KR20140134957A - Pharmaceutical Composition with Anti-Cancer Activity Comprising Alloferon - Google Patents

Abstract

The present invention relates to an anti-cancer pharmaceutical composition which comprises 2-4 μg/ml of alloferon. More preferably, the pharmaceutical composition targets colon cancer or prostate cancer. The anti-cancer composition, according to the present invention, facilitates the secretion of granzyme/perforin of NK cells to promote production of IFN-γ and TNF-α, and increases the cytotoxicity of NK cells to lead anti-cancer effects.

Description

[0001] The present invention relates to a pharmaceutical composition comprising alloperone,

The present invention relates to an anticancer pharmaceutical composition comprising alloperone.

Since insects with fly larvae can produce several types of immunostimulants, including anti-bacterial and / or antifungal peptides, to quickly overcome microbial infections, alopelone is a bacterially challenged blowfly Calliphora It was separated from vicina . Alopelone two types, allopelone 1 and 2 were reported to have 13 and 12 amino acids, respectively (S. Chernysh, SI Kim, G. Bekker, VA Pleskach, NA Filatova, VB Anilin, VG Platonom, P. Bulet, Alopelon 1 is known to have the sequence of HGVSGHGQHGVHG (SEQ ID NO: 1) and Alopelon 2 has the sequence of GVSGHGQHGVHG (SEQ ID NO: 2) (S. Chernysh, SI Kim, G. Bekker, VA Pleskach, NA Filatova, VB Anilin, VG Platonom, P. Bulet, Proc Natl Acad Sci USA 99 (2002) 12628-126232.) . Alopelone stimulated rat and human implants in vivo and induced interferon (IFN) synthesis in vivo in mouse experiments. Alopelone has been shown to enhance the synthesis of interferon when infected by viruses (SI Chernysh, SI Kim, GP Bekker, NB Makhaldiani, G. Hoffmann, F. Buhle, Patent No. 2172322, Byull. SI Chernysh, GP Bekker, N. Makhaldiani, J. Hoffman, P. Bulet, United States, Patent Application Publication, US 2002-0151679A1, Oct. 17,2002. SI Kim, SI Chernysh, GP Recently, there has been a report on the tumor-associated herpes virus of Kaposi, a human gamma-herpes virus of alopelone, (N. Lee, S. Bae, H. Kim, JM Kong, HR Kim, BJ Cho, SJ Kim, SH Seok, YI Hwang, S. Kim, JS Kang, WJ Lee, Ther. 16 (2011) 17.26.).

Patent Application No. 10-2000-0082812 discloses an immunomodulator comprising alloperone. In this patent application, alloperon promotes cytotoxic anticancer activity of mouse and human NK cells (natural killer cells). Experimental data on the immunoregulatory activity of alloperon suggest that electro-allopenone promotes the cytotoxic anticancer activity of human and mouse lymphocytes at very low concentrations. The minimum effective concentration was measured to be about 0.0005 ng / ml. Optimal concentrations were found to be between 0.05 and 0.5 ng / ml. 47, 187-375; Brittenden J., Heys SD, Ross J. and Eremin O., 1996, vol. 77, 1126-1243 Considering the important role of natural cytotoxicity as a major mechanism of action, alloperon may be useful as an antiviral, antimicrobial, and anti-cancer agent in an immunomodulatory mode of action. In addition, with respect to promoting the anticancer activity of cytotoxic lymphocytes, it has been disclosed that alloperon induces the synthesis of intensive and continuous interferon in experimental animals. It has been reported that alopelone effectively induces interferon synthesis and stimulates an immune response such as NK cell activity in a manner similar to interferon. In particular, it has been shown that alopelone is effective in the cytotoxic activity of human peripheral blood lymphocytes against A431 cancer cells. A431 is a prostate cancer cell line. Patent application 10-2009-0024979 relates to a peptide analogue including histidine and a hydrate or salt thereof, and also relates to an antiviral agent or an anticancer agent for the treatment of diseases associated with NF-κB containing the above-mentioned compound as an active ingredient . The histidine-containing peptide analog is an analog of alloperone. Unlike the report of patent application No. 10-2000-0082812 that alopelone of 0.05 to 0.5 ng / ml is effective for anticancer, the present inventor found that 2-4 μg / ml of alloperon activates NK cells and inhibits prostate cancer and colon cancer The present invention has been completed.

