KR101818865B1 - Pharmaceutical composition for combination therapy with anticancer drug - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for coadministration, which can be co-administered with a conventional anticancer drug to a histone deacetylation inhibitor-based compound. The pharmaceutical composition according to the present invention can effectively inhibit growth of cancer, especially, any one of bile duct cancer and gallbladder cancer and induces apoptosis to prevent and/or treat the cancer through apoptosis and proliferation of cancer cells by co-administering a conventional anticancer drug with a histone deacetylation inhibitor-based compound.

Description

[0001] PHARMACEUTICAL COMPOSITION FOR COMBINATION THERAPY WITH ANTICANCER DRUG [0002]

More particularly, the present invention relates to a pharmaceutical composition capable of providing a synergistic effect to the prevention or treatment of cancer in combination with commonly used bile duct cancer and / or gallbladder cancer anticancer agent .

Cholangiocarcinoma is a cancer that occurs in the liver bile ducts and is known to occur in stem cells such as liver cancer (Sell and Dunsford Am. J. Pathol. 134: 1347-1363, 1989). Worldwide, the incidence of biliary cancer is much lower than that of liver cancer, but the incidence is higher in Southeast Asia than in Europe or North America. Biliary cancer is characterized by a high recurrence rate, which is not effective, and general chemotherapy or radiotherapy is not effective (Pederson et al. Cancer Res. 4325-4332, 1997).

Also, gallbladder cancer is a tumor composed of cancer cells that develop in the gallbladder, and adenocarcinoma arising in the gallbladder cell is mostly occupied. Generally, gallbladder cancer means gallbladder adenocarcinoma. The cause of the disease has not yet been clearly identified, but risk factors include gallstone, chronic gallbladder disease, pancreatobiliary dysplasia, porcelain gallbladder, and typhoid carriers.

On the other hand, histone proteins are known as five types (H1, H2A, H2B, H3 and H4). Histones H2A, H2B, H3 and H4 are found in the nucleosomes and H1 is the linker located between the nucleosomes. Each nucleosome contains two of the histone forms within its core, except for H1, which is present only in the outer portion of the nucleosome structure. When the histone protein is hypoacetylated, it is known that there is a greater affinity of the histone for the DNA phosphate backbone. This affinity is known to cause DNA to bind tightly and render DNA unavailable for transcriptional control elements and machinery. The regulation of acetylation of histone proteins occurs through a balance of activity between histone acetyl transferase (HAT) and histone deacetylase (HDAC). Histone deacetylase catalyzes the removal of the acetyl group of the chromatin core histone, and it is generally reported that the hypoacetylated state inhibits the transcription of DNA.

Despite advances in the field of cancer treatment, there is currently no report on the treatment of biliary cancer. Therefore, although it is urgent to develop an effective chemical therapeutic agent for biliary cancer treatment other than surgical treatment, effective therapeutic methods have not been developed yet, and research and development thereof are required.

On the other hand, gemcitabine, cisplatin, oxaliplatin and 5FU have been used for the treatment of the above-mentioned bile duct cancer, but the therapeutic effect is insufficient due to the resistance of the therapeutic agent due to tolerance . Thus, although GP therapy is used to treat biliary cancer using gemcitabine and cisplatin in combination, there is a problem that the combination therapy alone provides only insignificant efficacy compared with administration of each drug.

It is an object of the present invention to provide a synergistic effect for prevention and / or treatment of biliary cancer and / or gallbladder cancer by more effectively inducing the proliferation inhibition and cell death of the cancer cell when the biliary cancer and / The present invention also provides a pharmaceutical composition comprising the same.

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

The inventors of the present invention have found that when a histone deacetylation inhibitor-based compound is administered in combination with a conventional anticancer agent, the growth inhibition and cell apoptosis of biliary cancer and / or gallbladder cancer cells are effectively induced, Cancer can be prevented and / or treated, thereby completing the present invention.

However, in the present invention, the term " histone deacetylation inhibitor " is intended to inhibit the activity of histone deacetylase (HDAC), which is known to play an important role in the regulation of gene expression, Induced hypoacetylation and thus gene expression changes. The HDAC inhibitor may be a) a domain capable of binding to a metal (especially zinc), b) a linker capable of filling the channel of the HDAC, and c) a moiety capable of interacting with the structures at the edge of the HDAC active region. (J. Med. Chem., 2003, 46 (24), 5097-5116).

