JPS6122018A - Enhancer for cancer immunotherapy - Google Patents

Abstract

PURPOSE:An ehnancer for cancer immunotherapy, containing at least one acetylsalicylic acid and a salt thereof as an active constituent, capable of exhibiting remarkable antitumor activity in use with an immunity activator, and useful for cancer immunotherapy without particular gstrointestinal disorder by intravenous injection. CONSTITUTION:An enhancer for cancer immunotherapy containing at least one selected from acetylsalicylic acid and a salt thereof as an active constituent. Attention is paid to the inhibitory action of the acetylsalicylic acid on synthesis of prostaglandin taking part in the immune response, and the use thereof in cancer immunotherapy is found to enhance the antitumor effect as compared with the simple administration. In particular, aspirin-DL-lysine salt can be intravenously injected, and the administration in a high dose is possible without causing gastrointestinal disorder such as a drug for internal use. Therefore, the compound is prefered.

Description

DETAILED DESCRIPTION OF THE INVENTION [Technical Field] The present invention relates to a cancer immunotherapy enhancer containing acetylsalicylic acid (aspirin) or a salt thereof as an active ingredient, particularly to an intravenous cancer immunotherapy enhancer.

[Background of the invention]

In general, although the host often recognizes autologous tumors and has the ability to immunologically reject and eliminate them, the tumors grow without being eliminated as foreign substances. That is, it is well known that tumors have inherent antigenicity but are difficult to provoke host immune responses. For example, it is known that tumor cells secrete substances that weaken the inflammatory response of lymphocytes and macrophages in order to proliferate, and therefore the activity of macrophages within tumor tissues is weak (and their cytotoxicity is also low). One of the reasons for this is thought to be the involvement of prostaglandins in the immune system.Because prostaglandins act in an immunosuppressive manner, macrophages infiltrating the tumor or around the tumor may be affected by prostaglandins. It is quite conceivable that tumors may escape attack by the host's immune response by secreting Gins.

On the other hand, prostaglandins are known to have a suppressive effect on cell-mediated immunity and humoral immunity.

The action of prostaglandins includes, for example, suppression of mitogen-induced lymphocyte blastogenesis (Smith).

J, H,: J, C1tn, Invest,, 5
0.442 (1971)), inhibition of lymphoid production (Rappaport+ R,S,: J.

Exp, Med, 155,943 (1982)
), suppression of cytotoxic T cells, antibody-dependent cytotoxicity (
APCC), NK cell induction and activity inhibition (B
runda+ M, J, ;J, Immunol,,
124.2Ei82 (1980)).

Generally, prostaglandins have little effect on the whole body and are understood to be local transmitters that are biosynthesized and act on the spot. Therefore, it is assumed that prostaglandins are produced in the immune system as well, and are involved in the immune response by acting on the immunocompetent cells there. Therefore, in the field of immune response, cancer immunotherapy using BRM such as an immunostimulant (generally, BRM directs the host's immune function in a positive direction) is implemented to suppress prostaglandins that act in a negative direction. In this case, if it can be reduced locally in the tumor, it is expected that the effect of cancer immunotherapy will be enhanced.

Now, as mentioned above, it has been proven not only in animal experiments but also in human cancer that cancer-bearing organisms respond immunologically to their own cancer. However, in response to the question of why cancer cells are not recognized as foreign substances and rejected and eliminated by such immunological surveillance of the living body,
Currie addresses the issue of antigens and hosts (C
urrie, G.A.: Immunologica
l escape of tomorrows, Curre
nt top-ics in immunology
5eries 2. Cancer and the
immune response, T and A
Con5table Ltd,, Fid-ingbr
agh, 1974. p.55. ).