Recently, Kuczer et al. Reported the use of the H1K point mutation of allopuron 1 to form a complex with copper to enhance water solubility (Kuczer, M. et al., Copper (II) complex formation processes of alloferon I with point mutation H1K ; combined spectroscopic and potentiometric studies, Journal of Inorganic Biochemistry, 111 (2012) 40-49).

It is an object of the present invention to provide an anticancer drug pharmaceutical composition comprising allopelone.

In the present invention, allopenone has the following general structural formula (1) and is characterized in that it exhibits anticancer activity at a concentration of 2 to 4 ㎍ / ml. A peptide consisting of up to 30 amino acid residues or a pharmaceutically acceptable salt thereof ) Or ether:

X ₁ -His-Gly-X ₂ -His-Gly-Val-X ₃ (1)

In this formula,

X < _{1 >} is absent or represents at least one amino acid residue,

X ₂ represents a peptide bond or at least one amino acid residue,

X ₃ is absent or represents at least one amino acid residue.

More concretely X ₁ does not contain any or only one of His-Gly-Val-Ser-Gly-, Gly-Val-Ser-Gly-, Val-Ser- Gly-, Ser-Gly-, Pro-Ser-Leu-Thr Leu-Ala-Ser-Leu-, Cys-Val-Val-Thr-Gly-, Ile-Ser-Gly-, Cys-Gly-, Phe-Ile-Val- Ser- Ala-, Thr-, A peptide selected from the group consisting of Ile-Val-Ala-Arg-Ile-, Phe-Gly-, His-Gly-Asp-Ser- Gly-, Ser- Gly- and Tyr- ego;

X ₂ is either a peptide bond, -Gln-, -Phe-, -Asp-, -Ser- , -Asn-, -Ala -, - Gln-Asn-, -Ala-Val- and -Ser-Asp-Gly- A peptide selected from the group consisting of: < RTI ID = 0.0 > And

X ₃ is either because it does not contain anything, -His-Gly, -His, -Tyr -Asp, -Phe-Val, -Pro, -Gln-His-Gly, -Leu-Ala, -Asp, -Pro-Leu, - Met and -Phe-Ile.

 The dosage of the allopenone-containing anticancer pharmaceutical composition to be used for achieving the therapeutic effect according to the present invention varies depending on the specific compound, the administration method, the subject to be treated, and the disease to be treated, and is usually 2 to 4 占 퐂 / Not effective at less than 2 ㎍ / ml. There is a problem that over 4 μg / ml is overdosed on the effect. The anticancer composition containing allopenol may be administered once or several times a day. The dose may vary depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, And the administration method can be administered by oral or parenteral administration (for example, intravenous subcutaneous, intraperitoneal, local or visual route) in the form of pills, capsules, powders, solutions, Topical administration is more preferred.

Tablets according to the present invention may be administered to a patient in any form or manner that is bioavailable in an effective amount, i. E., In a parenteral route, and may be formulated in accordance with the nature of the disease condition being treated, the stage of the disease, The form and manner of administration can be readily selected and if the composition according to the invention is tablet, it can comprise one or more pharmaceutically acceptable excipients and the ratios and properties of such excipients will depend on the solubility and chemical properties of the selected tablet, Route of administration and standard pharmaceutical practice.

More particularly, a composition according to the present invention may comprise a therapeutically effective amount of the above-described active ingredients as an essential ingredient together with one or more pharmaceutically acceptable excipients. The excipient material can be a solid or semi-solid material that can function as a vehicle or medium for the active ingredient, and suitable excipients are well known in the art.

The anticancer composition according to the present invention is preferably, but not limited to, colon cancer or prostate cancer.

The anticancer composition according to the present invention promotes the granzyme / perforin secretion of NK cells Promotes the production of IFN-γ and TNF-α , and increases the cytotoxicity of NK cells, resulting in an anti-cancer effect. Particularly at a concentration of 2 to 4 [mu] g / ml, for colon cancer and prostate cancer.

