KR20230088107A - Pharmaceutical composition for anticancer inhibiting ovarian cancer cell invasion induced by endosome recycling promoters - Google Patents

Abstract

The present disclosure relates to an anticancer pharmaceutical composition that inhibits cancer cell invasion. According to the present disclosure, the anticancer pharmaceutical composition containing 7-methyl-2-(m-tolyl)cinnolin-3(2H)-one, a solvate thereof, or a pharmaceutically acceptable salt inhibits cancer cell invasion caused by beta1-integrin overexpression induced by at least one of Rab25 and RCP, thereby inhibiting metastasis and migration of cancer cells.

Description

Anticancer pharmaceutical composition for inhibiting ovarian cancer cell invasion induced by endosome recycling promoters {Pharmaceutical composition for anticancer inhibiting ovarian cancer cell invasion induced by endosome recycling promoters}

The present disclosure relates to an anti-cancer pharmaceutical composition that inhibits the invasion of ovarian cancer cells induced by factors that promote endosome recycling, and more specifically, beta1-integrin that induces cancer cell invasion by activating EGFR (epidermal growth factor receptor). It relates to a pharmaceutical composition for anticancer that inhibits the overexpression of.

The most lethal factor for cancer patients is “metastasis of cancer cells,” in which cancer cells move to other organs and grow. The cancer cell metastasis process is very complicated. First, cancer cells secrete various proteolytic enzymes to degrade the surrounding extracellular matrix, such as collagen, through an invasion process. In particular, ovarian cancer is the fifth most fatal cancer in women, and difficulties in diagnosis and invasion and metastasis into the peritoneal cavity threaten the lives of ovarian cancer patients. Therefore, suppressing invasion and metastasis of cancer cells to other organs in cancer patients, especially in ovarian cancer patients, is very important for establishing cancer treatment strategies and for improving the quality of life and life extension of cancer patients.

On the other hand, overexpression of beta1-integrin is closely related to the invasion of these cancer cells. Beta1-integrin has been known as a substance that transmits biochemical signals related to the extracellular environment, especially growth, differentiation, invasion, and metastatic potential of malignant cells (Juliano RL. The role of beta 1 integrins in tumors [J]. Semin Cancer Biol, 1993;4(5):277-283.). In addition, overexpression of beta1-integrin is known to promote tumor cell survival and confer resistance to chemotherapy in several tumor cell types (Hodkinson PS, Elliott T, Wong WS, et al. ECM overrides DNA damage-induced cell cycle arrest and apoptosis in smallcell lung cancer cells through beta1 integrin-dependent activation of PI3-kinase[J].Cell Death Differ, 2006;13(10):1776-1788.;Aoudjit F, Vuori K. Integrin signaling inhibits paclitaxel- induced apoptosis in breast cancer cells[J].Oncogene, 2001;20(36):4995-5004.;Morozevich GE, Kozlova NI, Preobrazhenskaya ME, et al.The role of beta1 integrin subfamily in anchorage-dependent apoptosis of breast carcinoma cells differing in multidrug resistance [J].Biochemistry (Mosc), 2006;71(5):489-495.).

It has been reported that cytoplasmic proteins such as Rab25 and Rab coupling protein (RCP) are closely related to the overexpression of beta1-integrin. Cells combine a pocket called the endosome with the lysosome to promote the degradation of beta1-integrin. Some types of cancer cells, including ovarian cancer, express high levels of Rab25 and RCP, preventing the endosome from binding to the lysosome, thereby preventing the degradation of beta1-integrin. By recycling beta1-integrin in the endosome to the cell membrane, beta1-integrin activates the epidemal growth factor receptor (EGFR) in the cell membrane and accelerates the tumor-promoting signaling system, thereby increasing cancer cell growth and invasion.

Therefore, it is required to develop an anticancer agent that inhibits cancer cell invasion by suppressing the overexpression of beta1-integrin by Rab25 or RCP in relation to metastasis of cancer cells, especially ovarian cancer cells.