Specifically, according to one embodiment of the present invention, there is provided a pharmaceutical composition for administration together with an anticancer agent comprising a histone deacetylation inhibitor as an active ingredient. In the present invention, the histone deacetylation inhibitor compound may exert a very high synergistic effect in inducing growth inhibition and cell death of biliary cancer cells or gallbladder cancer cells when administered in combination with a common anticancer drug.

In the present invention, the histone deacetylation inhibitor is selected from the group consisting of (E) -N1- (3- (dimethylamino) propyl) -N8-hydroxy-2 - ((naphthalen-1-yloxy) methyl (E) -N1- (3- (dimethylamino) propyl) -N8-hydroxy-2- ((naphthalen-1-yloxy) methyl) oct-2-enediamide; (3- [(dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] -1-benzofuran-2-carboxamide represented by the following formula (Dimethylamino) methyl] -N- {2- [4- (hydroxycarbamoyl) phenoxy] ethyl} -1-benzofuran-2-carboxamide); (6 - ((diethylamino) methyl) naphthalene represented by the following general formula (3): (6 - [(diethylamino) methyl] naphthalen-2-yl} methyl [4- (hydroxycarbamoyl) phenyl] carbamate -2-yl) methyl (4- (hydroxycarbamoyl) phenyl) carbamate); (S) -N-hydroxy-4- (3-methyl-2-phenylbutanamido) benzamide represented by the following formula (4) ) benzamide); (S) -2-cyclohexyl-2- ((4- (8- (hydroxyamino) -8-oxooctanamido) benzyl) amino) acetate 2-cyclohexyl-2 - ((4- (8- (hydroxyamino) -8-oxoctanamido) benzyl) amino) acetate); And 2- (diphenylamino) -N- (7- (hydroxyamino) -7-oxoheptyl) pyrimidine-5-carboxamide represented by the following formula (E) -N1- (3- (dimethylamino) -7-oxoheptyl) pyrimidine-5-carboxamide represented by the following formula (1) Amino) propyl) -N8-hydroxy-2 - ((naphthalen-1-yloxy) methyl) oct-

 [Chemical Formula 1]

 (2)

 (3)

 [Chemical Formula 4]

 [Chemical Formula 5]

 [Chemical Formula 6]

In the present invention, the "joint administration" can be achieved by administering the individual components of the therapeutic regimen simultaneously, sequentially or separately. The combination therapy is obtained by administering two or more drugs simultaneously or sequentially, or alternatively at a predetermined or unspecified interval. The combined treatment method is not limited to this, and for example, the degree of reaction, the rate of reaction , The duration to disease progression or the duration of survival is defined as being therapeutically superior and synergistic than the efficacy obtained by dosing one or the other of the components of the combination therapy at conventional doses .

According to another embodiment of the present invention, there is provided a pharmaceutical composition for preventing or treating any one of bile duct cancer and bile duct cancer, which comprises the aforementioned histone deacetylation inhibitor and an anticancer agent as an active ingredient. Specifically, the pharmaceutical composition of the present invention induces an increase in the expression of BAX, a protein involved in apoptosis, and cleaved caspase 3 and PARP, and induces cleaved form of phosphotyrosine, which is an active form of AKT, AKT expression and decrease the expression of phospho-ERK, which is related to cell proliferation, so that it can give a very high synergy effect to induce the growth inhibition and cell death of the cancer cells. In addition, the pharmaceutical composition according to the present invention can be used as a marker for oncogenes or cancer stem cells (Oncogene 7 (1): 3-7, Gastroenterology. 2011 Dec; 141 (6): 2218 -2227) can be used to effectively treat cancer stem cells as well as general cancer cells by reducing the expression of C-met.