FIG. 1A shows the effect of alloperon on the cytotoxicity of NK cells after co-cultivation of isolated human NK cells and PC3 cell lines.
Figure 1b shows the effect of allopenone on cytotoxicity of NK cells after co-cultivation of isolated human NK cells and HCT116 cell lines.
FIG. 1c shows the effect of allopenone on the cytotoxicity of NK cells after co-cultivation of isolated human NK cells and PC3 cell lines.
Figure 2a shows the expression changes of NK cell activation receptors (2B4 and NKG2D) by alloparon.
Figure 2b shows the expression changes of NK cell inhibitory receptors (CD94 and KIR) by alloparon.
Figure 3a shows cytokine production of NK cells by treatment with alopelone in vitro .
Figure 3b shows cytokine production of NK cells by treatment with alopelone in vivo .
Figure 4a shows the association of granulosa exocytosis with increased cytotoxicity of allopenone treated NK cells after co-culture of NK cells and PC3 cell lines.
Figure 4b shows the production of granzyme B in NK cells.
Figure 4c shows the cytotoxicity of NK cells when conconamycin A is treated or untreated.
Figure 5a shows the effect of alopelone on tumor growth in 6-week-old female nude mice.
Figure 5b shows the effect of alopelone on tumor growth in 9-week-old male NOD / SCID / IL-2Ry (- / -) mice.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

<Methods and Materials>

1) cell separation

Primary NK cells were isolated from peripheral blood mononuclear cells in healthy humans by density gradient centrifugation using Ficoll-Paque PLUS (Amersham Pharmacia Biotech, Piscataway, NJ, USA). The NK cells were then purified from the mononuclear cells by a MACS negative selection system using an NK cell isolation kit (Miltenyi Biotec, Bergisch Gladbach, Germany). NK cell purity was determined by flow cytometry after staining with FITC-conjugated anti-CD3 and CD16 antibody, PE-conjugated anti-CD56 antibody (Pharmingen, San Diego, CA, USA). Pure NK cells were used in each experiment after treatment with 0, 2, or 4 μg / ml alopelon for each fixed period of time. Allopelone was synthesized by the solid-phase synthesis technique Peptide synthesis Ltd. (Moscow, Russia) and then supplied by Allotech Co., Ltd. The purity of the synthetic peptide measured by HPLC is 98% or more.

2) Cell line

Human prostate cancer cell line (PC3) and human colorectal cancer cell line (HCT116) were purchased from the American Type Culture Collection (Manassas, Va., USA) and cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 U / ml penicillin , 100 μg / ml streptomycin, 2 mM L-glutamine (Invitrogen, Grand Island, NY, USA). All cells were maintained in a 37 ° C, 5% CO ₂ incubator.

3) Chrome ( ⁵¹ Cr) release assay

NK cells were maintained in a 5% CO ₂ incubator at 37 ° C for 6 hours, 9 hours, and 12 hours, respectively, after 0, 2, or 4 μg / ml allopenone treatment. The cells were then rinsed twice with phosphate buffered saline and used as an actuator for a chromium ( ⁵¹ Cr) release assay. Target cells PC3 and HCT116 (1x10 ⁶ cells) were labeled with 100 μCi sodium chromate (Na ₂ ⁵¹ CrO ₄ , Amersham Pharmacia Biotech, Piscataway, NJ, USA) for 1 hour at 37 ° C in a 5% CO ₂ incubator. Cells were divided into U-bottom 96-well plates and mixed with ⁵¹ Cr-labeled target cells (1 × 10 ⁴ cells / well) to give a ratio of 30: 1 working cells to target cells. After incubation for 4 hours, the supernatant was collected and the radioactivity was measured by an automated gamma counter. The maximum release of ⁵¹ Cr was when treated with 2% NP-40 (Sigma Aldrich, St. Louis, MI, USA) to dissolve the target cells and the normal release of ⁵¹ Cr was measured at the place where the bait was. The results are expressed as% specific release, (emittance normal emittance) / (maximum emittance normal emittance)) × 100. To analyze whether granulocyte exocytosis by allopurin treated NK cells is involved in killing cancer cells, NK cells were treated with 10 nM ofconjumamycin A (Calbiochem, USA), an inhibitor of granzyme / perforin secretion, San Diego, Calif., USA) was pretreated and assayed.