The present disclosure provides an anti-cancer pharmaceutical composition that inhibits invasion of cancer cells by inhibiting the overexpression of beta1-integrin induced by at least one of Rab25 and RCP.

According to one specific example of the present disclosure,

To provide a pharmaceutical composition for anticancer comprising a compound represented by Formula 1, a solvate thereof or a pharmaceutically acceptable salt thereof.

[Formula 1]

Wherein R ₁ and R ₂ are each independently an alkyl group having 1 to 6 carbon atoms,

는 R₁이 2번, 3번, 4번 및 5번 위치 중 적어도 하나에 위치하고, of Formula 1

Is R ₁ is located at least one of positions 2, 3, 4 and 5,

는 R₂가 2번, 3번, 4번, 5번 및 6번 위치 중 적어도 하나에 위치할 수 있다.of Formula 1

R ₂ may be located at least one of positions 2, 3, 4, 5 and 6.

According to another embodiment,

To provide a pharmaceutical composition for anticancer comprising a compound represented by Formula 3, a solvate thereof or a pharmaceutically acceptable salt thereof.

[Formula 3]

The anti-cancer pharmaceutical composition of the present disclosure can inhibit overexpression of beta1-integrin by at least one of Rab25 and RCP. Therefore, cancer cell metastasis can be prevented by suppressing the invasion of cancer cells induced by beta1-integrin overexpression, and furthermore, anticancer effects can be obtained.

On the other hand, when an anticancer agent is further included in the anticancer pharmaceutical composition of the present disclosure, or when administered in combination with an anticancer agent, a more efficient anticancer effect can be obtained.

1 is a graph showing that cancer cells are not killed when SH-131 is treated with 10 μM.
2 is a graph showing whether beta1-integrin is overexpressed by Rab25 and whether SH-131 inhibits the overexpression of beta1-integrin induced by Rab25.
3 is a graph showing whether cancer cell invasion is induced by Rab25 and whether SH-131 inhibits cancer cell invasion induced by Rab25.
4 is a graphical representation of whether beta1-integrin is overexpressed by RCP and whether SH-131 inhibits the overexpression of beta1-integrin induced by RCP.
5 is a graph showing whether cancer cell invasion is induced by RCP and whether SH-131 inhibits cancer cell invasion induced by RCP.

The present disclosure can all be achieved by the following description. The following description should be understood as describing specific examples of the present disclosure, but the present disclosure is not necessarily limited thereto. In addition, it should be understood that the accompanying drawings are for illustrative purposes only, and the present disclosure is not limited thereto.

Embodiments of the present disclosure may be subject to various changes and implemented in various forms. Therefore, it should be understood to include all modifications, equivalents, or substitutes to the extent that the sameness of spirit and technical features of the present disclosure is recognized.

Unless otherwise specified, all numbers used in this disclosure are to be understood as modifying the term "about" in all instances. The modifier “about” is intended to have a commonly recognized approximate meaning, which can be more accurately interpreted as a meaning within a certain percentage of the modified value, and more specifically ±20%, ±10%, ± It can mean 5%, ±2% or ±1% or less.

According to one specific example of the present disclosure,

A compound represented by Formula 1, a solvate thereof or a pharmaceutically acceptable salt thereof is provided.

[Formula 1]

The R ₁ and R ₂ may each independently be an alkyl group having 1 to 6 carbon atoms. Specifically, R ₁ and R ₂ may each independently be an alkyl group having 1 to 4 carbon atoms. More specifically, R ₁ and R ₂ may each independently be an alkyl group having 1 to 2 carbon atoms.

