GB2143732A - Homocarnosine for antitumor formulation - Google Patents

Abstract

Pharmaceutical or veterinary antitumor formulations comprise homocarnosine or a physiologically acceptable salt thereof as an effective ingredient. The formulation may include an immunopotentiator e.g. OK-432 and may be applied internally or externally.

Description

SPECIFICATION Antitumor formulation The present invention relates to an agent for treating tumors comprising homocarnosine (or a physiologically acceptable salt thereof) as an effective ingredient.

The development of antitumor agents is now conducted based on two basic ideas. One idea is to control cancer by inhibiting vigorous biosynthesis of nucleic acids by the tumor tissues and the other idea is to control cancer by non-specific active immunotherapy utilizing the immunity of a host.

However, these therapeutic methods are defective in that the intended clinical effect cannot be completely attained. More specifically, the former method is defective in that the action of inhibiting the biosynthesis of nucleic acids is not specific to cancer. The latter method using an immunopotentiator is defective in that the degree of immunity response is restricted by the inherent response function of an organ of the reticuloendothelial system and there is no means for promoting regeneration of the connective tissue capable of encapsulation and removing the cancer tissue, which is considered to be another action of controlling cancer by biophylaxis. In order to control and exterminate cancer, it is indispensable to increase two spontaneous healing functions, that is, immunity and regeneration, beyond the physiological thresholds.This invention is based upon the discovery that promotion of granulation, which is a symbol of immunity and regeneration, can be attained by homocarnosine, though this promotion has not heretofore been attained.

The antitumor action of homocarnosine which promotes the non-specific active immunoreaction (promotion of immunity) or the tumor immunization on transplanted cancer, which is not a direct action on cancer cells of transplanted cancer or is different from an action of a known immunopotentiator e.g.

OK432 sold by Chugai Pharmaceutical Co., Ltd., under the trade mark PICIBANIL, PSK sold by Kureha Chemical Industry Co., Ltd., under the trade mark KRESTIN and SSM sold by Zeria Shinyaku Co., Ltd., as MARUYAMA'S Vaccine, host defense stimulator, has been tested by using two experimental systems of DDY-S-180 of the same kind but different strains and BALB/C-METH-A of the same kind and the same strain.

The present invention provides an antitumor agent comprising homocarnosine or its physiologically acceptable salt thereof, which shows a good effect in the healing of tumors, especially by increasing tumor immunity response efficiency.

In accordance with the present invention there is enabled a method for treating tumors, which comprises administering an effective amount of homocarnosine to a patient.

The invention thus preferably provides a pharmaceutical or veterinary antitumor fomulation comprising homocarnosine or a physiologically acceptable salt thereof as an effective ingredient and adapted to provide a daily dosage of less than about 100mg per Kg body weight of homocarnosine.

In another aspect the invention provides a pharmaceutical or veterinary antitumor formulation active against tumors by the suppression or regression, which comprises homocarnosine or a physiologically acceptable salt thereof and an immunopotentiator. In 1971, Fujii, Elton S. Cook et al. (The Journal of Medical Chemistry, Vol. 14, page 354) suggested that homocarnosine has an anti-infectious action to infection by Staphylococcus aureus. The dosage proposed was 250 mg/Kg body weight per day. There has, however, been no known clinical use of homocarnosine for this or any other purpose before this invention. The antitumor action of homocarnosine in particular has not hitherto been known or suspected.

It will be noted that the maximum daily dosage for the formulations of the present invention (no more than about 100 mg/Kg body weight homocarnosine per day) is considerably lower than that proposed for treatment of Staphylococcus aureus. It is thus clear that even if the above proposals had been put into clinical effect such use would not be relevant to the present invention.

Homocarnosine is a dipeptide, that is, L-histidinyl-y-aminobutyric acid, extracted from the bovine brain by Pisano in 1961, and it is contained in the brain in an amount of about 0.007%.

Homocarnosine is represented by the following chemical structural formula:

It is a white crystalline powder having a melting point of 242 to 243"C and [a]20 = +23.2"C.