4) Flow cytometry

NK cells were treated with 0, 2 or 4 μg / ml alopelone and maintained in a 5% CO ₂ incubator at 37 ° C for 12 hours. Cells were then washed twice with phosphate buffered saline, and Fc receptors on NK cells were treated with Fc blocking reagent (Miltenyi Biotec GmbH, Bergisch Gladbach, Germany). Cells were incubated with FITC-conjugated anti-2B4 (CD244) antibody, APC-conjugated anti-NKG2D antibody (Becton Dickinson, Mountain View, Calif. , MN, USA). After washing twice with FACS buffer, the expression pattern of NK-activated receptor and inhibitory receptor was analyzed by FACS Calibur (BD Biosciences). FlowJo software (Tree Star, Ashland, OR) was used for data analysis. The results are shown as a histogram of the dyeing intensity (the fluorescence intensity on the X axis and the number of cells on the Y axis) and the geometric mean fluorescence intensity (MFI) according to the number of stained cells.

5) Cytokine ELISA

NK cells were maintained in a 5% CO ₂ incubator at 37 ° C for 6 hours and 12 hours after treatment with 0, 2 or 4 μg / ml alopelone. Cells were then washed twice with phosphate buffered saline, divided into U-bottom 96-well plates, and target cells (PC3) were mixed to give a ratio of 30: 1 working cells to target cells. After incubation for 4 hours, the supernatant was collected. In addition, allopenes were inoculated into nude mice (BALB / c nude mice) with tumors and IFN-γ and TNF-α were produced in vivo. From the day following the inoculation of nude mice, phosphate buffer or allopenone (50 μg / ea) was injected intraperitoneally daily, and after 4 weeks, blood was collected from heparinized capillaries of retinal tissue under the eyes and centrifuged to remove plasma . IFN-γ and TNF-α in the supernatant and plasma thus obtained were measured by ELISA kit (R & D systems, Minneapolis, MN, USA).

6) CD107a transfer assay

NK cells were treated with 0, 2 or 4 μg / ml alopelone and maintained in a 5% CO ₂ incubator at 37 ° C for 6 hours and 12 hours. Cells were washed twice with phosphate buffered saline, divided into U-bottom 96-well plates, and target cells (PC3) were mixed to achieve a 30: 1 ratio of working cells to target cells. Subsequently, FITC-conjugated anti-CD107a antibody (Becton Dickinson, Mountain View, Calif., USA) was added and the cells were incubated in a 5% CO ₂ incubator at 37 ° C for 1 hour, , Sigma Aldrich, St. Louis, MI, USA) for 3 hours. Monensin is a protein transport inhibitor commonly used to suppress intracellular cytokine staining signals by inhibiting protein transport during cell activation. At the end of the incubation period, the cells were collected and stained with PE-conjugated anti-CD56 antibody. Results were analyzed by FACS Caliber (Becton Dickinson, Mountain View, CA, USA). Granzyme B was collected from the upper layer of the culture and analyzed with the Granzyme B ELISA kit (Bender Medsystems, Burlingame, CA, USA).

7) Tumor grafting into immunodeficient mice

Six-week-old female nude mice (BALB / c nude mice) were purchased from Japan SLC Inc. (Shizuoka, Japan). Nine to ten weeks old mice with non-obesity diabetes / severe immunodeficiency / interleukin receptor gamma chain deficiency (NOD / SCID / IL-2Rγ (- / -)) were received from Professor Lee Sang-seop of the Implant Research Institute at Seoul National University Hospital. NOD / SCID / IL-2Rγ (- / -) mice were produced by interbreeding NOD / SCID deficiency and IL-2Rγ deficient mice among NOD-bearing mice. Genotypes of the offspring were analyzed by PCR, and all animals were maintained in a pathogen free environment at the Animal Research and Development Center of Seoul National University College of Medicine. The animal experiment process was reviewed and approved by the Ethics Committee of Seoul National University. The human colon cancer cell line (HCT116) was subcutaneously injected with 5x10 ⁵ cells per mouse on the left side of the mouse after the nude mice were anesthetized with hepatine / methopain. From the day of tumor inoculation, 50 μg of alloperone was injected intraperitoneally into each nude mouse daily. Tumor size was measured every 2 days and the volume of the tumor was calculated by the formula of ½ × (length × width × height).

