JPH0418016A - Cancer suppressing agent - Google Patents

Abstract

PURPOSE:To obtain a cancer suppressing agent comprising ntritriacontane-16,18- dione, a compound having a beta-diketone structure contained in a plant composition, as a main component. CONSTITUTION:A cancer suppressing agent comprising n-tritriacontane-16,18- dione shown by the formula as a main component. n-Tritriacontane-16,18-dione shown by the formula is a component contained in leaf wax of eucalyptus and can be obtained by extraction and chemical synthesis.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to cancer suppressants obtained from plant components.

[Prior art and problems to be solved by the invention] Many antitumor agents and cancer suppressors have been developed and put into practical use, but they all have advantages and disadvantages in terms of antitumor effects and side effects, and it is difficult to meet the necessary conditions. The current situation is that there is no solution that is fully satisfactory. Therefore, the development of therapeutic agents for new types of cancer is desired.

Cancer occurs when target cells become cancerous due to the action of carcinogenic factors, and only after they proliferate can it be recognized as an obvious cancer. During this period, carcinogenesis may be promoted or inhibited by the involvement of numerous internal or external factors. is known to be modified.

In recent years, the carcinogenicity of food additives has been viewed as a problem, and many studies have been conducted and reported.

Long-term observation is required to investigate the in vivo antitumor and isogenic properties of chemical substances. especially,
The current search for ismagenicity requires approximately 30% until the final evaluation.
Long-term isletogenicity tests that require years have been conducted, but since the time and cost required for this is extremely enormous, various screening methods have been tried before conducting long-term isletogenicity tests.

The A+WES test method, which is a typical search method, is 1nv
This is a mutagenicity test using the itro method, and a large number of false positives and false negatives were observed.
It has been desired to develop a more accurate 1nviν0 medium-term search method that connects the ro long-term search method (Weis-burge
r J, H, eL, a], 5science, 21L
401-407゜1981).

[Means to solve the problem]

The present inventors investigated methods for testing and evaluating the antitumor and isletogenicity of chemical substances in vivo, and considered a more accurate in vivo medium-term search method that connects long-term isletogenicity tests and in vitro short-term search methods. and reported it.

1) N, ITO et al, Carcinog
enesis, 9+ 387-394, 1988 2) N. ITO et al., CRCCr1ti
caJ Reviews in Toxicology,
19+ 19893) Ito Practice, Cancer and Chemotherapy, 7
．． 55-63.19804) Akihiro Fukushima, General Clinical Practice, 3
0.215-218.19815) N, ITOet
al., Gann, 71.415-416.19
806) N, Summer TOet al,, Tox
icologic Pathology, 10
+37~49.1982 In other words, the in vivo mid-term search method using precancerous lesions as an indicator can determine not only the carcinogenicity of a compound but also its inhibitory effect, and is an excellent method for screening chemical substances from a wide variety of perspectives. It is.

The present inventors used this method to screen for chemical substances that have an antioxidant effect, and as a result, they discovered that compounds with a β-diketone structure contained in plant ingredients have a cancer-suppressing effect, and thus completed the present invention. .

That is, the present invention provides a cancer suppressant characterized by containing n-tritriaconcune-16,18-dione represented by the following formula (r) as a main component.

The n-4 lydria concun-16,18-dione of the present invention is a component contained in the leaf wax of a eucalyptus tree, and can be obtained either by extraction or chemical synthesis. This component has been isolated and structure determined (8usL, J
, Chcv, 1964.17°464).

Antioxidants generally do not show mutagenicity against grouperia, such as in the Awes test, and are known to suppress mutagenicity caused by mutagens (Kahl R, T
oxycology, 33.185.1984).

Furthermore, in carcinogenesis experiments, it has been found that when administered at the same time as carcinogenic substances, carcinogenesis in the forestomach, pancreas, mammary gland, skin, etc. is suppressed.

(Wattenberg L, W, J, Envir
on, Pathol, Sci.

Health, C(4), 42.1986) Therefore, antioxidants not only exhibit antioxidant effects, but also attract attention as chemopreventive agents against carcinogenesis.

For example, butylatedh, a typical antioxidant,
Hydroxy anisole (BHA) and buty
lated hydroxytoluene (BIT)
Notoku phenolic antioxidants, feed-use antioxidants, etc.
A study by Wattenberg et al. has reported on the suppressive effects of drugs such as hoxyquinone (Wa et al.
ttenberg, L., W., J., Nath, Can.
cer In5t, +60, 11-18.1978).

Many studies have also been conducted on the carcinogenesis-inhibiting mechanism of antioxidants.

For example, the inhibitory effect of antioxidants is due to the fact that the reactive group of the carcinogenic agent reacts with the antioxidant and is captured, resulting in the deactivation of the active form, and that the enzyme system involved in the metabolism of the carcinogenic agent is modified. This is thought to be due to the effect of indirectly inhibiting the production of active forms of carcinogens.