또는

는 벤젠고리에 치환되는 치환기와 치환위치, 치환개수를 특정하지 않겠다는 의미로 볼 수 있다. 예를 들어,

또는

는 R₁ 또는 R₂가 옥텟 규칙에 따라 결합할 수 있는 위치 중 적어도 하나의 위치에 각각 독립적인 치환기가 치환될 수 있다는 의미를 포함할 수 있다. 또한 예를 들어,

또는

는 R₁ 또는 R₂로 일괄적으로 표시했으나 서로 다른 R₁ 또는 R₂로 표시되는 복수개의 치환기가 서로 다른 위치에 치환될 수 있다는 의미를 포함할 수 있다. According to another embodiment, in Formula 1

or

can be seen as meaning that the substituent to be substituted on the benzene ring, the position of substitution, and the number of substitutions will not be specified. for example,

or

may include the meaning that each independent substituent may be substituted at at least one position among positions to which R ₁ or R ₂ may bind according to the octet rule. Also for example

or

is collectively represented by R ₁ or R ₂ , but may include a meaning that a plurality of substituents represented by different R ₁ or R ₂ may be substituted at different positions.

는 R₁이 2번, 3번, 4번 및 5번 위치 중 적어도 하나의 위치에 각각 독립적인 치환기가 치환될 수 있다는 의미를 포함할 수 있다. for example,

R ₁ may include the meaning that each independent substituent may be substituted at at least one of positions 2, 3, 4, and 5.

는 R₂가 2번, 3번, 4번, 5번 및 6번 위치 중 적어도 하나의 위치에 각각 독립적인 치환기가 치환될 수 있다는 의미를 포함할 수 있다. Also for example

R ₂ may include the meaning that each independent substituent may be substituted at at least one of positions 2, 3, 4, 5, and 6.

According to specific examples of the present disclosure,

A compound represented by Formula 2 below, a solvate thereof or a pharmaceutically acceptable salt thereof is provided.

[Formula 2]

According to specific examples of the present disclosure,

A compound represented by Formula 3 below, a solvate thereof or a pharmaceutically acceptable salt thereof is provided.

[Formula 3]

Anti-cancer pharmaceutical composition according to the present disclosure may include a compound represented by Formula 1, Formula 2 or Formula 3, a solvate thereof, a pharmaceutically acceptable salt, or a combination thereof.

Anti-cancer pharmaceutical composition of the present disclosure may have the effect of preventing the proliferation, metastasis, migration or invasion of cancer cells. Specifically, the anticancer pharmaceutical composition may be a pharmaceutical composition for inhibiting cancer cell invasion. More specifically, the pharmaceutical composition may be a composition for inhibiting cancer cell invasion that inhibits the invasion of cancer cells by beta1-integrin by inhibiting the overexpression of beta1-integrin induced by at least one of Rab25 and Rab coupling protein (RCP).

The pharmaceutically acceptable salt may be a salt that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The salt may be, for example, at least one selected from the group consisting of inorganic acid salts, organic acid salts and metal salts.

According to another embodiment, the inorganic acid salt may be at least one selected from the group consisting of hydrochloride, bromate, phosphate, sulfate, and disulfate, and the organic acid salt may be mesylate, formate, acetate, propionate, lactate, oxalate, Tartrate, Malate, Maleate, Citrate, Fumarate, Besylate, Camsylate, Edisyl Salt, Trichloroacetic Acid, Trifluoroacetate, Benzoate, Gluconate, Methanesulfonate, Glycolate, Succinate, It may be at least one selected from the group consisting of 4-toluenesulfonate, galacturonate, embonate, glutamate, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and aspartate, and the metal salt is calcium salt, sodium salt, magnesium It may be at least one selected from the group consisting of salts, strontium salts and potassium salts.

The solvate may be a compound formed by attraction between solute and solvent molecules. The solvate may be, for example, a hydrate.

The pharmaceutical composition may be a pharmaceutical composition targeting a subject capable of developing cancer. Specifically, a subject capable of developing cancer may refer to an animal, and the animal may be a human, cow, horse, pig, dog, sheep, goat, monkey, or cat, but is not limited thereto.