Example 1 . Prostate cancer cell line (PC3) and In colorectal cancer cells (HCT116)  about NK  Related to cytotoxicity of cells Alophoron  effect

To examine the effect of alopelone on the cytotoxic activity of NK cells on tumors, NK cells were isolated from mononuclear cells of peripheral blood in healthy humans. The purely isolated NK cells are CD3-CD16 ^bright CD56 ^dim . It is a typical phenotype of NK cells with cytotoxicity. NK cells were activated in a 5% CO ₂ incubator at 37 ° C for 6 hours, 9 hours, and 12 hours after each treatment with 0, 2, or 4 μg / ml alopelone. Were incubated with chromium ( ⁵¹ Cr) labeled prostate cancer cell line (PC3). As a result, allopelone increased the cytotoxicity of NK cells to PC3 (Fig. 1A and Fig. 1C), as time and amount increased, as compared to NK cells cultured without treatment with alloperon. However, less than 2 μg / ml alloperon had no effect on activation. The effect of alopelone, which increases the cytotoxicity of NK cells, was confirmed in colon cancer cells (HCT116) (Fig. 1B).

Example 2 . NK  Lt; RTI ID = 0.0 &gt; (2B4) &lt; / RTI &gt; Alophoron  effect

The cytotoxic activity of NK cells is known to be regulated by the expression of active receptors and inhibitory receptors on cell surfaces (Moretta et al. 2000; Tomasello et al. 2000). Thus, we investigated whether alloporone regulates the expression of activated receptors such as 2B4 and NKG2D and inhibitory receptors such as KIR and CD94. As a result, it was confirmed that 2B4 significantly increased expression by alopheline and NKG2D increased slightly (Fig. 2a). Further, it was found that there was no change in the expression of CD94 and KIR, which are human bodies for suppression (FIG. 2B).

Example 3 . NK  From the cell IFN -γ and TNF for the production of -α Alophoron  effect

2B4 has also been reported to induce the secretion of IFN-y as well as to increase the cytotoxicity of NK cells (Nakajima et al., 1999; Chuang et al., 2001) Based on the results of an increase in cytotoxicity and an increase in the expression of 2B4 in NK cells, the present inventors have found that the expression of IFN-? And? As a result, it was confirmed that production of TNF-α from allopenone-treated NK cells was inhibited by IFN-α and TNF-α, respectively, when compared with NK cells cultured without treatment with alloperon, (BALB / c nude mice) in the presence of IFN-γ and TNF-α in the tumor (FIG. 3A) The results showed that inoculation of alopelin resulted in a decrease in IFN-γ The amount of TNF-α were significantly increased confirmed (Fig. 3b).

Example 4 . NK  Granules in cells Exocytosis  Increase Alophoron  effect

Granulocyte exocytosis is known to be important for the removal of viral infected cells and cancer cells by NK cells (Shi et al., 1992; Shresta et al., 1995). In addition, the interaction between 2B4 and its ligand, CD48, is known to increase granule exocytosis in NK cells (Garni-Wagner et al., 1993; Nakajima et al., 1999). When NK cells are activated by virus-infected cells and cancer cells, the soluble granules migrate to where they interact with the target cells and aggregate with the cell membrane. In the meantime, soluble components of the granules, including granzyme and perforin, come out, and CD107a appears temporarily on the cell surface. Therefore, increased expression of CD107a indicates exocytosis of granzyme and perforin (Alter et al. 2004). The present inventors confirmed that the expression of CD107a was increased by treating allopelone (FIG. 4A). In addition, it was confirmed that the secretion of granzyme B from allopenone treated NK cells was markedly increased with time and amount when compared with NK cells cultured without treatment with alloperon. To investigate whether increased cellular cytotoxicity of NK cells by alopelone was associated with granule exocytosis, 10 nM of concanamycin A (Calbiochem A, Calbiochem A) was used as an inhibitor that caught calcium and blocked the polymerization of perforin , San Diego, CA, USA) was used to perform inhibition assays. As a result, it was confirmed that when NK cells treated with alloperon were cultured with cancer cells labeled with ⁵¹ Cr in the presence of concanamycin A, increased cytotoxicity by allopenone was completely eliminated (FIG. 4C).

