JPH07165582A - Agent for enhancing anticancer effect of immunnoanticancer agent - Google Patents

Abstract

PURPOSE:To obtain a medicine capable of assisting so as to enhance anicancer effect of an immunoanticancer agent by increasing immune reactivity when the immunoanticancer agent is administered to a cancer patient lowered in immunity. CONSTITUTION:A medicine containing histamine or a pharmaceutically permissible acid addition salt of the histamine as active ingredient is jointly administered in an extremely small amount together with an immunoanticancer agent consisting of a protein or a glucoprotein or of both the substances having immunoanticancer activity. The histamine acts as a medicine for enhancing anticancer effect of the immunoanticancer agent.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is used for enhancing the anticancer effect of an immune / anticancer drug comprising a protein or glycoprotein having an immune / anticancer activity, and containing histamine or a histamic acid addition salt as an active ingredient. It relates to an effect enhancer. Also,
The present invention also relates to an anticancer agent composition containing both histamine or a histamic acid addition salt and an immune anticancer agent comprising a (glyco) protein having an immune anticancer activity.

[0002]

2. Description of the Related Art In order to treat and prevent cancers and viral diseases utilizing immune action, it is essential to strengthen immunological surveillance and activate immunocompetent cells. Various anti-cancer agents, which are anti-cancer agents or anti-tumor agents that have no direct killing activity on cancer or tumor cells, but are effective via the immune system, are already known, and for example, lentinan and picibanil are It is used clinically.

Among the immuno-anticancer agents described in Japanese Examined Patent Publication No. 4-74337 as the immuno-anticancer agent developed by the present inventors, from the live cell membrane of fetal bovine thymus shown in Example 1 or 6 thereof. The obtained immuno-anticancer drug is ATS-
It is named 651F. This immune anticancer drug ATS-6
The therapeutic and preventive results of cancer by 51F are superior to those of other immune anti-cancer agents. The mechanism of action of any immune anticancer drug is that it does not directly act on cancer cells, but activates the immune cells specific to the experimental animal or human given the immune anticancer drug, It is clear that it exerts an anti-cancer effect through its action.

Therefore, the administration of immuno-anticancer drugs
Whether the cancer shrinks, disappears completely, or is expected to prolong life depends largely on the immunity of the host to which the cancer has been administered. Immune anti-cancer drug for patients with congenital abnormal immune system and weakened immunity, or for patients with extremely decreased immune cells due to chemotherapy anti-cancer drug, radiation therapy, etc. It is often observed that the results of the treatment by administration of do not improve.

On the other hand, although neither chemotherapy nor radiation therapy is applied, there is a case where it does not respond to the administration of the immune anticancer drug, or its response may be weak, and as a result, the therapeutic results do not improve. Is often recognized.

Immune anticancer agent A developed by the present inventors
TS-651F, lentinan and picibanil,
In some cases, the expected therapeutic effect was not obtained when administered to cancer-bearing patients with weakened immunity or experimental animals.

When a patient or an experimental animal as described above is treated with administration of an immune / anti-cancer agent, it is possible for the subject to immunologically react to the immune / anti-cancer agent and to perform more efficient treatment. A study was conducted to search for drugs. As a result, the present inventors have discovered that the effect of the immune anticancer drug can be further enhanced and ensured by administering and administering histamine or its hydrochloride in combination with the immune anticancer drug ATS-651F or other immune anticancer drug.

[0008] Histamine is a known substance which is mainly produced in mast cells in vivo and is secreted by mast cells when various allergens enter the body and causes redness and rash as symptoms of allergy.

Therefore, histamine is understood as a physiologically harmful substance. Therefore, antihistamines are clinically used to recover allergy symptoms.

However, such secretion of histamine is originally a physiological or pathological biological reaction, and it is considered appropriate to interpret it as a kind of biological defense reaction.

