JPH0558892A - Carcinogenesesis-preventing agent - Google Patents

Abstract

PURPOSE:A carcinogenesis-preventing agent capable of preventing naturally generating malignant tumors, having low toxicity and good stability, easily used, and capable of lowering the carcinogenicity, when used together with a medicine having a carcinogenic action. CONSTITUTION:A carcinogenesis-preventing agent containing at least one of compounds of the formula (R is higher alkyloxy), its salt, and a substance producing the compound of the formula in the living body (hereinafter referred to as OAA compound). 2-O-Octadecylascorbic acid is preferable as the compound of the formula. The OAA compound is preferably used at a does of 0.1-50mg/kg/ day. In the simultaneous employment system of the OAA compound with a medicine estimated to have a carcinogenic action, such as azathioprine or cisplatin, both the medicines are administered preferably at a time interval of 6-24hr, when both the medicines are separately prepared and administered at some interval.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel antitumor agent applied to humans and other mammals.

[0002]

2. Description of the Related Art Malignant tumors are currently one of the most deadly diseases, and various therapeutic agents and treatment methods have been investigated, but a fundamental solution has not been found yet. Under such circumstances, how to prevent the disease from occurring is an important issue. By the way, in the treatment of various pathological conditions including malignant tumors and various organ transplants,
Carcinogenic agents such as antitumor agents and immunosuppressive agents are often used. However, alkylating agents,
Although various drugs such as antimetabolites, antibiotics, hormonal agents, alkaloids, and specific antibodies have been shown to have effective effects in these treatments, secondary carcinogenesis such as acute leukemia and malignant lymphoma after the start of administration There is a problem that occurs. Especially azathioprine, cyclosporin, FK
-506, predonin, prednisolone, methylprednisolone, bredenin, deoxyspergarin, OKT
Immunosuppressants such as 3 and chlorambucil, cycle fosfamide, melphalan, busaruphan, nitrodiene mustard, procarbazine, actinomycin D, adriamycin, BCNU, CCNU, cisplatin,
Antitumor agents such as dacarbazine and thiotaper are considered to be carcinogenic to humans.

[0003]

The present invention has been made in view of the above circumstances, and an object of the present invention is to prevent spontaneously occurring malignant tumors and to have low toxicity and stability. It is to provide an easy-to-use anti-cancer agent. Another object of the present invention is to provide a carcinogenic preventive agent which can be used in combination with a carcinogenic drug to reduce its carcinogenicity.

[0004]

The carcinogenic agent of the present invention which has been able to solve the above-mentioned problems forms a compound represented by the following general formula (a), a pharmaceutically acceptable salt thereof and the above-mentioned compound in vivo. It is essential to contain at least one selected from the substances listed below. Further, the carcinogenicity can be reduced by using the above substance in combination with a drug having carcinogenicity.

[0005]

[Chemical 2] (However, in the formula, R is a higher alkyloxy group)

[0006]

Action: Free radicals are said to be involved in various stages of carcinogenesis, and particularly act at the promotion stage to induce carcinogenesis. Therefore, ascorbic acid, retinoid, cysteine and the like, which are known as low molecular weight compounds having a free radical scavenging action, were expected to have a carcinogenic preventive action. However, in reality, it should be considered that it has no carcinogenic effect. For example, ascorbic acid [H. F. Stitch, Nature 260, p.722
(1976)], retinoids [E. W. Schroeder, J
NCI, 65, p.671 (1980)], cysteine [A. Wakata et al., Cancer Research 45, p.5867 (1985)] rather have the action of promoting carcinogenesis. 2-O-octadecyl ascorbic acid (hereinafter abbreviated as OOA) is also known as a compound having an action of scavenging active oxygen species and organic radicals [K. Journal of the Kato, etc.
Medical Chemistry, 31, p.793 (1988)]
There is no report that AA has a carcinogenic preventive action, and the present inventors have found that OAA has a carcinogenic preventive action for the first time. It was also found for the first time that co-administration of OAA with a carcinogenic drug can reduce the carcinogenicity of the substance.

Furthermore, the above OAA has the advantage of being significantly less toxic than known chemotherapeutic agents. For example LD ₅₀ for when administered OAA in mice, males orally
4000 mg / kg, female 3400 mg / kg, subcutaneously male and female 4000 mg / kg, intraperitoneal male 2000 mg / kg, female 1700 mg / kg. Therefore, it can be safely used without serious side effects. In addition, OAA is a low molecular weight compound, which can be orally administered and is easy to use.