Example 5 . The growth of tumor cells in immune deficient mice Inhibitory Alophoron  effect

To determine if alopelone inhibits tumor growth in vivo, 5x10 ⁵ colon cancer cells were injected subcutaneously into the left side of the nude mice. From the day of tumor inoculation, 50 μg of alloperone was injected intraperitoneally into each nude mouse daily. 5A, tumor growth was significantly increased in the nude mice injected with the phosphate buffer solution, but it was completely inhibited in allopenone injected mice. NK cells are normally present in nude mice, but T cells are deficient. Therefore, inhibition of tumor growth by allopelone in live cells seems to be related to the activation of NK cells. In addition, the same experiment was carried out in NOD-SCID IL2Rγ (- / -) mice lacking immune cells including NK cells. The growth of tumors in live birds in NOD-SCID IL2Rγ (- / -) mice injected with alopelone Did not show the same results as in the case of NOD-SCID IL2R? (- / -) mice injected with phosphate buffer solution. Nevertheless, tumor growth was observed in NOD-SCID IL2R? (- / -) mice injected with allopelone 13 days after the injection of cancer cells (Fig. 5B).

<110> SNU R & DB Foundation <120> Pharmaceutical composition with anti-cancer activity          alloferon <130> PN130019 <160> 2 <170> Kopatentin 2.0 <210> 1 <211> 13 <212> PRT <213> Calliphora vicina <400> 1 His Gly Val Ser Gly His Gly Gln His Gly Val His Gly   1 5 10 <210> 2 <211> 12 <212> PRT <213> Calliphora vicina <400> 2 Gly Val Ser Gly His Gly Gln His Gly Val His Gly   1 5 10

Claims (15)

