JPS58152816A - Enhancer for carcinostatic effect and enhancement of carcinostatic action - Google Patents

Abstract

PURPOSE:An enhancer for carcinostatic effect effective for enhancing the effect of a carcinostatic agent effective against cancerous cell, manifesting carcinostatic action on a cancerous cell having low sensitivity, reducing the dose of the carcinostatic agent, lowering side effects, etc., comprising nicardipine or its salt. CONSTITUTION:An enhancer for carcinostatic effect of a carcinostatic agent comprising nicardipine or its salt. Nicardipine or its salt raise the concentration of the carcinostatic agent (e.g., adriamycin, daunomycin, etc.) in a cancerous cell, and promote its accumulation and maintenance ratio, so that the effect of the carcinostatic agent is extremely enhanced. Consequently, they manifest the carcinostatic action of the carcinostatic agent not only on a cancerous cell wherein the carcinostatic agent is effective against it, but also on a cancerous cell having low sensitivity to it. Consequently, by the use of both nicardipine or its salt in combination with the carcinostatic agent, the reduction of the dose of the carcinostatic agent and side effect, the enlargement of carcinostatic spectrum, and the conquest of cacinostatic resistance, can be expected.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an anticancer effect enhancer and a method for enhancing anticancer effect. More specifically, the present invention relates to an anticancer drug effect enhancer containing nicardipine or a salt thereof, and a method for enhancing the anticancer effect of an anticancer drug by using nicardipine or a salt thereof in combination.

Nicardipine [Chemical name: 2,6-cymethyl-4-(3
'-nitrophenyl)-1,4-cyhydrohyricine-3
, 5-dicarbonyl-3-methyl ester-5-
[beta]-(N-benzyl-N-methylamine) ethyl ester] or a salt thereof has coronary and cerebral vasodilatory effects.

It is a useful drug for the treatment of cerebrovascular disorders, hypertension, and angina pectoris. Examples of the salts of nicardipine include pharmacologically acceptable acid addition salts, such as acid addition salts with acids such as hydrochloric acid, hydrobromic acid, and phosphoric acid.

Research and development of anticancer drugs has been actively conducted for a long time, and various anticancer drugs are used clinically to treat cancer. Although the results are improving year by year, in many cases it is only temporary, and the effect is not necessarily satisfactory in completely suppressing cancer growth and allowing patients to survive for a long period of time. In addition, many attempts have been made to enhance the anticancer effect and reduce side effects by combining conventionally used anticancer drugs with various other anticancer drugs, but none of them are based on cancer chemistry. It is not definitive as a therapeutic agent. In the current state of cancer chemotherapy, where the development of newly regulated cancer drugs is becoming increasingly difficult, it is an important issue to try to enhance the effectiveness of existing anticancer drugs. It is well known that many anticancer drugs are transported into cells through cell membranes and exert their effects, and their effects are closely related to the degree of intracellular accumulation and maintenance of the drug. be. In addition, when cancer cells have low sensitivity to a certain anticancer drug, or when cancer cells have become resistant to a certain anticancer drug (acquired resistance), which is a serious problem in cancer chemotherapy, the mechanism is It is known that this is often due to a decrease in the accumulation and maintenance of cancer cells.

In order to increase the intracellular accumulation and maintenance rate of anticancer drugs, two methods can be considered: (1) increasing the transport of anticancer drugs into cancer cells; and (2) inhibiting the outflow of anticancer drugs from cancer cells.

Regarding (2), it is possible to use metabolizing substances such as vitamin A, polyene compounds, and lipids, or to attach an anticancer drug to a carrier to give it membrane affinity, and to have it taken up by a transport mechanism different from that of the original anticancer drug. It has been reported that transport into cells can be enhanced by imparting non-hydrophilic properties to anticancer drugs and increasing their membrane affinity. However, there have been very few reports regarding ■.