A 10% aqueous solution of homocarnosine is colorless and transparent and is weakly alkaline, and it has a weuk alkaline taste. Administered homocarnosine is hydrolyzed to L-histidine and -aminobutyric acid. L-histidine is an amino acid ordinarily ingested as a nutrient in a large quantity from daily food, and y-aminobutyric acid is marketed as a brain metabolism promotor [Gammalon (trademark) supplied by Daiichi Pharmaceutical Co., Ltd.] and the safety of this compound has been confirmed. The effective amount of homocarnosine, which may be 50mg/Kg (s.c.) (2.5g for adults), corresponds to about 1.1g of y aminobutyric acid.The permissible amount of -aminobutyric acid is 0.75 to 19/300 to 500ml of glucose solution/2 to 3 hours/once to thrice a day in case of instillation. Accordingly, in view of the foregoing, it is seen that the effective antitumor amount of homocarnosine, which may be less than 50mg/Kg (s.c.), is less than 1/2 of the amount administered in case of instillation. It may therefore be presumed that homocarnosine has sufficient safety.

Various processes are known for the synthesis of homocarnosine. For example, homocarnosine is synthesized according to the following process (Journal of Biological Chemistry, 236, No. 2, 499-502, 1961).

Triethylamine is added to a suspension of carbobenzyloxy-w-aminobutyric acid in methylene chloride.

The obtained solution is cooled to -5 C, and ethylchloroformate is added and the mixture is maintained at the above temperature for 10 minutes. A solution of L-histidine methyl ester prepared by adding triethylamine to a suspension of L-histidine methyl ester dihydrochloride in methylene chloride cooled at 0 C in advance is abruptly added to the above solution, and the obtained mixture is kept overnight at 25"C.

Then, the mixture is washed with water and 1N-NaHCO3, dried over Na2SO4 and concentrated to a syrup.

The so-obtained product is dissolved in methanol and 1 N-NaOH is added to the solution. The mixture is maintained at 25"C for 3 hours and the pH value is adjusted to 5 with dilute sulfuric acid, and the solution is concentrated to dryness under reduced pressure. The residue is extracted with hot ethanol twice, and water is further added to the extract. Then, 10% palladium-charcoal is added and the mixture is hydrogenated in an apparatus equipped with a Caroxite tube for absorbing CO2 therein. After the hydrogenation, the formed solution was filtered and concentrated under reduced pressure. The residual syrup is dissolved in water and the pH value is adjusted to 3 with dilute sulfuric acid. When ethanol is gradually added to the solution, the dipeptide sulfate is separated in the form of granular crystals.The product is recovered by filtration and recrystallized from water-ethanol according to the same procedures as described above to obtain homocarnosine sulfate having a melting point of 240 C (decomposing point).

A column is packed with Dowex 50, and the ion exchange resin is treated with 1N-HCI and washed with water until the washing liquid proves to be neutral by detection with Thymol Blue. Then, a 10% solution of homocarnosine sulfate is passed through the column, the sulfuric acid radical is removed by effecting water washing until the washing liquid proves to be neutral by detection with Thymol Blue, and homocarnosine is eluted with 1N-NH4OH. The eluate is concentrated and ethanol is added, and the mixture is allowed to stand in a cold room to obtain a crystal of free homocarnosine.

The present invention includes a tumor-curative agent comprising a salt of homocarnosine. Such salts of homocarnosine include those based on its carboxyl group and physiologically acceptable acid addition salts based on its amino group, and those based on both its carboxyl and amino groups. As salts based on the carboxyl group, there can be mentioned salts with metals such as sodium, potassium, calcium, magnesium, zinc and aluminum, and ammonium and substituted ammonium salts such as salts with amines such as trialkylamines, e.g. triethylamine. As salts based on the amino group, there can be mentioned salts with inorganic and organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, succinic acid, maleic acid, benzenesulfonic acid and toluenesulfonic acid.These salts can be obtained by reacting homocarnosine with stoichiometric amounts of selected acids or bases.

The antitumor action of homocarnosine is very effective for remedy of cancers of various organs such as stomach cancer, rectum cancer, breast cancer, uterine cancer, mouth cancer, esophagus cancer, gallbladder cancer, bile duct cancer, biliary cancer, pancreatic cancer, prostate cancer, malignant thyroid tumor, lung cancer, cerebral tumor, liver cancer, tongue cancer, thymic tumor and skin cancer. Homocarnosine may be used alone and it is expected that when homocarnosine is used in combination with an immunopotentiator such as OK-432 (supplied by Chugai Pharmaceutical Co., Ltd.), the antitumor action of homocarnosine will be enhanced and a very excellent curative effect will be attained. Of course, there has hitherto been no proposal or use in the art of a pharmaceutical or veterinary formulation for any purpose comprising homocarnosine and an immunopotentiator.

