JPS63258816A - Anticancer agent composition - Google Patents

Abstract

PURPOSE:To obtain an anticancer agent composition, containing an anticancer agent, such as vincristine, and a highly unsaturated fatty acid and capable of synergistically enhancing respective drug effects and reducing side effects. CONSTITUTION:An anticancer agent composition obtained by containing an anticancer agent having low selective toxicity selected from vincristine, daunorubicin, VP-16 and cisplatin and a highly unsaturated fatty acid (e.g. gamma-linolenic acid, arachidonic acid or eicosapentaenoic acid) having high selective toxicity. The anticancer agent is used at 1/10-1/10<5>:1 weight ratio to the highly unsaturated fatty acid.

Description

[Detailed description of the invention] [Industrial application field] TECHNICAL FIELD The present invention relates to an anticancer composition.

[Conventional technology]

In general, even with anticancer drugs, it is not possible to strictly distinguish between tumor cells and normal cells, and anticancer drugs are more or less cytotoxic and cause side effects. Therefore, a satisfactory anticancer agent with strong anti-tumor cellularity and very low normal cytotoxicity, so-called high selective toxicity, has not been developed.

On the other hand, the physiological activities of highly unsaturated fatty acids such as γ-lylunic acid, arachidonic acid, eicosapencitric acid, and docosahexaenoic acid have been studied in relation to prostaglandins and thromboxanes, and are used to treat various adult diseases. It is attracting attention as a medicine and preventive medicine. Furthermore, many studies have been conducted on the anticancer effects of these highly unsaturated fatty acids.
Some saturated fatty acids are also said to have this effect (Numata et al., Kagaku to Kogyo, Kaminia 63. (1986);
M.E.

Begin et al, Prostagrandi
ns Leukotrienes and Medici
ne 19:177, (1985)). The toxicity of these highly unsaturated fatty acids to normal cells is 20-60μP/
- The amount used (in vitro test) is low, and among them, γ-lylunic acid has almost no adverse effect on normal cells and has been recognized to have excellent antitumor cellularity.

The anticancer effects of highly unsaturated fatty acids have so far been demonstrated in osteosarcoma (o
esophageal cancer (steogenic sarcoma), esophageal cancer (es
ophageal carcinoma A), liver cancer (he
pa toma), breast cancer
inoma), lung cancer (lungcarcinoma)
, prostate cancer
) and other cultured tumor cells. The effective concentration of polyunsaturated fats in these tumor cells is 20
-60 μJ'/II/, its activity is less than 1/1000 compared to commercially available anticancer drugs, and direct contact between cancer cells and fatty acids is required. However, at these concentrations,
human fibroblast
, monkey kidney cell
), dog kidney cells
, bovine kidney cells
The toxicity of polyunsaturated fatty acids to normal cells such as It is clear.

[Problem that the invention seeks to solve]

Almost all conventionally used anticancer drugs have low selective toxicity and therefore have a problem of having large side effects. Furthermore, when highly unsaturated fatty acids are used alone as anticancer agents, relatively large amounts are administered, and direct contact between cancer cells and the fatty acids is required, so there are many problems that need to be solved in the method of administration.

The present invention is intended to solve these problems,
The purpose of this invention is to provide an effective anticancer composition with higher selective toxicity than conventional ones by coexisting highly unsaturated fatty acids with commercially available anticancer agents.

[Means for solving problems]

As a result of intensive studies, the present inventors have found that by coexisting a commercially available anticancer drug with low selective toxicity and a polyunsaturated fatty acid with high selective toxicity, the proportion of commercially available anticancer drugs used can be reduced, and its side effects can be further reduced. They discovered this and completed the present invention.

That is, the present invention is an anticancer composition characterized by containing an anticancer agent selected from pink crystals, daunorubicin, vP-16, and cisplatin, and a highly unsaturated fatty acid.

The anticancer agent in the present invention is vincristine, daunorubicin, VP-16, or cisplatin, which are often used clinically.

Further, the highly unsaturated fatty acid used in the present invention is a fatty acid consisting of a hydrocarbon chain having 18 to 24 carbon atoms and having 2 to 6 double bonds. Specific examples include linoleic acid,
Examples include n-6 series highly unsaturated fatty acids such as γ-lylunic acid and arachidonic acid, and n-3 series highly unsaturated fatty acids such as α-lylphinic acid, eicosapentaenoic acid and docosahexaenoic acid.

The ratio of the anticancer agent and the highly unsaturated fatty acid used in the present invention is 1/10 to 1/1 of the anticancer agent to 1 part of the highly unsaturated fatty acid.
105 (weight ratio) is preferable.