A more detailed description will be given below. In the present invention, an ascorbic acid derivative represented by the general formula (a) containing OAA (hereinafter represented by OAA) can be used. However, the group represented by R in the formula is preferably a higher alkyloxy group having 9 to 21 carbon atoms, and particularly preferably an octadecyloxy group having 18 carbon atoms. OAA
When used as a drug, it can be used in the form of an acid, a pharmacologically acceptable salt, or a derivative of OAA that produces OAA in vivo. 3 above
Each of the forms of OAA compounds alone exhibits a carcinogenic effect. Therefore, in the present invention, at least one of the above OAA compounds may be contained.

The remarkable effect of the present invention is that the carcinogenicity of the carcinogenic drug can be reduced, and the above OAA compound can be used in combination with the carcinogenic drug. Carcinogenic drugs in that case include chlorambucil, cyclophosphamide, melphalan, busaruphan, nitrogen mustard, procarbazine, actinomycin D, adriamycin,
Various antitumor agents such as BCNU, CCNU, cisplatin, dacarbazine, and thiotaper, and various immunosuppressive agents such as azathioprine, cyclosporine, FK-506, predonin, prednisolone, methylprednisolone, bledenin, deoxyspergarin, and OKT3. ..

The anti-carcinogenic agent of the present invention contains the above OAA compound as an essential component and, if necessary, simultaneously contains a drug having carcinogenicity. The OAA compound and the carcinogenic drug may be an aqueous solution, may be solidified by freeze-drying or the like, or may be a combination thereof.

The carcinogenic agent of the present invention is prepared by preparing these active ingredient compounds in various forms according to known pharmaceutical manufacturing methods by using pharmaceutically acceptable diluents, excipients and the like as desired. Can be converted. At this time, in the combined use system of the OAA compound and the carcinogenic drug, both can be mixed with a diluent or an excipient to form one agent. In addition, each active ingredient is separately formulated using a pharmaceutically acceptable diluent, excipient, etc., if desired, and a dosage form in which it is administered as a single agent by using a diluent at the time of administration It is also possible to prepare a dosage form in which different formulations are separately administered to the same subject at the same time or at different times by the same route or different routes.

[0012] The specific dosage form is not particularly limited, and when orally administered, tablets, pills, granules, powders,
Capsules, syrups, emulsions, suspensions, microcapsules and the like can be mentioned, and for parenteral administration, intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, drip injection, etc. Examples include injections and suppositories.

Compositions for oral administration are prepared by known methods and include carriers or excipients (eg lactose, starch, sucrose), binders (eg glucose, gum arabic, ethyl cellulose), disintegrants (eg starch, Additives such as methyl cellulose), lubricants (eg magnesium stearate and calcium stearate), moisturizers (glycerin, propylene glycol) and the like are used.

The injection solution for parenteral administration is usually provided in a suitable ampoule, and when the carcinogenic agent is a solution, an aqueous solvent (eg distilled water), a water-soluble solvent (eg physiological saline). , Ringer's solution), a solvent such as an oily solvent (eg sesame oil, olive oil), or a solubilizing agent (eg sodium salicylate, sodium acetate), if desired,
Additives such as buffers (eg glucose, invert sugar), stabilizers (eg human serum albumin, polyethylene glycol), preservatives (eg benzyl alcohol, phenol), soothing agents (eg benzalkonium chloride, procaine hydrochloride), etc. And produced by a known method. If the product is made into a solid form by freeze-drying, etc. (in the case of a solution for injection before use), use distilled water, physiological saline or monosaccharides, sugar alcohols, amino acids, surfactants, etc. It is used as an injectable solution by dissolving it using a solution containing it and having its pH adjusted. Suppositories used for rectal administration include cocoa butter, glycerogelatin, and Pharmasol B-.
It is prepared by a known method using a base material such as 112 (manufactured by NOF CORPORATION).

The amount of the OAA compound used for administration varies depending on the method of use, the tumor to be treated, etc.
It is preferably used at about 100 mg / kg / day, more preferably about 0.1 to 50 mg / kg / day.
In the combination system of an OAA compound and a carcinogenic drug, the former is used in the above range and the latter is different depending on its type.
It may be used in a usual dose. For example, when administered as an injection, the daily dose is preferably about 0.1 to 500 mg / kg for mice and about 0.01 to 100 mg / kg for mammals other than mice. In addition, drug delivery system (DDS)
It is also possible to administer based on.

There is no particular limitation on the time lag when the OAA compound and the carcinogenic drug are separately formulated in a combination system and the two are separately formulated, but the time lag is, for example, 1 hour to 7 days. Good, preferably about 6 hours to 72
Time intervals are preferred, more preferably within about 6 to 24 hours.