The form of the antitumor agent of the present invention is not particularly critical, so far as oral or non-oral administration to patients is conveniently carried out. For example, there can be mentioned injectable forms, powder, granule, tablet, capsule, intestine-soluble form, ointment, suppository, enteric preparation and troche. These preparation forms may be adopted alone or in combination according to the kind of the tumor and the disease condition of the patient. The clinical amount for an adult, estimated from the results of the basic effect test, is 0.5 to 39 per day (oral administration), and it is preferred that this amount be administered dividedly at appropriate time intervals.

Since homocarnosine is easily soluble in water, 3%, 5% and 10% aqueous solutions of homocarnosine can easily be prepared by an aseptic operation. Such an aqueous solution is sealed in an ampoule in a current of an inert gas and is injected by an ordinary injector. Furthermore, there may be adopted a method in which a powder of homocarnosine freeze-dried and sealed in an ampoule or vial by an aseptic operation is dissolved in sterile distilled water just before injection and a 3%, 5% or 10% aqueous solution is immediately injected.

A powder, granule, tablet or capsule for oral administration is prepared according to customary procedures by using a binder such as syrup, gum arabic, gelatin, sorbitol, tragacanth gum or polyvinylpyrrolidone, an excipient such as lactose, corn starch, calcium phosphate, sorbitol or glycine, a lubricant such as magnesium stearate, talc, polyethylene glycol, hydroxypropylmethylcellulose or silica, a disintegrating agent such as potato starch, or a wetting agent such as sodium lauryl sulfate. The tablet may be coated according to a known method.

An ointment may be prepared according to known procedures by mixing a fine powder of homocarnosine in an amount giving an ointment having a predetermined concentration with an ointment base such as bleached besswax, spermaceti, anhydrous lanolin, white petrolatum, higher alcohol, macrogols, Plasti Base (hydrocarbon gel ointment base supplied by Taisho Pharmaceutical Co., Ltd.), hydrophilic or waterabsorptive ointment, or a mixture of two or more of these ointment bases, optionally adding an oil such as sesame oil, peanut oil or olive oil, a resin, glycerine, propylene glycol, a surfactant, a germicide, a fungicide, or an antioxidant, and kneading the mixture until the mixture becomes homogeneous.

A suppository is prepared according to a method similar to that adopted for preparing an ointment. For example, an antiseptic agent and homocarnosine are added to a dissolved suppository base, the mixture is sufficiently kneaded, cast into a mold and solidified, and the obtained suppository is taken out.

The antitumor agent of the present invention will now be described with reference to the following preparation examples.

Preparation Example 1 (Injection) A 3%, 5% or 10% (as homocarnosine) aqueous solution of synthetic homocarnosine was aseptically filled in an ampoule.

Preparation Example 2 (Granule) By using synthetic homocarnosine, a granule was prepared according to the following recipe: Homocarnosine 0.2 g Lactose 0.349 Corn starch 0.459 Hydroxypropylmethylcellulose 0.01g Granule 1.00g Preparation Example 3 (Ointment) By using synthetic homocarnosine and a hydrocarbon gel ointment base, a 0.2% ointment was prepared according to the following recipe: Homocarnosine 0.2 g Hydrocarbon gel ointment base 99.8 g 100 g Preparation Example 4 {Suppository) A suppository was prepared by using synthetic homocarnosine and Hosco S-55 (supplied by Maruishi Pharmaceutical Co., Ltd.) as the base according to the following recipe (for one suppository):: Homocarnosine 0.02 g Ethyl p-hydroxybenzoate 0.00085 g Hosco S-55 appropriate amount Homocarnosine and ethyl p-hydroxybenzoate were passed through a 200-mesh sieve, and Hosco S-55 melted at 509C was added little by little and the mixture was rendered homogeneous. The mixture was cast into a mold at 38"C, left to be cooled and solidified at room temperature, and cooled in a refrigerator. The formed suppository was taken out from the mold and wrapped up in paraffin paper.

Test 1 Antitumor action of homocarnosine on sarcoma of mouse by two administration methods Test animal: Five-week-old male DDY mice (obtained from Shizuoka Prefecture Experimental Animals Agricultural Coop.) Tumor cells: Sercoma 180 (Department of Cancer and Pathology, Institute of Kitazato, Komiyama maintained strain) Transplantation: 105 cells were transplanted subcutaneously on the median portion of the shoulder.

