JPS5936615A - Carcinostatic agent - Google Patents

Abstract

PURPOSE:A carcinostatic agent, containing a specific azaguanine compound or a salt thereof as an active constituent, and having a role as a vitamin for preventing the carcinogenicity with slight side effects. CONSTITUTION:A carcinostatic agent containing a 7-deazaguanine compound of formula I (R is formula II, CH2NH2 or CN; R1 is H or mannosyl or galactosyl) or a salt thereof as an active constituent. The agent is administered by a usually used method in the form of a granule, tablet, capsule, suppository or injection, etc. by using a pharmacologically acceptable carrier. The dose varies depending on the animal to be the object, diseases, symptoms, kinds of the compound, administration routes, etc., but is within about 0.5-400mg/kg, preferably 3-50mg/ kg, both weight per day. PreQ1 base in which R is -CH2NH2, PreQ0 base in which R is -CN, etc. have the biological protecting function in humans and animals in the same way as the Q base.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a carcinogenic preventive agent characterized in that the 7-deazaguanine derivative t9 represented by the following general formula 1 contains a salt thereof.

(indicates an elementary atom, Mannoshi μ, or Gafukudocyl group)
,-C! H2NH2 or -CH) In the above formula, the compound in which R1 is a hydrogen atom is known as Q base (Queuine), which is a natural supermodified base, and Q base is tilisin-t-RNA (t-RNAt7).
”), histidine-t-RiA (t-RNAHili
), asbafugin-t-RNi (t,-RNmu)
As a component of asbafugic acid-t-RNA (t-RNA muap), it is widely distributed in animals, plants, and microorganisms, and it has been found that the first letter K of the anticodon of these t-RNAs exists. ing. These tRNAs are DNA
It is an important low-molecular-weight ribonucleic acid that mediates the conversion of genetic information printed on structural genes into the amino acid sequence of proteins, and is actively involved in regulating cell expression and metabolism. Estimated.

Many aspects of the biosynthetic mechanism of Q base are still unknown.

It is known that it is induced from guanine in bacteria, but the process involved is unknown.

Animals cannot biosynthesize Q bases. In the animal body, (Q+) t RH is generated by transcription from NA.
CG) Guanine tRNA (tRNA containing guanine as a component in place of the Q base), which is a precursor of A (tRNA containing Q base as a component), is synthesized, and guanine and Q base exchange catalytic enzyme, In the presence of tRNA-guanine transglycosidase, externally derived Q
By introducing a base into the first position of the anticodon (Q
+) has been shown to be converted to tRnA.

Animals cannot biosynthesize Q base in their bodies, so they must obtain the necessary amount from the outside world. It mainly depends on production by intestinal bacteria and supplementation from food. Q10 groups present in foods are generally found in very low concentrations (coconut juice, 0.087-0, 53/g/g/i malt 0.087-0.
19119/wl i) Mado 0.0219/Il;
Milk 0.016μ9/g/).

With recent advances in basic cancer research, the relationship between Q bases and cancer is becoming increasingly clear. In other words, cancer cells, which are different from normal cells, naturally contain an anticodon.
mf tRNAtyr lacking the Q base that should be present in the character, t
RmeH18, tRNiA8p, tRNAA8n ((Q
The existence of ltRNA) has been recognized, and it is becoming clear that these are universal facts observed in all cancer cells. The Q-deficient tRNA is present at the first position of its anticodon. Guanine is bonded to the substitute for the base [Q+
] tRNA biosynthetic intermediate, incompletely modified tR
It is a compound that should be called NA. Like this (Q
-) The presence of tRNA is thought to change the binding ability with ribosomes during the protein biosynthesis process, leading to less modulation of protein biosynthetic function, in other words, the fidelity of translation of genetic information decreases. However, no concrete proof has been provided regarding this point. The q base deficiency in t-RNA present in tumor tissue is related to the aforementioned guanine. tR, an exchange enzyme with bases
It has been proven that the activity of NA-guanine adenine transglycosidase is not reduced. However, the true cause is still unknown.

In the above formula, R1 is a mannosyl group or a galacto V/l
Compounds in which R is -CH are called man Q bases or gal Q bases, respectively, and are similarly distributed in animal cells as Q base derivatives, and compounds in which R is -CH are called Pr
eQo base and compounds where R is CH2NH2 are Pr
eQ4 base and are known as precursors of Q base, and both of these compounds ultimately become Q base.
It is understood to be a Q base analog that has the same physiological activity as the base.

The present inventors expected that eliminating the Q base deficiency state in tumor-bearing animals would lead to tumor regression, and
, a large amount of Q base was administered orally or intraperitoneally to tumor-bearing mice that had been intraperitoneally implanted with L-5178Y, but contrary to expectations, no effect could be observed.

Almost nothing is known about the specific symptoms caused by Q base deficiency. The present inventors experimentally subjected mice (germ-free mice) to a Q base-deficient state and then observed the presence or absence of related abnormal findings, but could hardly find any. No evidence was found to suggest an increasing trend in tumor incidence. However, the present invention has surprisingly found that administration of a sufficient amount of Q base markedly increases the biological defense function of individuals subjected to carcinogenic conditions, and has a carcinogenic preventive effect. That is, although Q base is a substance that cannot be biosynthesized in the body and is considered a type of vitamin, we have discovered that it has a role not as an antitumor vitamin but as a vitamin for preventing cancer development, and have completed the present invention.

■ Of 7-deazaguanine represented by the formula, R--CH
Pre Q1 base represented by 2NHg, Pre QO base represented by R=-CM, and m with mannose or galac F-ose bonded to the hydroxyl group of the cyclopentene ring of the Q base.
An-Q base and Gal-Q base are free types.

