of PS-K, an extract of C. versicolor.
When the same amount of 0 Tf19/Kg was orally administered, the inhibition rate was only 8%. Example 2 In order to examine the effect of the anticancer agent of the present invention on preventing cancer metastasis, a metastasis prevention test was conducted using a type of cancer that causes lung metastasis, that is, Lewis lung cancer.

107 cancer cells of Lewis lung cancer. was removed from a solid tumor and transplanted into the right hoof of BDFL female mice (10 mice per group). 24 hours after transplantation, 50 mg of squalene-2,3-epoxide per animal was orally administered 10 times every other day. The cancer transplanted to the hoof grew, and when the leg was amputated from the thigh two weeks later, the untreated group only survived for an average of 27 days after the transplant, all due to lung metastasis of the cancer. He died. However, in the treatment group administered with squalene-2,3-epoxide, the animals survived for an average of 36 days, showing a marked increase in the number of days of survival. In this way, there have been almost no examples of lung cancer drugs preventing lung metastasis by increasing the host's resistance to cancer. Example 3 BDF1 female mice were divided into groups of 6 mice, and the first group was given squalene-2.3 epoxide 55η once a day per mouse.
The mice were orally administered for 5 days, and the second and third groups were orally given distilled water as a control.

One day after administering the drug, mouse leukemia L-1210
1.0×10 5 ascites-type cells are implanted intraperitoneally. Twenty-four hours after implantation, the first and second groups of mice will be whole-body irradiated with 600 rats of radiation. At this time, the average survival days of the mice in the third group, that is, the untreated group, was 8.0 days, and the average survival days of the mice in the second group, that is, the group that was treated with radiation only.
However, the average survival days of the mice in the first group, that is, the group treated with oral administration of squalene-2.3 epoxide and radiotherapy, was 11.2 days, and the average survival days extension rate was 40%. It was hot. Reference Example (Production of squalene-2,3-epoxide) Squalene 5y. N-bromosuccinimide 2.

57 is dissolved in 86 ml of tetrahydrofuran and 24 ml of water, stirred for 1 hour at 0.degree. C., extracted with benzene, washed with water, dried, and the benzene is distilled off to obtain a crude bromohydrin.

This product is purified using a silica gel column, and the effluent fractions are collected using hequinanebenzene (2:3) to obtain pure bromohydrin with a yield of about 20%.

This was mixed with 200ml of methanol, 11 potassium tannate (K2CO3
) 107 for 15 minutes under reflux, extracted with ether after cooling, washed the ether layer with water, dried over sodium sulfate, and distilled off the ether to obtain squalene-2,3-epoxide.

Note that the crude bromohydrin obtained by this method is a mixture with squalene, so a mixture of squalene-2,3-epoxide and squalene (approximately 1:2) obtained by treatment with an alkali without purification is used. However, we found similar cancer-fighting effects.

Claims (1)

[Claims] 1. An anticancer agent containing squalene-2,3-epoxide or squalene and squalene as main ingredients.