Administration: Starting 24 hours (1 day) after the tumor transplantation, the homocarnosine solution was subcutaneously administered at a point about 2cm apart from the site of transplantation toward the tail once every other day (15 times as a whole, up to the 29th day) or for 10 consecutive days once a day. To the control group, 0.1 my of physiological saline was subcutaneously administered on the back at a point about 2cm apart from the site of transplantation. To the experimental group, a solution of 0.01, 0.05, 0.2 or lmg of homocarnosine in 0.1 my of physiological saline was subcutaneously administered on the back at a point about 2cm apart from the site of transplantation.

TABLE 1 Effect of homocarnosine on sarcoma 180 tumor (105s.c.J Treatment Survival days Number of dead Regression* animals every other day (15th) Saline 20.3 (16-25) 10/10 (100) 0 Homocarnosine 0.05mg 27.4 (21-53) 10/10 (100) 0 0.2 25.4 (22-29) 9/10 ( 90) 1 1 32.9 (23-48) 8/11 ( 73) 3 every day (10th) Saline 29.2 (16-39) 6/6 (100) 0 Homocarnosine 0.01mg 24.3 (19-33) 7/8 ( 88) 1 0.05 28.9 (17-51) 7/7 (100) 0 0.2 39.9 (27-51) 7/7 (100) 0 1 33.1 (20-50) 8/9 ( 89) 1 * Regression : Tumor solids had grown a few weeks but then they began regression and were taken into normal tissues.

Note (the same shall apply in the subsequent tables) 1. The average survival days are expressed by dividing the sum of (respective survival days x number of mice surviving for said survival days) by the total number of mice. Since the number of animals of regression is not counted, the effect should be evaluated while both the average survival days and the number of animals of regression into consideration.

2. The number of dead animals is expressed by the number of dead animals/number of test animals.

3. "Regression" means that the tumor cells grew after the transplantation and a tumor was macroscopically formed, but regression was caused, the tumor began to disappear and the test animal could not be distinguished from the normal animal. "Regression" in the table indicates that the tissue could not be distinguished from the normal tissue after 60 days from the transplantation by the anatomical and histological examinations.

4. The size of the tumor is expressed by long diameter x short diameter (mm2).

Results Effect on Sarcoma-180.

As shown in Table 1, the administration of homocarnosine alone had a life-sustaining effect, as compared to the control group. Particularly, the effect for the mice given homocarnosine every other day was marked, the mean number of survival days being extended by 12 days and the mortality being reduced to 73%. The surviving animals showed the regression of the tumor. The histological finding at the local area of transplantation was only brown fat, no tumor cells being detected.

Test 2 Antitumor effect of homocarnosine alone or with the immunopotentiator OK-432 on sarcoma of mouse Test animal: Same as in Test 1 Tumor cells: Same as in Test 1 Transplantation: 10S cells were transplanted subcutaneously on the median portion of the shoulder.

Administration: Starting 24 hours (1 day) after the tumor transplantation, the drug was subcutaneously administered at a point about 2cm apart from the site of transplantation toward the tail for 10 consecutive days once a day. To the control group, 0.1 my of physiological saline was subcutaneously administered on the back at a point about 2cm apart from the site of transplantation. To the experimental group, a solution of 0.1, 0.5 or 1mg of homocarnosine in 0.1 my of physiological saline was subcutaneously administered on the back at a point about 2cm apart from the site of transplantation. In case of single use of OK-432, 0.5KE in 0.1 my of physiological saline was administered in the abdominal cavity once every other day 5 times as a whole. In case of concomitant administration of homocarnosine and OK-432, 0.5KE of OK-432 in 0.1ml of physiological saline was administered once every other day 5 times as a whole, and a solution containing 1mg of homocarnosine was subcutaneously administered on the back at a point about 2cm apart from the site of transplantation once every day 10 times as a whole.