An anticancer drug pharmaceutical composition, comprising a substance of the general structural formula (1).
X ₁ -His-Gly-X ₂ -His-Gly-Val-X ₃ (1)
In this formula,
X &lt; _{1 &gt;} is absent or represents at least one amino acid residue,
X ₂ represents a peptide bond or at least one amino acid residue,
X ₃ is absent or represents at least one amino acid residue.
An anticancer drug pharmaceutical composition, comprising a substance of the general structural formula (1).
X ₁ -His-Gly-X ₂ -His-Gly-Val-X ₃ (1)
In this formula,
X ₁ is does not contain anything, His-Gly-Val-Ser -Gly-, Gly-Val-Ser-Gly-, Val-Ser-Gly-, Ser-Gly-, Pro-Ser-Leu-Thr-Gly- Leu-Ala-Ser-Leu-, Cys-Val-Val-Thr-Gly-, Ile-Ser-Gly-, Cys-Gly-, Ile-Val -Ala-Arg-Ile-, Phe-Gly-, His-Gly-Asp-Ser-Gly-, Ser-Gly- and Tyr-Ala-Met-Ser-Gly-;
X ₂ is either a peptide bond, -Gln-, -Phe-, -Asp-, -Ser- , -Asn-, -Ala -, - Gln-Asn-, -Ala-Val- and -Ser-Asp-Gly- A peptide selected from the group consisting of: &lt; RTI ID = 0.0 &gt; And
X ₃ is either because it does not contain anything, -His-Gly, -His, -Tyr -Asp, -Phe-Val, -Pro, -Gln-His-Gly, -Leu-Ala, -Asp, -Pro-Leu, - Met and -Phe-Ile.
3. The method according to claim 1 or 2,
Wherein the substance of the general structural formula (1) is contained at a concentration of 2 to 4 占 퐂 / ml.
3. The method according to claim 1 or 2,
Wherein the substance of the general structural formula (1) is alloperone 1 of SEQ ID NO: 1.
3. The method according to claim 1 or 2,
Wherein the substance of the general structural formula (1) is alloperone 2 of SEQ ID NO: 2.
A pharmaceutical composition for the treatment of colorectal cancer, which comprises a substance of the following general structural formula (1).
X ₁ -His-Gly-X ₂ -His-Gly-Val-X ₃ (1)
In this formula,
X &lt; _{1 &gt;} is absent or represents at least one amino acid residue,
X ₂ represents a peptide bond or at least one amino acid residue,
X ₃ is absent or represents at least one amino acid residue.
A pharmaceutical composition for the treatment of colorectal cancer, which comprises a substance of the following general structural formula (1).
X ₁ -His-Gly-X ₂ -His-Gly-Val-X ₃ (1)
In this formula,
X ₁ is does not contain anything, His-Gly-Val-Ser -Gly-, Gly-Val-Ser-Gly-, Val-Ser-Gly-, Ser-Gly-, Pro-Ser-Leu-Thr-Gly- Leu-Ala-Ser-Leu-, Cys-Val-Val-Thr-Gly-, Ile-Ser-Gly-, Cys-Gly-, Ile-Val -Ala-Arg-Ile-, Phe-Gly-, His-Gly-Asp-Ser-Gly-, Ser-Gly- and Tyr-Ala-Met-Ser-Gly-;
X ₂ is either a peptide bond, -Gln-, -Phe-, -Asp-, -Ser- , -Asn-, -Ala -, - Gln-Asn-, -Ala-Val- and -Ser-Asp-Gly- A peptide selected from the group consisting of: &lt; RTI ID = 0.0 &gt; And
X ₃ is either because it does not contain anything, -His-Gly, -His, -Tyr -Asp, -Phe-Val, -Pro, -Gln-His-Gly, -Leu-Ala, -Asp, -Pro-Leu, - Met and -Phe-Ile.
8. The method according to claim 6 or 7,
A pharmaceutical composition for the treatment of colorectal cancer, which comprises the substance of the general structural formula (1) at a concentration of 2 to 4 占 퐂 / ml.
8. The method according to claim 6 or 7,
A pharmaceutical composition for the treatment of colorectal cancer, wherein the substance of the general structural formula (1) is alloperone 1 of SEQ ID NO: 1.
8. The method according to claim 6 or 7,
A pharmaceutical composition for the treatment of colorectal cancer, wherein the substance of the general structural formula (1) is allophone 2 of SEQ ID NO: 2.
A pharmaceutical composition for the treatment of prostate cancer, which comprises the substance of the general structural formula (1).
X ₁ -His-Gly-X ₂ -His-Gly-Val-X ₃ (1)
In this formula,
X &lt; _{1 &gt;} is absent or represents at least one amino acid residue,
X ₂ represents a peptide bond or at least one amino acid residue,
X ₃ is absent or represents at least one amino acid residue.
A pharmaceutical composition for the treatment of prostate cancer, which comprises the substance of the general structural formula (1).
X ₁ -His-Gly-X ₂ -His-Gly-Val-X ₃ (1)
In this formula,
X ₁ is does not contain anything, His-Gly-Val-Ser -Gly-, Gly-Val-Ser-Gly-, Val-Ser-Gly-, Ser-Gly-, Pro-Ser-Leu-Thr-Gly- Leu-Ala-Ser-Leu-, Cys-Val-Val-Thr-Gly-, Ile-Ser-Gly-, Cys-Gly-, Ile-Val -Ala-Arg-Ile-, Phe-Gly-, His-Gly-Asp-Ser-Gly-, Ser-Gly- and Tyr-Ala-Met-Ser-Gly-;
X ₂ is either a peptide bond, -Gln-, -Phe-, -Asp-, -Ser- , -Asn-, -Ala -, - Gln-Asn-, -Ala-Val- and -Ser-Asp-Gly- A peptide selected from the group consisting of: &lt; RTI ID = 0.0 &gt; And
X ₃ is either because it does not contain anything, -His-Gly, -His, -Tyr -Asp, -Phe-Val, -Pro, -Gln-His-Gly, -Leu-Ala, -Asp, -Pro-Leu, - Met and -Phe-Ile.
13. The method according to claim 11 or 12,
A pharmaceutical composition for the treatment of prostate cancer, which comprises the substance of the general structural formula (1) in a concentration of 2 to 4 占 퐂 / ml.
13. The method according to claim 11 or 12,
A pharmaceutical composition for the treatment of prostate cancer, wherein the substance of the general structural formula (1) is allophone 1 of SEQ ID NO: 1.
13. The method according to claim 11 or 12,
A pharmaceutical composition for the treatment of prostate cancer, wherein the substance of the general structural formula (1) is alloperone 2 of SEQ ID NO: 2.

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