According to the experiments by the present inventor, the anticancer agent ATS- was administered with histamine or histamine hydrochloride at a dose of 0.1 μg to 3 μg per day, which is an extremely low dose that does not induce allergic symptoms. 6
51F, or lentinan and picibanil, when co-administered with them at the same time, or when they are co-administered at different time points, the anti-cancer effect of the administered immuno-anticancer drug can be enhanced, which is completely unexpected. is there.

[0012]

Therefore, according to the first aspect of the present invention, an immune anticancer activity is characterized in that histamine or an addition salt of histamine and a pharmaceutically acceptable acid is used as an active ingredient. There is provided an enhancer of the anticancer effect of an immune anticancer agent, which comprises a protein or glycoprotein having the following: or a mixture thereof.

The histamic acid addition salt that can be used in the first aspect of the present invention includes histamine and a pharmaceutically acceptable inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or a pharmaceutically acceptable organic acid such as acetic acid. , Addition salts with propionic acid, malic acid and methanesulfonic acid.

Examples of the immuno-anticancer drug that can be used in combination with the immunopotentiator according to the present invention include immuno-anticancer activity that is separated from the cell membrane of live cells of fetal bovine thymus and undergoes protein denaturation by glutaraldehyde treatment. There is an immuno-anticancer substance consisting of a protein-glycoprotein mixture possessed, and its manufacturing method is described in Japanese Patent Publication No. 4-74337. A particularly preferred immune anticancer agent is the immune anticancer agent ATS-651F produced according to the method of Example 1 or 6 of the specification.

Lentinan and picibanil can also be used as such an immuno-anticancer agent.

The enhancer according to the first aspect of the present invention is in the form of a solution dissolved in a pharmaceutically acceptable liquid carrier such as water or saline, or in the form of a powder mixed with a solid carrier such as glucose. But it can be administered. The administration method includes subcutaneous injection, intraperitoneal administration, and oral administration. It can be administered to the same site at the same time as the immune anti-cancer drug, or can be administered at staggered times, but in parallel.

Further, histamine or its acid addition salt is
Even when administered in the form of a mixture with an immune anti-cancer drug, the anti-cancer effect can be enhanced. Therefore, according to the second aspect of the present invention, it comprises histamine or an addition salt of histamine and a pharmaceutically acceptable acid, and an immune / anticancer agent comprising a protein or glycoprotein having immune / anticancer activity or a mixture thereof. An anticancer agent composition characterized by the above can be provided.

For the purposes of the present invention, histamine can be administered in an amount of 0.1 μg to 3 μg per adult, and histamine or a salt thereof can be administered simultaneously with, or concurrently with, the administration of the immuno-anticancer drug, but at different times. Can be administered. Immune anticancer drug A
TS-651F can be administered in an amount of 1 mg to 20 mg, preferably 1 mg to 10 mg per adult once daily as a protein-equivalent amount by the Burett assay method. Lentinan or picibanil can be administered in clinically usual dosages.

After administration as the anticancer effect enhancer of the present invention,
Although not all the mechanism of histamine's immunopotentiation enhancing action in vivo has been clarified, as is clear from the test examples described below, the enhancement and rapid-acting effect of the immunoanticancer drug are observed. , Administration of histamine in combination with immune anti-cancer agents promotes the induction of leukocytes, especially granular leukocytes, further promotes the secretion of immunotransmitters (cytokines) of granular leukocytes, and induces and recruits lymphocytes and macrophages by cytokines. It can be seen that there is an acceleration and activation involved, and that this enhances the in vivo action of the immune anti-cancer agent.

The present invention will be described below with reference to the following test examples and examples.

Test Example 1 Female ICR mice aged 6 weeks were made into 10 groups each, a control group (untreated), a histamine hydrochloride (0.1 μg / mouse) administration group, an immune anticancer agent ATS-651F (1 mg / mouse). )
There were 4 groups of administration groups, a combination administration group of the immuno-anticancer agent ATS-651F (1 mg / mouse) and histamine hydrochloride (0.1 μg / mouse). The tumor cells used in the experiment were Sarcoma 180 (S-180), and 3 × 10 ⁶ cells were subcutaneously transplanted.