TABLE 2 Effect of homocarnosine and OK-432 on sarcoma 180 tumor (106s.c.) Tumor size (cm2) Treatment (long x short axis) Survival days No. of dead Regression lOd 20d animals Saline 287.4 690.5 22.5 (14-32) 10/10 (100) 0 Homocarnosine 0.lmg 202.7 428.1 27.3 (17-44) 7/10 ( 70) 2 0.5 204.0 592.1 27.6 (16-57) 10/10 (100) 0 1 145.3 289.8 31.9 (20-54) 9/10 ( 90) 1 OK-432 0.5KE 226.8 695.4 27.2 (16-44) 10/10 (100) 0 OK-432 0.5KE + Homocarnosine lmg 166.1 383.6 34.8 (19-45) 6/10 ( 60) 4 Results Concomitant administration of OK-432 and homocarnosine.

As shown in Table 2, the antitumor effect of homocarnosine was further augmented by the concomitant use with the immunopotentiator OK-432. As compared to the average survival days for the control group of 22 days, the life of the mice administered homocarnosine alone was sustained by 10 days, making the average number of survival days 32 days, and 40% of the mice survived. This tendency was also seen in the mean values for tumor size and tumor weight (Table 3), which were both smaller than those for the control group. (The wet weight of the tumors extracted on the 13th day after the tumor transplantation was compared.) Test3 Effect of homocarnosine on tumor weight Test animals: Same as in Test 1 Tumor cells: Same as in Test 1 Transplantation: 105 cells were subcutaneously transplanted on the median portion of the shoulder.

Administration: Starting 24 hours (1 day) after the tumor transplantation, a solution of 1 mug of homocarnosine in O.lml of physiological saline was subcutaneously administered on the back at a point about 2cm apart from the site of transplantation for 10 consecutive days once a day.

Measurement: After passage of 13 days from the day of the tumor transplantation, the tumor was exenterated and weighed. A mean value of five animals was calculated.

TABLE 3 Effect of homocarnosine on tumor weights Treatment Tumor weight (g) x + S.E.

Saline 1.10 1.48 2.02 2.43 2.54 1.91 + 0.62 Homocarnosine 1mg 0.11 0.60 1.52 1.98 2.12 1.27 i 0.88 Results As is seen from each mean value of five animals, homocarnosine shows an excellent effect of decreasing the tumor weight.

Test4 Antitumor action of homocarnosine on sarcoma of mouse (clean bench used).

Test animals: Five-week-old male BALB/C mice (obtained from Shizuoka Prefecture Experimental Animals Agricultural Coop.) Tumor cells: METH-A (3-A-1-2) (Hokudai strain maintained at the Research Center of Daiichi Pharmaceutical Co., Ltd.) Transplantation: 5 x 105 abdominal dropsy type cells (Table 4-1) or 2 x 105 abdominal dropsy type cells (Table 4-2) were subcutaneously tranplanted in the median portion of the shoulder.

Administration: Starting 24 hours (1 day) after the tumor transplantation, the drug was administered subcutaneously on the back at a point about 2cm apart from the site of transplantation toward to tail for 10 consecutive days once a day. To the control group, 0.1 my of physiological saline was subcutaneously administered on the back at a point about 2cm apart from the site of transplantation, and to the experimental group, a solution of 0.5mg (Table 4-1) or 1.Omg (Table 4-2) of homocarnosine in 0.1 my of physiological saline was subcutaneously administered on the back at a point about 2cm apart from the site of transplantation.

TABLE 4-1 Effect ofhomocarnosine on METH-A tumor (2x 105s.c.J Tumor size (cm2) No. of dead Treatment (long x short axis) Survival Days animals Regression 23d 27d Saline 544.4 709.9 34.6 (24 -44) 9/9 (100) 0 Homocarnosine 0.5mg 407.1 624.7 35.8 (26 -55) 10/11 ( 91) 1 TABLE 4-2 Effect of homocarnosine on METH-A tumor (5x 105s.c.) Treatment Survival days Number of dead animals Saline 34.1(25 - 43) 10/10 (100) Homocarnosine Img 42.1 (28-59) 11/11(100) Results Effect on METH-A As shown in Tables 4-1 and 4-2, homocarnosine had an antitumor effect on the syngeneic experimental system METH-A BALB/C, though the effect was weaker than that on the DDY-Sarcoma-180 system. Only one animal in the group to which 2 x 105 tumor cells had been transplanted and 0.5mg homocarnosine administered showed tumor regression, and extension of the survival period by 8 days was seen in the group to which 5 x 105 had been transplanted, and 1mg homocarnosine was administered.