The anti-tumor agent of the present invention is a mammal (for example,
Mice, rats, cats, dogs, cows, horses, sheep, goats, rabbits, humans), which are useful for treating or preventing various pathological conditions including malignant tumors, and for example, antitumor in mammals bearing tumors The drug is remarkably effective in preventing secondary carcinogenesis after the start of administration of an immunosuppressive drug in mammals after organ transplantation such as an agent and kidney transplantation, liver transplantation, heart transplantation, lung transplantation, pancreatic transplantation. Such neoplastic diseases include various leukemias, malignant lymphomas, osteosarcomas, malignant melanomas, malignant villous epithelioma, myomas, ovarian cancer, uterine cancer, prostate cancer, pancreatic cancer, gastrointestinal cancer such as stomach and intestine, liver cancer, bladder. Cancer, testicular tumor, seminome, skin cancer, lung cancer, esophageal cancer, head and neck tumor, brain tumor and the like can be mentioned. Besides this,
The anti-tumor agent of the present invention is highly effective in preventing malignant tumors that naturally occur in humans and mammals, regardless of the administration of carcinogenic drugs and the like.

The present invention will be described in more detail with reference to the following examples, but the following examples do not limit the present invention.
All modifications and implementations are included in the technical scope of the present invention without departing from the spirit of the description below.

[0019]

【Example】

Experimental Example Female C3H / He mice aged 6 weeks were divided into 4 experimental groups, each of which was not administered, OAA (2-O-octadecyl ascorbic acid) alone, and cisplatin (CDDP) alone. Things, OAA and CD
It was assumed that DP was administered. OAA is biweekly from 7 weeks after birth
CDDP was administered 10 times subcutaneously, and CDDP was administered intraperitoneally 10 times biweekly from 6 weeks after birth. In the group that co-administered OAA and CDDP,
CDDP and OAA were administered alternately every week for 20 weeks. OAA was suspended in physiological saline using gum arabic and adjusted to a dose of 0.1 ml / 20 g mouse body weight (solution concentration 1 mg / ml), and CDDP was diluted with physiological saline. The dose was adjusted to 0.1 ml / 20 g mouse body weight (solution concentration 0.4 mg / ml).

The carcinogenicity-preventing effect was evaluated by observing the carcinogenic rate and the average number of days until tumor death in each experimental group of mice by observing for 2 years. The dose of the drug per dose was expressed as the drug weight per mouse body weight (mg / kg).

Table 1 shows the experimental results.

[0022]

[Table 1]

Mice treated with OAA alone (group 2) had a lower carcinogenic rate and a longer number of days until tumor death, compared to mice that received no administration (group 1). Also OAA and CDD
The mice co-administered with P (group 4) had a lower carcinogenic rate and the tumor death days were significantly longer than those of mice coadministered with CDDP (group 3).

Example 1 (tablets) 2-O-octadecyl ascorbic acid 50 mg corn starch 90 mg lactose 25 mg hydroxypropyl cellulose 25 mg magnesium stearate 5 mg (per tablet) 50 g of 2-O-octadecyl ascorbic acid corn starch 90 g, lactose 25 g and hydroxy. 25 g of propylcellulose was added to granulate, 5 g of magnesium stearate was added, and the mixture was compressed to give tablets.

Example 2 (intramuscular injection) 2-O-octadecyl ascorbic acid 50 mg sesame oil 2 ml (per ampoule) 2-O-octadecyl ascorbic acid 25 g sesame oil 1
It was dissolved in 1 liter, and after filtering bacteria, it was immediately filled in an ampoule and sealed.

Example 3 (suppository) 2-O-octadecyl ascorbic acid 50 mg Pharmasol B-112 (manufactured by NOF CORPORATION) 2.5 g (per piece) 2-O-octadecyl ascorbic acid 10 g at 34 ° C. After mixing with warmed Pharmasol B-122 (500 g), it was immediately injected into a suppository mold and solidified by cooling.

[0027]

The present invention is configured as described above,
It has become possible to provide a low-toxicity, stable and easy-to-use carcinogenicity preventive agent capable of preventing naturally occurring malignant tumors and reducing carcinogenicity by using anticancer agents and the like.

Claims (2)

[Claims] 1. A carcinogenic agent comprising at least one compound selected from the compound represented by the following general formula (a), a pharmaceutically acceptable salt thereof and a substance which produces the compound in vivo. .. [Chemical 1] (However, in the formula, R is a higher alkyloxy group) 2. A compound represented by the general formula (a), a pharmaceutically acceptable salt thereof, and at least one substance selected from the substances which produce the compound in vivo and a drug having carcinogenicity. A characteristic anti-cancer agent.