The anticancer drug, histamine, or both of them were administered once a week, and subcutaneously administered every 7th day for a total of 3 times, and tumor cells were transplanted 21 days after the first administration day of the anticancer drug. On the 16th day after the transplantation, the animals were dissected, the tumor weight (g) was measured, and the average tumor weight of each group and the tumor weight reduction rate (T / C,
%) And inhibition rate (100-T / C,%).

[0023]

[Table 1]

As is clear from the results in Table 1 above, the inhibition rate in the histamine hydrochloride-administered group was 13. compared to the control group.
In 65%, no effect was observed. In contrast, the suppression rate was 93.26 in the group administered with the immuno-anticancer drug ATS-651F.
%Met. Further, in the group in which the immuno-anticancer drug ATS-651F and histamine hydrochloride were co-administered, the suppression rate was 98.89%, which was almost completely suppressed.

Test Example 2 Female ICR mice aged 6 weeks were made into 10 groups each, and a control group (untreated), a histamine hydrochloride (0.1 μg / mouse) administration group, an immune anticancer drug ATS-651F (1 mg / mouse) )
There were 4 groups of administration groups, a combination administration group of the immuno-anticancer agent ATS-651F (1 mg / mouse) and histamine hydrochloride (0.1 μg / mouse). The tumor cells used in the experiment were Sarcoma 180 (S-180), and 3 × 10 ⁶ cells were subcutaneously transplanted.

The immune anti-cancer drug or histamine or both were administered on the first day of the day when the tumor cells were transplanted, that is, once a week from the next day, and were subcutaneously administered every seven days for a total of three times. Three days after the last administration day (14 days after transplantation), that is, on the 17th day after transplantation, the animals were dissected, the tumor weight (g) was measured, and the average tumor weight of each group, T / C (%) and inhibition rate ( %).

[0027]

[Table 2]

As is clear from the results in Table 2, the inhibition rate was 0.11% in the histamine hydrochloride-administered group, compared with the control group.
4.88% in the group administered with the immuno-anticancer drug ATS-651F
Therefore, no effect was recognized. On the other hand, in the group in which the immuno-anticancer drug ATS-651F and histamine hydrochloride were co-administered, it was 28.65%, indicating that the suppression rate was increased.

This result shows that the immune anticancer drug ATS-651F
The effect is not observed until the tumor cells are transplanted, that is, when the cancer cells are transplanted before completion of immunological preparation in the mouse, the tumor becomes large and cannot be suppressed. Means that. However, when histamine was co-administered with it, the suppression rate was slightly increased, so that histamine was not effective against ATS-651F.
It is recognized that there is an effect of shortening the time required for completion of immunological preparation or activation of immune cells caused by administration of.

Test Example 3 Female ICR mice aged 6 weeks were used as groups A to E, with 10 mice each.

Group A: Control group (untreated) Group B: Cyclophosphamide (150 mg / kg) administration group C: Cyclophosphamide (150 mg / kg) + histamine hydrochloride (0.1 μg / mouse) Combination administration group D group: Cyclophosphamide (150 mg / kg) + immune anticancer agent ATS-651F (1 mg / mouse) combination administration group E group: Cyclophosphamide (150 mg / kg) administration group + ATS-651F (1 mg / mouse) + histamine
(0.1 μg / mouse) combined administration group

For the first time, 21 days before the day of transplantation of tumor cell sarcoma S-180, histamine hydrochloride and the immune anticancer agent ATS-651F were administered once a week, and subcutaneously administered every 7th day for a total of 3 times. Tumor cells were subcutaneously transplanted on the 7th day from the last day of subcutaneous administration. Cyclophosphamide, which is an immunosuppressant, was administered on the 4th day before tumor cell transplantation.
On the 16th day after the tumor cell transplantation, the tumor was dissected, the tumor weight was measured,
Average tumor weight, T / C (%), and inhibition rate (%) of each group
I asked.