That is, from the perspective of tumor cells, immunological selection based on antigenic differences, the phenomenon in which a small number of tumor cells evade the body's immune response, modulation and shedding of tumor antigens, etc. can be considered. On the other hand, from the perspective of host immune responsiveness, there are immunological tolerance, immunological non-responsiveness, etc. It can be said that the combination of these factors leads to the evasion of tumor cells from immunological surveillance, which in turn leads to tumor growth. In addition, as the immune capacity of cancer patients is investigated, it has been found that their cellular and humoral immune capacities are decreased both specifically and non-specifically, and that this is significantly exacerbated by the progressive growth of tumors. is becoming clear. It is understood that suppressor immune cells (macrophages, T cells, etc.) induced by tumor antigens are largely involved in suppressing the immune function of cancer-bearing patients. It has become clear that prosufugladin, which is used in the treatment of cancer, is involved to a large extent. Therefore, when expecting effective cancer immunotherapy, if it is possible to selectively block the function of suppressor immune cells in cancer-bearing patients, that is, cancer immunotherapy in a place where negative immune regulation is canceled or weakened, would be possible. It is expected that the therapeutic effect will be enhanced compared to cancer immunotherapy where it is still present.

In the present invention, we focused on aspirin, which is one of the prostaglandin synthesis inhibitors, and in particular, we focused on aspirin, which can withstand long-term use without causing gastrointestinal mucosal damage as is known from oral aspirin drugs, and is effective in cancer treatment. Cancer immunotherapy using intravenously administrable aspirin, which allows the drug to migrate into tissues and tissues surrounding cancer, prepared in the form shown in the examples below, and an immunostimulant as shown in the test examples. When these drugs were used in combination, they were found to be more effective in inhibiting tumor growth than when each was administered alone, suggesting the usefulness of this preparation when used in humans.

Aspirin and its salts used in the present invention are preferably those that form a salt with a basic substance, especially a basic amino acid. Particularly preferred is aspirin-DL-lysine salt. Such salts are water-soluble, can be injected intravenously, and can be administered in large amounts without causing the gastrointestinal disorders known from oral medications.

The immunostimulants used in cancer immunotherapy in the present invention include BCG vaccine (tuberculin), Corynebacterium parvum
Examples include AR Vu IIs pertussis vaccine, muranyl dipeptide (MDP), bisibanil, and krestin.

The cancer immunotherapy enhancer of the present invention is prepared by incorporating aspirin or a salt thereof with a suitable and commonly used pharmaceutically acceptable carrier, and is administered orally or parenterally.

Examples of the drug layer include injections (especially intravenous injections), tablets, powders, capsules, and the like.

Aspirin, its salts, for example, when administered intravenously, usually
~125 mg/kg is administered with immunostimulants, but
The dosage may vary depending on the type of immunostimulant, age, body weight, severity of the symptoms to be treated, etc.

Test example 1 Animals are 6-7 weeks old and weigh 17-19 g.

Using male C57'BL/6 mice, Lee+is lung tumors (3LL), which had been passaged in the flank in syngeneic mice, were subcutaneously implanted into the abdomen (5X105), and BCG (dried vaccine) was administered 4 days before and immediately after tumor implantation. 5mg (5X1
07), or C. parvum (heat-killed bacteria, 5X
10B) was intraperitoneally administered to mice.

In addition, the intravenous aspirin preparation shown in Example 1 was dissolved in distilled water for injection, and the amount was 3.6 mg (180 mg/kg) per mouse in terms of acetylsalicylic acid.
mg (18n+g/kg) administered intravenously once a day,
Aspirin was also suspended in 1% cornstarch gel at a dose of 3.6 mg (180 mg/kg) per mouse and 0.
, 36 mg (18 mg/kg) was given once a day in the sun.

The tumor size and body weight of the mice were then measured over time.

Table 1 shows the results 20 days after 3LL transplantation.

As is clear from this, it has become clear that aspirin and its salts have antitumor effects on 3LL, but when used in combination with immunostimulants such as BCG or C, parvum, each of these alone administered groups It was revealed that the antitumor effect was markedly enhanced compared to the previous study. Furthermore,
When comparing the intravenous aspirin salt administration group and the oral aspirin administration group, no major difference was observed in antitumor effects; however, after continuous administration for 20 days, gastrointestinal mucosal damage, which is one of the side effects of oral aspirin, was observed. Anatomical findings were obtained that suggest that this may be one of the causes.

On the other hand, in the intravenous aspirin salt administration group, only a slight lateral inhibition of weight gain was observed.

Table 1 Treatment after 3LL tumor transplantation with 4 animals per group The results on the 26th day are shown.