The present inventors focused on substances that inhibit the outflow of anticancer drugs from cancer cells, and as a result of various studies aimed at adjusting the inflow and outflow of anticancer drugs, enhancing the effects of anticancer drugs, and overcoming resistance, the inventors found that carfram has an antagonistic effect. Compounds are effective, among them 1.
The present invention was completed by discovering that nicardipine, a 4-dihydropyridine derivative, or a salt thereof is extremely effective. Nicardipine or a salt thereof increases the concentration of the anticancer drug in cancer cells and increases the accumulation and maintenance rate, thereby significantly enhancing the effect of the anticancer drug. Therefore, the anticancer drug suppresses its expression in cancer cells. Furthermore, the anticancer drug exerts its anticancer effect even on cancer cells that have acquired resistance to the anticancer drug. Moreover, the enhancing effect of this anticancer drug has been confirmed not only at the cellular level but also in in vivo experiments, making it of extremely high clinical value. Therefore, by using nicardipine or its salt in combination with an anticancer drug.

It is possible to reduce the dose of anticancer drugs and reduce the occurrence of side effects of anticancer drugs, and it is expected to expand the anticancer spectrum of anticancer drugs and overcome resistance to anticancer drugs.

The anticancer agent to be used in combination with nicardipine or its salt is not particularly limited, but non-antimetabolites are preferred. Specifically, the following compounds may be mentioned. Anthracycline antibiotics 2 such as Adriamycin (Ad
riamycin), downmycin (Daunom
yctn), aclacinomycin A (Aclacin
omycin A); actinomycin antibiotics such as actinomycin C (actinomycin C);
C), Actinomycin D
D); Chromomycin antibiotics such as Mithramycin, Tayomycin; Vinca alkaloids such as Vincristine, Vin-blasLine, and Maytansine; Kinn derivative For example, VP]6-213; Homohorringtonine;
A/Anguidine: Bruceantin; Neocarzinostatin:
Anthramycin; Mitomycin C.

Many of the above anticancer drugs have cross-resistance to mouse leukemia P388 cells that are resistant to Ryodoriamycin [Gold
in & Johnson: Recent Adv.
, in Cancer Treatment *1
55°1977 and Johnson et at:
Cancer Treatment Reports,
62.1535°1978].

Below, Vincristine (Vincristine), which is said to have a strong cytocidal effect directly on cancer cells, is used as an anticancer drug.
ine (hereinafter abbreviated as VCR) as an example.

The present invention will be specifically explained by showing test examples. In addition, VCR-resistant murine leukemia P38 used in the following test example
8 cells and VCR-resistant human myeloid leukemia 562 cells have cross-resistance to various anticancer drugs including adriamycin.

Test Example 1゜Enhancing effect of anticancer drug on murine leukemia P388 cells or VCR-resistant murine leukemia P388 cells> Mouse leukemia P388 cells or VCRn-resistant murine leukemia Leukemia 8
10' cells/mtX 2mt/1ube
After 24 hours, the cells were treated with a drug, and after being in contact with the drug for 48 hours, the number of cells was counted, and the concentration that inhibited proliferation by 50% (IC60 value) was determined. The anticancer drug enhancing effect was determined by the following formula. The results are shown in the table below.

Enhancement effect of anticancer drug in murine leukemia P388 cell 1: VCR is serial dilution concentration test example 2゜〈Enhancing effect of anticancer drug in human myeloid leukemia 562 cells or VCR-resistant human myeloid leukemia 562 cells〉 Method described in Test Example 1 The test was conducted in the same manner as above, the IC6° value was determined, and the anticancer drug enhancing effect was determined. The results are shown in the table below.