The present invention is suitable for neuroblastoma cells, which are known to be resistant to conventional chemotherapy and have a high mortality rate among childhood cancers. In particular, cultured human neuroblastoma cells, such as the GOTO strain (a strain established at the University of Tokyo Institute of Medical Science), NKP
strain (established at St. Seude Children's Hospital, USA),
5K-N-D2 strain (established at Sloan Kettering Cancer Institute, USA), NCG strain (established at St. Seude Children's Hospital, USA), etc. are suitable.

The anticancer composition of the present invention, which uses a combination of an anticancer drug and a highly unsaturated fatty acid, can be used in various dosage forms by adding additives such as solvents, fillers, and excipients.

〔Effect of the invention〕

By using the anticancer drug of the present invention and a highly unsaturated fatty acid together, it is possible to enhance the effects of each drug through synergistic action. This makes it possible to obtain safer pharmaceuticals.

The anticancer composition of the present invention can be used as usual in applications where vinculi, sutin, daunorubicin, VP-16, or cisplatin is used.

(Example) The present invention will be explained with reference to Examples.The highly unsaturated fatty acids used are all 99 purity products.

Test method: Kostar IJ 12 consecutive petri dishes (1 petri dish: inner diameter 23
■ Inject 2 ml of RPM11640 medium supplemented with 100% tallow serum into a cylinder (φ x 17m high + 11mm), seed human neuroblastoma cells at 5x10 cells, and sterilize with 50% carbon dioxide gas. The cells were cultured for 48 hours at 37°C in air.

(a) Anticancer drug only (b) A combination of anticancer drug and highly unsaturated fatty acid was added in a predetermined amount to the medium as a 0.5% ethanol solution, and cultured for further 96 hours.

The number of living cells was measured by Trivan blue staining, and the 50% inhibitory concentration (IC5) of the anticancer drug against human neuroblastoma cells was determined.
o), and further reduced the I cso of the anticancer drug by adding a predetermined amount of highly unsaturated fatty acids.
/ml medium (final concentration) according to the above test method.

was calculated.

As a result, the IC5o of vincristine in the presence of γ-lyl/acid was 1.2 nJ'/a/medium, and the ICso of vincristine alone was 3.8 nJ'/i.
d medium. Therefore, it was found that the amount of vincristine used was reduced to 32 days by using 1-lirunic acid in combination.

Example 2 In Example 1, GOTO stock was used instead of NCG stock,
eicosapentaenoic acid 40 instead of r-linonnic acid
A similar test was performed using PP/ml medium.

As a result, the I cso of vincristine in the presence of eicosapentaenoic acid was 1.6 nP/Me medium, and the I cso of vincristine in the absence of eicosapentaenoic acid was 3.8 nJ'/m/medium. Ta.

Therefore, by addition of eicosapentaenoic acid in Example 3, 5K-N-DZ instead of NCG strain in Example 1
strain, daunorubicin instead of vincristine, r
- Arachidonic acid 40 μP/l medium was used instead of lyrinnic acid, and the same hardness was used.

As a result, the I cso of daunorubicin in the presence of arachidonic acid was 8. On 91 ml medium, the efficiency of daunorubicin in the absence of arachidonic acid was 12.5 nP/w+l medium. Due to the addition of arachidonic acid, the amount of daunorubicin used is 6
It became clear that section 4 was sufficient.

Example 4 In Example 1, VP-1 was used instead of vincristine.
6, α-lylunic acid 40μ//instead of γ-lylunic acid
ml medium was similarly tested.

As a result, the I of vP-16 in the coexistence of α-lylunic acid
cso is 0.13 μp/lIl medium, α-
The IC50 of VP-16 in the absence of lylunic acid is 0.
．． 16μ, P/1 medium. Therefore, it has become clear that the amount of VP-16 used can be reduced to 81 by adding α-lylunic acid.

Example 5 In Example 1, the NKP strain was used instead of the NCG strain, cisplatin was used instead of vincristine, and docosahexaenoic acid 60 μ//ml medium was used instead of r-lylunic acid.

As a result, the I Cso of cisplatin in the presence of docosahexaenoic acid was 39 nJ'/d medium, and the I Cso of cisplatin in the absence of docosahexaenoic acid was 39 nJ'/d medium.
so was 50 nP/ml medium. Therefore, it was revealed that the amount of cisplatin used could be reduced by 78% by adding docosahexaenoic acid.

As described above, it has been found that by using an anticancer drug and a highly unsaturated fatty acid in combination, it is possible to enhance the effect of the anticancer drug and reduce Icso, and the amount of reduction reaches a maximum of 68%.

Claims (1)

[Claims] 1. An anticancer composition comprising an anticancer agent selected from vincristine, daunorubicin, VP-16, and cisplatin and a highly unsaturated fatty acid.