Explanation of Table 1 ao; Physiological saline (control) ali Intravenous aspirin-DL-lysine salt 3.6 m
gc2; 0.3
6mga3; Oral aspirin 3.5
mgaq i 0
．． 36m'gba; BCG
5 mgbl; BCG (5, mg) + intravenous aspirin-DL-lysine salt 3.6 mgb2
B BCG (5mg) + intravenous aspirin-DL-lysine salt 0.36mgb3
; BCG (5mg) 10-day loaspirin 3.6
mgbs i + 0
．． 36mgc O; C, parvum (5x 10
8) c 1 ; C, parvum (5x 108)
+ Intravenous aspirin - DL-lysine salt 3.6 mgc
2; C, parvum (5x 108) + intravenous aspirin-DL-lysine salt 0.36 mgc 3. ;
C,parvum (5x 108) + oral aspirin 3.6 mgC4i C,parvu
mτS x 108) + oral aspirin
Q. For both 36 mg intravenous aspirin salt and oral aspirin, the values are shown in terms of acetylsalicylic acid administered per mouse. Moreover, B C0% C, parvum as a cancer immunovaccine indicates the amount administered per mouse.

Test Example 2 Animals were 7-9 weeks old, weighed 18-20 g, and were male C3H/H.
Using eN mice, X5563 myeloma cells that had been passaged intraperitoneally in syngeneic mice were transplanted subcutaneously into the abdomen (5
X10S). 5 mg (5X107) of BCG (dried vaccine) or Cop 4 days before and immediately after tumor implantation.
arvum (heat-killed bacteria, 5 x 10") was intraperitoneally administered to mice. In addition, the formulation shown in Example 1 was dissolved in distilled water for injection to give a solution of 3.6 mg per mouse (180 ml 1 g/kg) in terms of acetylsalicylic acid. ) and 0.
36+ng (18mg/kg) intravenously once daily, aspirin suspended in 1% cornstarch gel, 3.6o+g (180mg/kg) and 0.36mg (18mg/kg) once daily per mouse. The sun set. The tumor size and body weight of the mice were then measured over time.

Table 2 shows the results 30 days after tumor implantation. As is clear from the results, when intravenous aspirin salt and immunostimulant BCG or C,parvum are used in combination against X5563 myeloma cells, the tumor growth suppressive effect is enhanced compared to the group administered with each alone. I understand that.

In addition, when comparing the intravenous aspirin salt and oral aspirin administration groups, there was no significant difference in the antitumor effect enhancement effect between the two administration groups, but after continuous administration for 30 days, the oral administration mice increased body weight. A suppressive tendency was observed, but no such tendency was observed in the intravenous administration group.

(Margin below) Table 2 Treatment started after X5563 myeloma transplant with 4 animals per group.
The results after 30 days are shown.

Explanation of Table 2 ao; Physiological saline (control) al; Intravenous aspirin 3.6 m
ga2i 〃0.36mg a3; Oral aspirin 3.6 vg
a4; 0.36n
+gbo；BCG 5
mgbl; BCG (5mg) intravenous aspirin 3
．． 6 mgb2i
0.36mg+ b3 HBCG (5mg) 10-day loaspirin 3.6
mgb4 i 0
．． 36mg+ CD; C, parvum (5x 108)c 1
; C, parvum (5x 108) + IV aspirin 3.6 mg C2; C, par
vum (5x 108) + IV aspirin
0.36mgc3; C, parvum (5
x 108) + oral aspirin 3.6 m
gC4i Coparvum (5x 10 days) + oral aspirin 0.36mg6, Contents of amendment (1) The title of the invention in the application is corrected as shown in the attached sheet. .

(2) On page 2 of the specification, lines 2-3, [-lymphocytes and macrophages] should be corrected to "activities of lymphocytes and macrophages."

(3) “Pishhanil” on page 6, line 16 of the same book is changed to “
Corrected to "Pishihanil".

(4) On page 6 of the same book, in the last line, "prepared" is corrected to "prepared".

Claims (2)

[Claims] (1) A cancer immunotherapy enhancer containing at least one selected from acetylsalicylic acid and its salts as an active ingredient. (2) Claim No. (2) in the form of an intravenous preparation
1) Cancer immunotherapy enhancer according to item 1).