[0033]

[Table 3]

As is clear from the results in Table 3, the growth of tumors was enhanced in the groups B and C as compared with the control group (A). In contrast, the suppression rate was 20.61% in the D group administered with the immuno-anticancer drug ATS-651F, which was low but suppressed. Furthermore, in the E group, which was administered with histamine hydrochloride together, the inhibition rate was 90.22%, which was a high inhibition rate.

[0035] The results show that in mice whose immunity was reduced by the immune anti-cancer drug cyclophosphamide, the tumor weight was increased as compared with the mice in the healthy control group, and the immunity was reduced by administration of the cyclophosphamide. On the other hand, it means that the effect of histamine administration was not observed at all.
However, it was confirmed that the immunity was restored by the administration of the immune anti-cancer agent, and further, the immune anti-cancer agent acted efficiently by the combined administration of histamine,
It was found that the immunity was restored.

Test Example 4 Two patients with weakened immunity, one of which was a pancreatic cancer, and a tumor with a diameter of 2 cm was confirmed by examinations such as ultrasound and CT scanner, and a tumor marker CA19-9 was a normal value. A value close to the upper limit (37 or less) was recognized. Immune anticancer drug ATS-651F was administered to the patient, but the skin reaction was weak and the effect could not be expected. Therefore, the antitumor immunizing drug ATS-65 containing histamine hydrochloride (1 μg) was administered.
1F was injected at a dose of 10 mg / adult / day once every week every 7 days. The value of the tumor marker (CA19-9), which was measured from the 7th day before administration, increased as shown in the graph of FIG. 1 of the attached drawings, and decreased to the range of normal value in about one and a half months, and the mechanical The tumor could not be confirmed by inspection, and the patient was completely cured.

Another patient was hospitalized for liver cancer and surgically resected a 7 cm tumor in the left lobe of the liver. 2 after surgery
The tumor marker (AFP) value was about 700 (normal value was 20 or less) in a week, and it had already recurred. On the 7th day from the measurement start date of the marker (AFP), the antitumor immunizing agent ATS-651F containing histamine hydrochloride (1 μg) was also administered to this patient every 7th day in an amount of 10 mg / adult / day. As a result, the tumor marker started to rise in the 5th injection and reached a value of several thousand at one time, but thereafter decreased and returned to the normal value. 1-confirmed by inspection such as ultrasonic waves
Three 2 cm tumors were observed, but disappeared as the tumor marker decreased.

A graph showing changes in the measured values of the liver cancer tumor marker AFP and pancreatic cancer marker CA19-9 in the above two patients is shown in FIG. 1 of the accompanying drawings, and the immuno-anticancer agent ATS-651F and histamine hydrochloride were used. The day of concomitant administration (weeks) is indicated by an arrow. A change in the marker AFP is shown by a curve connecting black circles, and a change in the marker CA19-9 is shown by a curve connecting black triangles.

Upon examining the results of FIG. 1, the following evaluations were obtained. That is, it is generally believed that tumor markers are produced by cancer cells and secreted into the blood. Therefore, as the size of the tumor increases, the number of tumor markers increases, and the size of the tumor decreases as the tumor shrinks due to the treatment. Therefore, it can be applied as a means for determining the prognosis. However, as in the example of this test, the phenomenon in which the cancer cell rapidly rises from a certain point, decreases again, and returns to the normal value is actually the cancer cells being killed by immune cells, and the cells collapsed and were inside the cells. It can be assumed that the result is that the marker substance is released into the blood.

Test Example 5 Female ICR mice aged 6 weeks were made into 10 groups each, and a control group (A), a lentinan (1 mg / kg) administration group (B),
Lentinan (1mg / kg) + histamine hydrochloride (0.1μ
g / mouse) Combination administration group (C), picibanil (1K
E) The administration group (D) and the combination group of picibanil (1KE) + histamine hydrochloride (0.1 μg / mouse) administration group (E).
The tumor cells used in the experiment were Sarcoma 180 (S-18
0), 3 × 10 ⁶ cells were subcutaneously transplanted. Lentinan and picibanil, which are immuno-anticancer agents, were continuously administered 14 times every day from the next day after cell transplantation, and histamine was administered 4 times in total from 1 day to 5 days after cell transplantation up to 16 days.
The immune anticancer drug and histamine were administered intraperitoneally. On the 17th day after cell transplantation, dissect, measure tumor weight,
Average tumor weight, T / C (%), and inhibition rate (%) of each group
I asked.