The anticancer drug administered in combination with the histone acetylation inhibitor in the pharmaceutical composition of the present invention means a drug used for prevention and / or treatment of cancer due to the growth inhibition and induction of apoptosis of the cancer, But are not limited to, imatinib, oxaliplatin, rituximab, elotinib, neratinib, lapatinib, zetitib, vandetanib, nilotinib, semathanib, conservatib, acitinib, cediranib, lestauritinib, Cisplatin, cetuximine, biscuit alum, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estrameristin, cisplatin, cisplatin, , Gemtuzumab ozogamicin, ibritumomat cetane, heptaplatin, methylaminoburenic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, gemcitabine, But are not limited to, rheumatoid, ruridine, femetrexed, tegafur, capecitabine, gimeracin, oteracil, azacytidine, methotrexate, uracil, cytarabine, fluorouracil, fludarabine, enocitabine, But are not limited to, cholesterol, cholesterol, cholesterol, cholesterol, cholesterol, cholesterol, cholesterol, cholesterol, cholesterol, But are not limited to, atorvastatin, tinifoside, doxorubicin, dirubicin, epirubicin, mitoxantrone, mitomycin, blormomycin, daunorubicin, dactinomycin, pyrabicin, aclarubicin, But are not limited to, polysaccharides, polysaccharides, polysaccharides, polysaccharides, polysaccharides, polysaccharides, polysaccharides, Aminoglutethimide, anagrel As an adjuvant, as well as in combination with other drugs, such as, for example, lid, lavellin, paladazol, tamoxifen, toremifene, testolactone, anastrozole, letrozole, borozol, bicalutamide, Can be used without limitation as long as it is an anticancer agent generally used for cancer treatment. Preferably, the above-mentioned anticancer agent is one capable of effectively preventing and / or treating cancer of any one or more of biliary cancer and gallbladder cancer, more preferably a biliary cancer. Examples of the anticancer agent include gemcitabine, cisplatin ), 5FU, Capecitabine, Olsaliplatine, Vorinistat, and Entinostat, and more preferably, gemcitabine and A combination of cisplatin may be used.

In the present invention, when the above-mentioned histone deacetylation inhibitor compound, gemcitabine and cisplatin are administered in triplicate, biliary cancer and / or gallbladder cancer cells are significantly reduced at a significantly lower concentration than the conventional therapy using gemcitabine and cisplatin Growth inhibition and induction of apoptosis can be given to enhance the effect of the cancer treatment.

In one embodiment of the present invention, the histone deacetylation inhibitor and the anticancer agent may be contained in a weight ratio of 1: 0.2-100 or 1: 0.4-400, but the present invention is not limited thereto and may be appropriately selected depending on the type of anticancer agent used Can be adjusted. If the content is out of the above range, the synergistic effect of cancer treatment due to the co-administration can not be obtained, and the toxicity by the drug may occur in the desired individual.

In one embodiment of the present invention, the histone deacetylation inhibitor, gemcitabine, and cisplatin may be contained in a weight ratio of 1: 0.25 to 2: 0.2 to 5, but the present invention is not limited thereto. If the content is out of the above range, synergistic effects of the desired cancer treatment due to the triple combination administration can not be obtained, and the toxicity caused by the drug may occur in the desired individual.

As described above, the combination administration of the compound represented by any one of Chemical Formulas 1 to 6 and the anticancer agent of the present invention leads to inhibition of growth of cancer cells and cell death, thereby effectively preventing and / or treating cancer of any one or more of biliary cancer and gallbladder cancer But it is not limited thereto. Preferably, it is capable of preventing and / or treating the bile duct cancer by effectively inducing the proliferation inhibition and cell death of the bile duct cancer.

In the present invention, the pharmaceutical composition may be in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be a human.

The pharmaceutical composition of the present invention may be formulated in the form of oral preparations such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories and sterilized injection solutions according to a conventional method, have. The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizing agent, a dispersing agent, a stabilizer, a suspending agent, a coloring matter, a perfume or the like in the case of oral administration. A solubilizing agent, an isotonic agent, a stabilizer and the like may be mixed and used. In the case of topical administration, a base, an excipient, a lubricant, a preservative and the like may be used. Formulations of the pharmaceutical compositions of the present invention may be prepared in various manners by mixing with pharmaceutically acceptable carriers as described above. For example, oral administration may be in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. In the case of injections, they may be formulated in unit dosage ampoules or in multiple dosage forms have. Other, solutions, suspensions, tablets, capsules, sustained-release preparations and the like.