The inventors have discovered that many antioxidants, such as henzpyrene and 7,
It has been reported that when administered simultaneously with, immediately before, or immediately after carcinogens such as 12-dimethylbenzanthracene (BMB8) and diethylnitrosamine (DEN), it is possible to suppress carcinogenesis in labeled organs caused by these substances (N, rTOet).
al,, Adv, Cancer Res. .

1989, Ito Jitsugyo et al., History of Medicine, 141.96
5°1987).

In addition, BHA and aromatic amine 3,2゛-dimethyl-
When 4-aminobiphenyl (DMAB) or N-methylnitrosourea, which is an alkylating agent and does not require metabolic activation, was co-administered and the modifying effect was investigated, B)I
It has been reported that A inhibits DMAB4-induced cancer expression, but significantly promotes bladder carcinogenesis (Shibata et al. 1 General Meeting of the Japanese Cancer Society, Journal 47.80°, 1988).

Moreover, tumors in the forestomach and bladder are promoted by administration of BH^, but carcinogenesis in the liver and mammary glands is suppressed after administration of N-ethyl-N-hydroxyethylnitrosamine (EHEN). On the other hand, when catechol is given after administering dimethylhydramine or 2゜2゛-dihydroxypropylnitrosamine (DHPN), etc., it has a strong promoting effect on carcinogenesis in the tongue, esophagus, forestomach, glandular stomach, etc.; On the contrary, tumor development is suppressed.

Therefore, when an antioxidant is administered after administration of a carcinogen, that is, during the promotion stage of two-stage carcinogenesis, it exhibits a carcinogenesis-modifying effect. In other words, the completely contradictory modifying effects of promoting or suppressing carcinogenesis are expressed in various carcinogenic target organs of the same animal to which the same antioxidant is administered.

In order to improve the efficiency of searching for antitumor and isletogenic properties of compounds, the present inventors have developed a wider search system using a single device and a mid-term search method for carcinogenicity in multiple organs in a test system. As, DHPN, EIIEN, DMA
When administering B in stages and examining the carcinogenic modulating effects of various antioxidants, n-tritriaconcun-16,18-
They discovered that dione has an excellent cancer suppressing effect and completed the present invention.

The acute toxicity value (LD, (mouse oral)) of n-tritriaconcune-16,18-dione represented by formula (I), which is the main component of the cancer suppressor of the present invention, is 2 g/
It was more than kg.

The method for formulating the cancer suppressor of the present invention is not particularly limited. For example, when preparing as an oral solid preparation, n-tritriaconcune-16 represented by the above formula (I),
After adding excipients to I8-dione, and further adding binders, disintegrants, lubricants, coloring agents, flavoring/fragrances, etc. as necessary,
Form into powder, tablets, coated tablets, powders, granules, powders, capsules, etc. using conventional methods.

The cancer suppressor of the present invention is administered orally or parenterally. The dosage depends on the severity of symptoms (patient's age, gender,
It is not particularly limited and varies depending on the dosage (body weight, sensitivity, etc.), administration method (administration period, interval), properties of the pharmaceutical preparation (preparation, type), etc.

〔Effect of the invention〕

Hereinafter, the present invention will be explained in detail using experimental examples.

Experimental Example 1 (Carcinogenesis-modifying effect) In order to examine the carcinogenic-modifying effect of antioxidants in the carcinogenic process, a study was conducted using a compound having a natural antioxidant effect.

(I) Materials and Methods Using 6-week-old aF344 rats, 2.2゛-
Dihydroxypropylnitrosamine (DHPN) 1
000■/kg, N-ethyl-N-hydroxyethylnitrosamine (EHEN) 1500mg/kg in the second week
kg, 75 g/g of 3,2'-dimethyl-4-aminobiphenyl (oMAB) was administered twice each in the 3rd week, and then 1% γ-oryzanol and 2% γ-oryzanol were administered in the 4th week, respectively.
Phytic acid, 1% tannic acid, or 0.2% n-tritriacontane-16°18-dione was administered in the diet until 36 weeks.

After administration, the animals were sacrificed and autopsied, and various organs throughout the body were examined histopathologically.

In addition, the targets are DHPN, EIIEN, DM
After administering Hachihe, use one without administering antioxidants,
After 36 weeks, the cells were sacrificed and histopathologically examined in the same manner.

(2) Results The results are shown in Table 1.

As is clear from Table 1, a significant increase in lung cancer was observed in the T-oryzanol administration group compared to the control group. Bladder papillomas were significantly increased in the phytic acid administration group. On the other hand, in the n-tritriacontane-16,18-dione administration group, a significant decrease in hepatocellular carcinoma and eosinophilic cell nests in the pancreas was observed. Furthermore, tannic acid had neither promoting nor suppressing effects on carcinogenesis.

Therefore, it is considered that the multi-organ mid-term insulogenicity test clearly shows that it is possible to search not only for the carcinogenicity of chemical substances, but also for their carcinogenesis-inhibiting effects and their target organs.

Claims (1)

[Claims] n-tritriacontane represented by the following formula (I)
A cancer suppressor characterized by containing 16,18-dione as a main component. ▲There are mathematical formulas, chemical formulas, tables, etc.▼…(I)