JPH0426621A - Anti-cancer enhancer - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to a novel anticancer enhancer.

[Prior art] In recent years, amphotericin B has been used as an anticancer enhancer that has shown effectiveness in improving the absorption of drugs that are difficult to absorb into cancer cells and enhances the anticancer effects of anticancer drugs such as pleomycin and adriamycin. etc. are being developed.

[Problems to be Solved by the Invention] However, anticancer enhancers such as amphotericin B have not yet reached the point where they exhibit significant efficacy.
Furthermore, there is a need for the development of excellent anticancer enhancers that enhance the anticancer effects of anticancer drugs.

[Means for Solving the Problems] Therefore, the present inventors have conducted extensive research to develop anticancer enhancers with excellent anticancer enhancing effects, and have found that a specific α
The inventors finally discovered that ω-diol exhibits a remarkable anticancer enhancing effect, leading to the completion of the present invention.

That is, the present invention provides α represented by the general formula (■): OHOH (in the formula, n represents an integer of 6 to 33),
The present invention relates to an anticancer enhancer containing ω-diol as an active ingredient.

[Example 2] In the present invention, the anticancer enhancer contains an α,ω-diol represented by the general formula (I) (wherein n is an integer of 6 to 33) as an active ingredient. .

In the general formula (I), when n is an integer smaller than 6, no anticancer enhancing effect is exhibited at all, and when n is an integer larger than 33, the anticancer effect is similarly inhibited. Therefore, in the present invention, n is an integer of 6 to 33.

In the α,ω-diol represented by the general formula (I), n
Those whose value is an integer of 12 to 18 exhibit a particularly large anticancer enhancing effect.

The α,ω-diol used in the present invention can be obtained by decomposing natural products such as wax. Examples of the natural products include waxes such as wool wax, spermaceti wax, beeswax, Chinese wax, raw white wax, and carnauba wax.

The αω-diol used in the present invention can be obtained, for example, by the following method.

Commercially available anhydrous lanolin (wool grease) is reduced with lithium aluminum hydride. This reduced lanolin is fractionated into two fractions by column chromatography using Florisil (trade name, manufactured by Florisil). The methanol fraction is further fractionated (see Figure 1).

The benzene fraction is separated, and the alicyclic compound fraction such as sterols and l-literpene alcohol is removed from the methanol fraction by a urea addition method, and the aliphatic compound fraction is separated. This method is performed as follows.

A sample is added to a saturated aqueous solution of urea, a saturated methanol solution, or a mixed solution thereof, and the solvent is gradually evaporated and removed under reduced pressure at 30°C. At this time, if the sample is dissolved in ethyl methyl ketone, isobutyl methyl ketone, 5ee-butyl alcohol, methylene chloride, etc., adduct formation is promoted. After filtering and washing the adduct crystals, the alicyclic compound and the aliphatic compound urea adduct are separated by column chromatography. By adding water to the urea adduct of an aliphatic compound, the urea adduct is decomposed. and,
Extract the aliphatic compounds using a separatory funnel.

The obtained aliphatic fraction is fractionated by HPLC using silica gel. Before fractionation) esterify the sample with p-nitrobenzoyl chloride so that the 1P1,C U■ detector can be used. The peaks separated by 11 PLC are separated and hydrolyzed to return to alcohol.

This separation method was according to the following literature.

Satoshi Dekan, Makoto Yamanaka, Kikuhiko Saikimoto and Fumio Saito, Allergens of Lanolin: Part I and ■, Part 1-I: Isolation and Identification of...
The Allergens of Hydrogenated Lanolin, Journal of the Society of
Cosmetic Chemistry, Volume 34, 99-i
6 pages (1983) (SATO8III TAKAN
O, MAKOTOYAMANAKA.

KIKUt (IKOOKAMOTO, and PU old O
5AITO.

Allergens or 1anolin: pa
rts I and II.

PART l: l5OLATION AND ID
ENTIFICATION 0FTIIE ALLER
GENS'OF HYDROGENATED LAN
0LIN.

JOURNAL OF THE 5OCIETY OF
CO3METICCHEMISTS, 34. p
99-116.19H) Specific examples of α,ω-diols include 1,16-hexadicanediol,
, 17-hebutadecanediol, 1.18-octadecanediol, ■, 19-nonadecanediol, 1.20
- Examples include eicosandiol.

These diols may be used alone or in combination of two or more.

To make the anticancer enhancer of the present invention into a preparation for injection or infusion,
Pluronic F is used in the α,ω-diol used in the present invention.
-08 (product name, manufactured by Asahi Denka Kogyo ■), lIC0-[i
o (trade name, manufactured by Nikko Chemicals), etc., and disperse with ultrasonic waves, or form liposomes or oil-in-water emulsions, and add preservatives such as methyl p-hydroxybenzoate, lentin, linoleic acid, etc. , a non-aqueous vehicle such as coconut oil, and a suspending agent such as glucose.