Conclusion: (1) In case of the DDY-S-180 system, by administering homocarnosine once every other day during the period of the first day to the 30th day after the tumor transplantation 15 times as a whole or for 10 consecutive days during the period of the first day to the 10th day after the tumor transplantation once a day 10 times as a whole, homocarnosine showed an antitumor action of prolonging the average survival days and decreasing the tumor volume, as compared to the control group. Furthermore, when homocarnosine was administered continuously once a day 10 times as a whole, the tumor weight measured on the 13th day was much smaller than in the control group.Komiyama maintained strain of Department of Cancer and Pathology, Institute of Kitazato is considered to be much stronger than strains of Sarcoma180 maintained at any other research institutes, and this strain is hardly controlled by conventional immunopotentiating carcinostatic agents. The shown effect of homocarnosine to Komiyama strain (S-180) proves that homocarnosine will have an excellent carcinostatic effect to human cancers.

(2) The concomitant administration of homocarnosine and OK-432 used as a typical instance of the immunopotentiating agent shows marked prolongation of the mean survival days and marked regression, as compared with single administration of homocarnosine or OK-432. When the experimental results shown in Table 2 are calculated according to the standard for evaluating the effects of carcinostatic chemical substances, stipulated by the U.S. National Cancer Research Institute, data shown in Table 5 are obtained. It is seen that even by the T/C% evaluation method, homocarnosine has a higher effect than OK-432. Moreover, the concomitant administration of homocarcinone and OK-432 shows a higher effect than single administration of homocarnosine or OK-432 used as the active placebo, and the effect is en hanced by 33- by this concomitant use.

TABLE 5 Treatment 77C'/o Homocarnosine 1 mug 136 OK-432 0.5KE 113 OK-432 0.5KE + Homocarnosine 1mg 181 Evaluation Method The evaluation was made according to the following formula: T/C % = median value of treated group x 100 median value of comparative group (control group at this experiment) The evaluation was effected on the 60th day.The median survival time (M.S.T.) is expressed by the following formula: M.S.T. = L + CxJ fM wherein L stands for the lower limit value of the day when the median mouse died, C stands for one section of the days when mice died and is ordinarily 1, fM stands for the total number of mice which died on the day when the median mouse died, and J stands for the number of mice arriving at the me dian mouse among the mice which died on the day when the median mouse died.

In the screening of carcinostatic chemical substances, a chemical substance having a T/C% value larger than 120% is regarded as being effective.

(3) In two groups of the BALB/C-METH-A system, administration of homocarnosine prolongs the survival time and causes regression in some cases, and it is confirmed that homocarnosine has an antitumor effect. Since the BALB/C-METH-A system is of the same kind and same strain, the shown antitumor ac tion to the same kind and the same strain free of transplantation immunity proves that homocarnosine is effective for controlling human cancers.

Claims (13)

1. A pharmaceutical or veterinary antitumor formulation comprising homocarnosine or a physiologi cally acceptable salt thereof as an effective ingredient.

2. A pharmaceutical or veterinary antitumor formulation comprising homocarnosine or a physiologi cally acceptable salt thereof as an effective ingredient and adapted to provide a daily dosage of less than about 100mg per Kg body weight of homocarnosine.

3. A formulation as claimed in claim 1 or claim 2 adapted to provide a daily dosage of less than about 50 mg per Kg body weight of homocarnosine.

4. A formulation as claimed in any one of claims 1 to 3 and in divided dosage form.

5. A formulation as claimed in any one of claims 1 to 4 also comprising an acceptable diluent, carrier or excipient.

6. A formulation as claimed in any one of claims 1 to 5 and in the form of an ointment.

7. A formulation as claimed in any one of claims 1 to 5 and in the form of powder, granule, tablet or encapsulated enteric preparation.

8. A formulation as claimed in any one of claims 1 to 5 and in the form of a solution suitable for injection.

9. A formulation as claimed in any one of claims 1 to 5 and in the form of a suppository or troche.

10. A pharmaceutical or veterinary antitumor formulation active against tumors by the suppression of regression, which comprises homocarnosine or a physiologically acceptable salt thereof and an immuno potentiator.

11. A formulation as claimed in claim 10 and further defined by the specific feature of any one of claims 3 to 9.

12. An antitumor fomulation as claimed in claim 1 and substantially as hereinbefore described.

13. An antitumor formulation as claimed in claim 1 and substantially as hereinbefore described in any one of Preparation Examples 1 to 4.