[0041]

[Table 4]

As can be seen from the results in Table 4, the inhibition rate was increased by 11.66% in the combined administration of lentinan and histamine by the combined administration of histamine hydrochloride, as compared with the single administration group of lentinan or picibanil. The combined administration group increased 8.39%, and the antitumor effect was enhanced in all groups.

As is clear from the data of Test Examples 1 to 5, histamine alone does not have such an immunopotentiating effect. However, when used in combination with an immune antitumor agent, it can be used in vivo against the immune antitumor agent. Increase the immunoreactivity of.
The summary is as follows.

1) A very small dose of histamine, and no effect by itself. 2) Immunity When administered in combination with an anti-cancer agent, the immune system of the living body is enhanced. 3) Since histamine is administered in a very small amount, no side effects are observed. Specifically, the combined administration of histamine shortens the time until the expression of immunity by the administration of a) immune anti-cancer agent. b) Increases the effect as an immune anti-cancer agent. c) When the immunity is congenitally decreased, when the immunity is decreased due to chemotherapy, anticancer drug, radiation therapy, etc.,
Alternatively, the effect of the immune / anti-cancer drug can be expected even on patients with advanced cancer.

Example 1 10 mg (white water-soluble powder obtained in Example 1 of Japanese Examined Patent Publication No. 4-74337) of an immuno-anticancer agent, ATS-651F, was measured in 1 ml of distilled water for injection (measured by the Burett method. It was dissolved so as to contain 50 mg of glucose). This aqueous solution was sealed in a 1 ml vial and freeze-dried.

This lyophilized product was dissolved in a solution prepared by containing 1 μg of histamine in 1 ml of distilled water for injection to prepare an injection solution. The whole amount is administered to humans.

Example 2 Immune anticancer drug, 1 mg of lentinan, was dissolved in 1 ml of distilled water for injection and freeze-dried. The lyophilized product was dissolved in a solution prepared by containing 1 μg of histamine in 1 ml of distilled water for injection to prepare an injection solution.

Example 3 Physibanil 1KE, an immune anticancer drug, was injected into physiological saline 1.
It was dissolved in ml and freeze-dried. The lyophilized product,
An injection solution was prepared by dissolving 1 ml of a physiological saline solution for injection in a solution prepared so as to contain 1 μg of histamine.

[Brief description of drawings]

FIG. 1 Tumor marker A measured in Test Example 5 of the present invention
It is a graph figure of the time-dependent change of FP and tumor marker CA19-9.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 35/26 7431-4C 35/74 A 7431-4C 38/00 ADU // (A61K 31/715 31: 415) (A61K 35/74 31: 415) (A61K 38/00 ADU 31: 415) A61K 31: 415)

Claims (5)

[Claims] 1. An immune anticancer agent comprising a protein or glycoprotein having immunoanticancer activity or a mixture thereof, which comprises histamine or an addition salt of histamine and a pharmaceutically acceptable acid as an active ingredient. Anti-cancer effect enhancer. 2. An anticancer agent comprising histamine or an addition salt of histamine and a pharmaceutically acceptable acid, and an immune anticancer agent consisting of a protein or glycoprotein having an immune anticancer activity or a mixture thereof. Composition. 3. An immuno-anticancer substance comprising a mixture of a protein and a glycoprotein having an immuno-anti-cancer activity, wherein the immuno-anticancer drug is separated from the cell membrane of live cells of fetal bovine thymus and undergoes protein denaturation by glutaraldehyde treatment. The anticancer agent composition according to claim 2. 4. The immune anticancer agent is lentinan.
The anti-cancer agent composition according to. 5. The anticancer agent composition according to claim 2, wherein the immune anticancer agent is picibanil.