In addition, for oral preparations, binders such as gelatin, stabilizers such as magnesium stearate, excipients such as lactose, disintegrants such as potato starch, cellulose acetate phthalate, acrylic Capsules suitable for intestinal absorption may be prepared by forming an enteric coating with a methyl acid/methacrylic acid copolymer or the like. The anticancer enhancer of the present invention is also available in granules, sustained release capsules, halved capsules,
It can also be formulated as a nebulizer or buccal agent.

When the anticancer enhancer of the present invention is used as a parenteral administration agent such as intravenous, subcutaneous injection, or infusion, the dosage of the active ingredient (per kg of adult body weight per day) o, go ~ l [ 1
0 mg, particularly preferably 3 to 30 mg, and 0.01 to 60 g when used as an oral administration agent such as a capsule.
1, particularly preferably 0.08 to 1.5 g.

The anticancer enhancer of the present invention is effective not only for ascites cancer and leukemia but also for solid cancers, and has a wide range of indications such as adenocarcinoma, squamous cell carcinoma, undifferentiated carcinoma, and sarcoma of various tissues. has. In addition to cancer-transplanted animals, humans, mice, rats,
It is also effective against cultured malignant cells such as hamsters,
The anticancer enhancer of the present invention has a direct cancer cell killing effect, shows a promoting effect on the intracellular uptake of other anticancer drugs even at low doses, and is not species specific. It can be used as a medicine and a cancer chemotherapeutic agent for livestock and animals.

Furthermore, therapeutic effects have been observed not only by direct administration to the site of tumor implantation but also by remote administration. Acute toxicity LD50 is 3.1-15 g/kg by subcutaneous injection in rats, and 1-2 g/kg.
No side effects were observed even after continuous administration of 10 kg of the drug for 10 days.

The effect of α,ω-diol, which is the active ingredient of the anticancer enhancer of the present invention, will be explained below by giving Examples.

Examples 1 and 2 and Comparative Example 1 When pleomycin is used alone and when pleomycin is used and 1,16-hexadecanediol or 1.1
When using 8-octadecanediol in combination,
Mouse ascites cancer Ehrlich cells and human lung cancer type A
The cell killing effect (IC9o) was investigated using 349 cells.

The results are shown in Table 1.

As is clear from the results shown in Table 1, when the α, ω-diol used in the present invention is used in combination with an anticancer drug, compared to when the anticancer drug is used alone. It can be seen that the cell killing effect is significantly improved.

Examples 3 and 4 and Comparative Examples 2 and 3 106 Ehrlich ascites cancer cells were transplanted intraperitoneally into 5-week-old female mice of the ddY strain. After 24 hours, 0.25
Weight 96 Pluronic F68 physiological saline solution (Comparative Example 3
), a suspension of 1.00 mg/ml of pleomycin in 0.25 wt% Pluronic FG8 saline solution (Comparative Example 2), 1.00 mg/ml of pleomycin in 0.25 wt% Pluronic F68 saline solution
mg/ml, 1.16-hexadecanediol to 1.00 x 10' mg/ml suspension (Example 3), 0.25 wt% Pluronic P68
1. Pleomycin in saline solution. oomg/m
l, ■, 1.0OX of 18-octadecanediol
The suspension (Example 4) prepared at 10' rng/ml was
Group of 8 animals, Pluronic FB8 saline solution at 10 ml/kg/day as an aqueous solution, pleomycin alone at 10 mg/kg/day as solid content, and pleomycin in combination with anticancer enhancer at 11 mg/kg/day as solid content. Injected intraperitoneally for 5 days. Next, the average survival time of the injected mice was determined. The results are shown in Table 2.

[Margin below] From Table 2, it is recognized that the α,ω-diol used in the present invention is useful as an active ingredient of an anticancer enhancer.

[Effect of the invention] The anticancer enhancer of the present invention exhibits an excellent anticancer enhancing effect when used in combination with an anticancer drug, and furthermore, its active ingredient is derived from living organisms (higher animals), so it does not affect living organisms. It does not show any serious side effects.

[Brief explanation of drawings]

Figure 1 shows α and ω in the present invention. It is a flow chart showing a manufacturing method. of diol

Claims (1)

[Claims] 1. General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (in the formula, n represents an integer from 6 to 33) α,
An anticancer enhancer containing ω-diol as an active ingredient. 2. The anticancer enhancer according to claim 1, wherein the active ingredient is an α,ω-diol in the general formula (I), where n is an integer of 12 to 18.