The pharmaceutical composition of the present disclosure is not limited thereto, but powders, granules, powders, capsules, tablets, aqueous suspensions, n-coated tablets (n is 2, 3 or 4), orally disintegrating tablets, respectively according to conventional methods, Oral formulations such as sublingual tablets or film tablets, external preparations, suppositories, and sterile injection solutions may be formulated and used.

A pharmaceutical composition of the present disclosure may include a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier may use at least one selected from the group consisting of a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a colorant, and a flavoring agent for oral administration, but is limited thereto. It is not. In the case of injection, a buffer, preservative, analgesic agent, solubilizer, isotonic agent or stabilizer may be mixed and used, and in the case of topical administration, a base, excipient, lubricant or preservative may be mixed and used.

Formulations of the pharmaceutical compositions of the present disclosure may be variously prepared by mixing with pharmaceutically acceptable carriers as described above. For example, for oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in unit dosage ampoules or multiple dosage forms. It can also be formulated into solutions, suspensions, tablets, capsules, sustained-release preparations, and the like.

On the other hand, examples of carriers, excipients or diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil and the like can be used. In addition, fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like may be further included.

Routes of administration of the pharmaceutical composition according to the present disclosure include, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, These include topical, sublingual or rectal. Oral or parenteral administration is preferred.

In this disclosure, “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intracapsular, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. A pharmaceutical composition of the present disclosure may also be administered in the form of a suppository for rectal administration.

In the present disclosure, “cancer” is a malignant tumor, which has rapid growth, invasive growth, and angiogenic effect, and can mean a malignant tumor that spreads and metastasizes to various parts of the body, causing a risk to life, and can be found in all parts of the body. can develop Specifically, “cancer” means leukemia, thyroid cancer, breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colon cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, It may be at least one selected from the group consisting of skin cancer and liver cancer, but is not limited thereto.

The pharmaceutical composition may include an effective amount of the compound of Formula 1, Formula 2 or Formula 3, a solvate thereof, a pharmaceutically acceptable salt, or a combination thereof. The term "effective amount" refers to an amount sufficient to produce an effect according to the purposes of the present disclosure when administered to a subject in need thereof. The effective amount can be appropriately selected by a person skilled in the art according to the selected cell or organism, and the severity of the disease, the patient's age, weight, health, sex, sensitivity to the drug of the patient, administration It may be determined according to factors including time, route of administration and excretion rate, duration of treatment, drugs used in combination or concurrently with the composition used, and other factors well known in the medical arts.

An effective amount of the compound of Formula 1, Formula 2 or Formula 3, a solvate thereof, a pharmaceutically acceptable salt thereof, or a combination thereof may be, for example, about 0.5 μg to about 2 g per 10 g of the pharmaceutical composition, for example for example about 1 μg to about 1 g, for example about 10 μg to about 500 mg, for example about 100 μg to about 100 mg, for example about 1 mg to about 90 mg , for example about 5 mg to about 80 mg, for example about 10 mg to about 70 mg, for example about 15 mg to about 60 mg, for example about 20 mg to about 50 mg, for example about 10 μg to about 1 mg, for example about 1 μg to about 100 μg, for example about 1 μg to about 10 μg. there is.

The dosage of the pharmaceutical composition may be, for example, about 0.001 mg/kg to about 1,000 mg/kg, for example, about 0.01 mg/kg to about 500 mg/kg, or er. for example about 0.01 mg/kg to about 100 mg/kg, for example about 0.01 mg/kg to about 50 mg/kg, for example about 0.01 mg/kg to about 10 mg/kg. and may be, for example, from about 0.01 mg/kg to about 5 mg/kg, such as from about 0.01 mg/kg to about 3 mg/kg, such as from about 0.1 mg/kg to about 10 mg. /kg, for example from about 0.1 mg/kg to about 5 mg/kg.

The frequency of administration may be 1 to 6 times a day, 1 to 4 times a week, 1 to 4 times a month, 1 to 12 times a year, or any time.