Regardless of the salt, like Q base, when given orally or parenterally, it improves the biological defense function of humans and animals.

All 7-deazaguanine derivatives used in the present invention are known compounds. It may be in free form or as a salt with an acid. Specific examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, and organic acids such as succinic acid and phthalic acid. The free form of the acid reacts with the mole or como to form a salt.

The carcinogenic preventive effect of 7-deazaguanine derivative (1) and its salts is confirmed as follows. Carcinogenic initiators (ini
7,12-dimethylbenz (a
) Carcinogenic promoter using anthracene and aflatoxin (
A method is used in which carcinogenesis is induced in an animal using 12-0-tetradecanoylphorbo p-13-acetate as a promoter, and a 7-deazaguanine derivative or a salt thereof is administered.

The carcinogenesis suppression rate was measured using the number of tumors that developed on the skin as an indicator, or using chromosomal abnormalities that are correlated with carcinogenesis as an indicator. The cancer suppression rate can be calculated by comparing the percentage of chromosomal abnormalities in the bone marrow cells of animals in the groups administered with both.

Even in experiments using different carcinogenic sites such as the skin, liver, and bladder, carcinogenic inhibitors centered on Q bases showed remarkable preventive effects. Furthermore, it is noteworthy that these drugs exhibit their effects not when administered locally to the carcinogenic site with an initiator or accelerator applied, but when administered orally, intravenously, or intraperitoneally from a distant site.

Since the cancer prevention agent of the present invention is a normal biological component, there are no noticeable side effects and it is extremely safe.

Therefore, it can withstand continuous use over a long period of time and is extremely useful as a cancer prevention agent. Each compound represented by the formula (2) is soluble in water, regardless of whether it is in free form or as a salt, and has properties suitable for injection. Furthermore, when given as an intraperitoneal preparation, it has good absorption from the gastrointestinal tract. When given to normal animals and healthy people, it remains at high concentrations in the blood and other tissues for a long period of time.

The present compound (1) may be administered as such, or may be administered as a powder, granule, tablet, capsule, etc. using a pharmaceutically acceptable carrier, excipient, diluent, etc. by a commonly used method. It can be administered in the form of tablets, suppositories, injections, etc. The dosage varies depending on the target animal, disease, symptoms, type of compound, administration route, etc., but it is approximately 0.5 cm per day.
-400 W/kg, preferably from 3 to 50 Cape βg body weight.

EXPERIMENTAL EXAMPLE Preventing Carcinogenesis in Mice Experiments The following experiments were conducted with 30 mice per group after the back skin of mice CD-1, female, 8 weeks old, was depilated with a depilatory agent. First, in the carcinogenesis experiment, 100μ was used.
Yumizono, Ding, Tomiyoshi) (Apply 11μ9.M ass on the back of the mouse twice a week.
2-O-tetradecanoylph/%/-13-acetate (12-0-tetradecanoylph
or-bol-13-acetate, hereafter TP
abbreviated as A)
Click here.

6. I 冫ζ(呵4)ke3! (1st edition) (
p, t4 cis H (η ga 1 hing 2+) group (Queine
) was administered parenterally (Group B) twice, 1 w each, 1 day before and 1 hour before the same gα application.
g/mice of Qbase♂;NzT;>, group A), and after initiation with DMBA as a negative control, TPA (11μ9fqus) alone was administered twice a week; -t;f-"=v, Proceed with the experiment with f; νi 30
It continued for a week and ended. In the control group, every TPA
Persistent skin redness was observed upon application, and tumors began to develop at about 6 weeks, rapidly appearing thereafter, and numerous tumors were observed in all mice at about 16 weeks. The number of tumors greater than lnui increased to 14/mouse), and as a result of the diagnosis, approximately 859
6 is papilloma.

Approximately 10% were squamous cell carcinoma, and the remaining 5% were other tumors. On the other hand, in groups A and B2 administered with DMBA + TPA + Q base, skin redness was hardly observed after TPA application, and no tumor development was observed after 6 to 7 weeks.
Tumor development was significantly suppressed. In group A to which Q base was administered, about 20 weeks passed, and about half of them developed an average of 2 tumors, and even at 30 weeks, the average number of tumors (per mouse) remained below 3. Tumor development was also significantly suppressed in group B administered with Q base, with an average number of tumors occurring at 30 weeks of 4.
ke/mouse was shown.

Formulation Example / Injection Q Base 50 (1) is dissolved in 5.0 l of distilled water, and after sterile filtration, dispense 1 ml each into too many vias μ under aseptic conditions, freeze-dry, and seal tightly after drying.

On the other hand, 5j of distilled water containing 300 g of xylit or mannitol was aseptically dispensed into 5 d ampoules for injection, and the ampoules were melted and sealed to make 1000 ampoules.

When using, dissolve one vial of the former powder in xylitate solution for injection (or mannitol solution).

Formulation Example 2 Amount used per tablet: 11) Q base dihydrochloride 200q (2) Lactose 200 da13) Cornstarch 51 li (4)
Hydroxypropyl cellulose 9 capes were mixed and granulated using a conventional method, mixed with cornstarch (8W) and magnesium stearate (29), and then compressed into tablets to give 1 tablet of 47.
09. Form into tablets with a diameter of 9.5+nm.

Agent: Patent attorney Sakuji Amai

Claims (1)

[Scope of Claims] A 7-deazaguanine compound represented by the formula (wherein R1 represents a hydrogen atom, a mannoVfi/group or a gafukudocyl group) -CH2NH2 or -CH) or a salt thereof as an active ingredient. Characteristic cancer prevention agent.