Examples of suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltoditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil. Further, it may further include a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, an antiseptic, and the like.

The route of administration of the pharmaceutical compositions according to the present invention may be, but is not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, Sublingual or rectal. Oral or parenteral administration is preferred. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions of the present invention may also be administered in the form of suppositories for rectal administration.

The pharmaceutical composition of the present invention varies depending on various factors including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease to be prevented or treated. And the dosage of the pharmaceutical composition may be appropriately selected by a person skilled in the art depending on the condition of the patient, the body weight, the degree of disease, the type of administration, the route of administration and the period of time, and may be 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way. The pharmaceutical composition according to the present invention can be formulated into pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions.

When the pharmaceutical composition according to the present invention is administered in combination with a conventional anticancer compound, it is possible to effectively prevent and / or treat any one or more of biliary cancer and gallbladder cancer by imparting a synergistic effect to growth inhibition and cell apoptosis of cancer cells .

FIGS. 1 (a) to 1 (d) show growth inhibition results of the bile duct cancer cell line according to an embodiment of the present invention.
FIG. 2 shows growth inhibition results of the pancreatic cancer cell line according to a comparative example of the present invention.
FIGS. 3 (a) and 3 (b) show growth inhibition results of triple combination administration in a bile duct cancer cell line according to an embodiment of the present invention.
4 (a) and 4 (b) show Western blot assay results according to an embodiment of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to 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 .

[ Example ]

[ Example  One] Cholangiocarcinoma cell line ( SNU308  And SNU1196 ) And culture of pancreatic cancer cell lines

(E) -N1- (3- (dimethylamino) propyl) -N8-hydroxy-2 - ((naphthalen-1-yloxy) methyl) oct-2-enedamide (CG200745) In order to inhibit the survival of biliary cancer cells and to confirm the expression of drug releasing genes, SNU308 and SNU1196, a cholangiocarcinoma cell line, and Cfpac1, a pancreatic cancer cell line, were subcultured. The Cfpac1 cell line was purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA), the SNU308 and SNU1196 cell lines from the Korean Cell Line Bank (KCLB, Korean Cell Line Bank, Seoul, Korea). Cfpacl cell lines were grown in IMDM (Invitrogen Gibco, Grand Island, NY) containing 10% fetal bovine serum (FBS; hyclone, logan, UT), 10% fetal bovine serum (FBS; hyclone, the culture in RPMI1640 (Invitrogen Gibco, Grand Island, NY) in a nutrient medium 37 ℃, 5% CO ₂ incubator was carried out including a.

[ Example  2] Inhibition of growth inhibition by combination administration in biliary cancer cell lines

MTT experiments were conducted to investigate the growth inhibitory effects of the combination of the anticancer agent and CG200745 in the cholangiocarcinoma cell lines (SNU308 and SNU1196). The MTT assay was performed by attaching the above-described cholangiocarcinoma cell line to a 96-well plate at a concentration of 3 x 10 ³ cells / well, followed by the addition of 0.25 to 0.5 μM of gemcitabine, cisplatin, oxaliplatin, and 5FU and CG200745, Respectively. After the incubation, MTT (3- [4,5-dimethylthiazol-2-yl] -2,5 diphenyl tetrazolium bromide , Sigma-Aldrich))) was added at a rate of 100 μl / well and reacted for 3 hours under light shielding conditions. After 3 hours, the reaction solution was removed, and 100 μl / well of DMSO (dimethyl sulfoxide) was added thereto, followed by measurement at 570 nm. The results are shown in FIGS. 1 (a) to (d).

As shown in FIGS. 1 (a) to 1 (d), when chimeric hepatocyte, cisplatin, oxaliplatin, and 5FU were administered alone in combination with CG200745 drug, It can be confirmed that the survival rate of the cholangiocyte cell line is remarkably reduced.