According to the present disclosure, other anticancer agents may be further included in the pharmaceutical composition. Specifically, the weight ratio of the compound represented by Formula 1, Formula 2 or Formula 3 and the active ingredient of another anticancer agent may be, for example, 1: about 0.001 to 1000, for example 1: about 0.01 to 100, , or for example 1: about 0.1 to 10.

The pharmaceutical composition of the present disclosure may be used alone or in combination with other anticancer agents, or may be used in combination with surgery, radiation therapy, hormone therapy, other chemotherapy, and methods using biological response modifiers.

The “other anticancer agents” may be pharmaceuticals including compounds, extracts, synthetic drugs, biopharmaceuticals, etc., which are commercially available as anticancer agents, and compounds, extracts, proteins, cells, body secretions reported to have anticancer effects. , antibody therapy, cell therapy, gene therapy, etc. According to a specific embodiment, the anticancer agent is nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib nip, cediranib, lestaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, bevacizumab, cisplatin, cetuximab, viscum album, asparaginase, tretinoin, hydroxyl Carbamide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomabtucetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, nitric acid Holmium chitosan, gemcitabine, doxifluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacitidine, methotrexate, uracil, cytarabine, fluorouracil, fludabine, eno Citabine, flutamide, decitabine, mercaptopurine, thioguanine, cladribine, carmophor, raltitrexed, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, Vinblastine, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleromycin, daunorubicin, dactinomycin, pirarubicin, aclarubicin, pepromycin, temsirolimus, busulfan, ifosfamide, cyclophosphamide, melpharan, altretmin, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, exmestane, in the group consisting of aminoglutesimide, anagrelide, navelbine, fadrazole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine and carmustine At least one selected may be used, but is not limited thereto.

The present disclosure is described in more detail through the following examples. However, the present disclosure is not limited by these examples.

Example 1: Compound

In the present invention, the substance that inhibits cancer cell invasion is a compound represented by Chemical Formula 3, and its chemical name is 7-methyl-2-(m-tolyl)cinnolin-3(2H)-one and is named SH-131.

[Formula 3]

Example 2: Setting drug administration concentration

The anticancer composition of the present invention aims to inhibit cancer cell infiltration, and is not aimed at suppressing the growth of cancer cells or killing cancer cells by cytotoxicity, so the anticancer composition reduces the growth of cancer cells by 15% or more. A non-inhibiting concentration was applied to cancer cells. Accordingly, an MTT experiment was conducted to determine the concentration at which SH-131 does not affect the growth of cancer cells. According to FIG. 1, even when ovarian cancer SKOV3 cells were treated with 10 µM of SH-131, the growth of cancer cells was not inhibited by more than 15%.

Example 3: Effect of inhibiting beta1-integrin overexpression by Rab25 or RCP

To confirm whether SH-131 can suppress the increase in beta1-integrin expression by Rab25 or RCP, ovarian cancer SKOV3 cells were selectively treated with 10 μM SH-131 and Rab25 or RCP for 24 hours and the expression of beta1-integrin The pattern was observed. According to Figures 2 and 3, Rab25 and RCP increased the expression of beta1-integrin compared to the control group treated with the vector, and when SH-131 was concurrently treated, the expression level of beta1-integrin was not significantly different from the control group, SH It was confirmed that -131 suppresses the increase in beta1-integrin expression of Rab25 or RCP.

Example 4: Inhibition of ovarian cancer cell invasion by Rab25 or RCP of SH-131

In order to verify the effect of SH-131 of the present disclosure, cancer cell invasion assay was performed using Boyden chamber assay. As described above, SH-131 was treated with 10 μM.

Type I collagen-coated polycarbonate filters with pore membranes of 8 μm size and no polyvinylpyrrolidine were used for the cancer cell invasion assay. After incubating the sample at 37 °C for 6 hours for migration and 17 hours for invasion, the migrated or invaded cells were sequentially fixed, and Diff-Quik reagent (Dade Behring Inc., Newark, DE, USA). The number of cells was counted and quantified under an optical microscope.