Enhancement effect of anticancer drug in 562 cells in human myeloid leukemia Test example of enhancement effect of anticancer drug in 562 cells in VCR-resistant human myeloid leukemia 3゜(Enhancement effect of anticancer drug in VCR-resistant mouse Shiromen disease P388 tumor-bearing mice) 5 CDF1 mice per group (♀) lX106 VCs
R-resistant murine leukemia P388 cells were intraperitoneally transplanted and the drug was administered intraperitoneally for 10 days, and then the number of survival days was observed and the survival rate (T/C) compared to the control was determined.

The anticancer drug enhancing effect was determined by the following formula. The results are shown in the table below.

(T/C) As a result of the above test, by using nicardipine hydrochloride in combination with an anticancer drug, the anticancer effect of the anticancer drug is significantly enhanced, and the anticancer effect is also noticeable against cancers that have acquired resistance to the anticancer drug. It is clear that it is possible to overcome resistance by overcoming resistance.

Therefore, the combined use of nicardipine or a salt thereof when administering an anticancer agent is extremely useful for the treatment of various cancer diseases.

Nicardipine or a salt thereof can be administered at the same time, before or after the anticancer drug, in combination with the anticancer drug, or separately. That is.

Nicardipine or a salt thereof is formed into various dosage unit forms, and an anticancer drug which is molded into various dosage unit forms;
Although each can be administered separately, the two can be blended in advance and administered after being formed into various dosage unit forms.

Various dosage unit forms can be selected depending on the anticancer drug, patient's symptoms, age, and purpose of treatment. Administration agent.

Solution or suspension injections (intravenous injections, subcutaneous injections, etc.),
Examples include parenteral preparations such as suppositories. When formed into such dosage unit form.

As carriers, those conventionally known in this field are used.

Manufactured according to methods commonly used in this field. The dosage of nicardipine or its salt is determined based on the patient's age, body weight,
Although it varies depending on the symptoms, etc., the daily dose for adults is usually 1~0.5g for oral administration, and 0.1~1g~100qH for parenteral administration.

It can be administered once or in divided doses.

In addition, various dosage forms selected for each anticancer drug can be used as they are, and the dosage of the anticancer drug may be the same as when nicardipine or its salt is not used.
Alternatively, lower doses such as %ZO.

Patent applicant: Human Cancer Research Foundation Patent applicant: Yamanouchi Pharmaceutical Co., Ltd. Agent Akira Sasaki - Procedural amendment (voluntary) June 1982, +λ day Director of the Japan Patent Office Kazuo Wakasugi 1, Indication of case: 1981 Patent Application No. 36131
No. 2, Name of the invention: Anticancer drug effect enhancer, skin anticancer effect enhancement method 3 Relationship with the case of the person making the amendment Patent applicant address: 2-5-1 Nihonbashi Honmachi, Chuo-ku, Tokyo Name
(667) Yamanouchi Pharmaceutical Co., Ltd. Representative Shigeru Morioka
Husband (and 1 other person) 4 Agent Address: 1-8-5 Azukizawa, Itabashi-ku, Tokyo, "Detailed Description of the Invention" column 6 of the specification to be amended, Contents of the amendment: 0) Specification, page 10 Add a new line before the third line from the bottom.

Add the following verses and tables.

[Test Example 4 Anticancer drug enhancement effect in adriamycin-resistant mice and Yamaga disease P388 tumor-bearing mice> 1 group of 5 CDFs, 7 mice (♀) ic t X 10
Adriamyein (hereinafter abbreviated as ADM) resistant murine leukemia P388 cells were intraperitoneally transplanted, and the drug was administered intraperitoneally for 10 days.The number of days of survival was observed and the number of days of survival was determined. T
/C) was calculated. The anticancer drug enhancing effect was determined by the above-mentioned Test Example 30 formula. The results are shown in the table below.

Book P<0.05 Japanese Patent Publication No. 58-152816 (5,)

Claims (2)

[Claims] (1) An anticancer drug effect enhancer containing nicardipine or a salt thereof. (2) A method of enhancing the anticancer effect of anticancer jL more than K by using nicardipine or a salt thereof in combination.