The degree of invasion of ovarian cancer SKOV3 cells transformed by amplification and expression of Rab25 or vector was confirmed. According to FIG. 4 , when only Rab25 was treated alone, ovarian cancer cell invasion was markedly increased, and it was confirmed that Rab25 promotes ovarian cancer cell invasion. However, when Rab25 and SH-131 were co-administered, ovarian cancer cell invasion was similar to that of the control group. Accordingly, it was confirmed that SH-131 significantly inhibits Rab25-induced ovarian cancer cell invasion.

In the same way, the degree of invasion of transformed ovarian cancer SKOV3 cells was confirmed by amplifying and expressing RCP or vector. According to FIG. 5 , when only RCP was treated alone, the invasion of ovarian cancer cells was markedly increased, and it was confirmed that RCP promoted the invasion of ovarian cancer cells. However, when RCP and SH-131 were administered together, ovarian cancer cell invasion was similar to that of the control group. Therefore, it was confirmed that SH-131 significantly inhibited ovarian cancer cell invasion by RCP.

Claims (11)

A pharmaceutical composition for anticancer comprising a compound represented by Formula 1, a solvate thereof or a pharmaceutically acceptable salt thereof;
[Formula 1]

Wherein R ₁ and R ₂ are each independently an alkyl group having 1 to 6 carbon atoms,
of Formula 1

Is R ₁ is located at least one of positions 2, 3, 4 and 5,
of Formula 1

is R ₂ is located at least one of positions 2, 3, 4, 5 and 6. According to claim 1,
The compound is a pharmaceutical composition for anti-cancer represented by Formula 3;
[Formula 3]

. According to claim 2,
The anti-cancer pharmaceutical composition for suppressing cancer cell invasion. According to claim 3,
The anti-cancer pharmaceutical composition for anti-cancer, which inhibits cancer cell invasion by inhibiting the overexpression of beta1-integrin promoted by at least one of Rab25 and RCP. According to claim 2,
An anti-cancer pharmaceutical composition further comprising an anti-cancer agent. According to claim 5,
The anticancer agent is nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib, lesta urtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, bevacizumab, cisplatin, cetuximab, viscum album, asparaginase, tretinoin, hydroxycarbamide, dasatinib , estramustine, gemtuzumab ozogamicin, ibritumomabtucetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, gemcitabine, Doxifluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacytidine, methotrexate, uracil, cytarabine, fluorouracil, fludabine, enocitabine, flutamide , decitabine, mercaptopurine, thioguanine, cladribine, carmophor, raltitrexed, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, tenipo Seed, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleromycin, daunorubicin, dactinomycin, pirarubicin, aclarubicin, pepromycin, temsirolimus, busulfan , ifosfamide, cyclophosphamide, melpharan, altretmin, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, exmestane, aminoglutethimide, At least one anti-cancer agent selected from the group consisting of anagrelide, navelbine, fadrazole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine and carmustine pharmaceutical composition. According to any one of claims 1 to 6,
The pharmaceutical composition for anticancer is leukemia, thyroid cancer, breast cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, colon cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, lung cancer, bladder cancer, kidney cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer , Anti-cancer pharmaceutical composition for at least one cancer selected from the group consisting of skin cancer and liver cancer. According to any one of claims 2 to 6,
The anti-cancer pharmaceutical composition is a pharmaceutical composition for anti-cancer targeting ovarian cancer. According to any one of claims 1 to 6,
The anti-cancer pharmaceutical composition is an anti-cancer pharmaceutical composition, characterized in that for oral or parenteral administration. According to any one of claims 1 to 6,
The dosage of the pharmaceutical composition for anti-cancer is 0.001 mg / kg to 100 mg / kg characterized in that the pharmaceutical composition for anti-cancer. According to claim 5 or 6,
The ratio of the anti-cancer pharmaceutical composition and anti-cancer agent is 1: 0.001 to 1000 characterized in that the anti-cancer pharmaceutical composition.

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