[ Comparative Example ] Inhibitory effect of growth inhibition on pancreatic cancer cell lines

MTT experiments were conducted to compare the inhibition of growth of cancer cells (SNU308 and SNU1196) by cancer chemotherapeutic agent and CG200745 compared to pancreatic cancer. Gemcitabine was administered at a concentration of 0 to 0.032 μM and CG200745 at a concentration of 0.25 and 0.5 μM, followed by incubation for 72 hours. After the incubation, the MTT experiment was carried out in the same manner as in Example 2, and the results are shown in FIG.

As shown in FIG. 2, when gemcitabine and CG200745 were co-administered, the survival rate of pancreatic cancer cell line Cfpac1 was about 90% when using gemcitabine at a concentration of 0.002 μM and CG200745 at a concentration of 0.5 μM, Is very small. On the other hand, in the case of the biliary cancer cell line SNU1196, the survival rate when using gemcitabine at a concentration of 0.001 μM and CG200745 at 0.5 μM drops to 40% or less.

The survival rate of the pancreatic cancer cell line was significantly lower than that of the bile duct cancer cell line of Example 2, indicating that the combined administration of gemcitabine and CG200745 in pancreatic cancer was more effective than bile duct cancer have.

[ Example  3] Inhibition of cell growth by triple combination administration in biliary cancer cell line

In order to investigate the synergistic effect of inhibition of cell growth in the case of triple combination administration of CG200745 in addition to the combination administration of gemcitabine and cisplatine, which are used as standard treatment for biliary cancer, the cholangiocarcinoma cell line SNU308 And SNU1196). In the case of SNU308, gemcitabine (G) was administered at 0.015625 to 1 μM and cisplatin (P) at 0.35938 to 2.3 μM, and SNU1196 was administered at 0.001563 to 0.1 μM gemcitabine (G) and 0.064063 to 4.1 μM cisplatin . CG200745 was administered with 0.5 μM triple combination to each of the bile duct cancer cell lines and cultured for 72 hours. After culturing, the cell growth inhibitory effect was confirmed in the same manner as in the MTT experiment of Example 2, and the results are shown in FIGS. 3 (a) and 3 (b).

As shown in FIGS. 3 (a) and 3 (b), compared with the case of administering 0.01625 μM of gemcitabine (G) and 0.14375 μM of cisplatin (P) to the SNU308 bile duct cancer cell line, It was confirmed that the cell growth inhibition remarkably increased to about 40% when the combination administration was performed. In addition, in the case of the SNU1196 cholangiocarcinoma cell line, when the addition of 0.5 μM of CG200745 in addition to triple combination, the inhibition of cell growth was about 40 (P) in comparison with the case of administration of 0.001563 μM of gemcitabine (G) and 0.064063 μM of cisplatin % Increase. In addition, the effect of triple combination on cell growth inhibition increased with increasing drug concentration.

[ Example  4] Cell signaling mechanism by triple combination administration in biliary cancer cell line

Western blotting was performed in order to confirm the cell signaling mechanism in the bile duct cancer cell line by the triple combination administration of Example 3 above.

The preparation method of the protein used in Western blotting is as follows. The cholangiocarcinoma cell line was harvested by treatment with Accutase (Sigma-Aldrich), washed with PBS, and then lysed using a cell lysis buffer containing a protein degradation inhibitor. The whole solution was fractionated using a centrifuge, and only the protein-containing solution was extracted. The extracted proteins were quantified by the Bradford method. Proteins at the same concentration were separated by performing SDS-polyacrylamide gel electrophoresis through quantification, and transferred to a PVDF membrane. The membranes from which the proteins were transferred were blocked with TBS-T (Tris-buffered saline / 0.05% Tween-20) solution containing 5% non-fat milk for 1 hour at room temperature to reduce non-specific binding (1: 1000 dilution) was reacted overnight at 4 ° C, and the secondary antibody (1: 5000 dilution) was reacted at room temperature for 1 hour. For visualization, an enhanced chemiluminescence system of the PIERCE product was used.

Western blot analysis was performed using a GAPDH marker, a housekeeping gene for quantitative comparison of Ac-Histone H3, C-met, phospho-AKT, AKT, p21, BAX, Caspase3, PARP and protein expression. The results are shown in Fig.

(Oncogene 7 (1): 3-7, Gastroenterology. 2011 Dec; 141 (6): 2218-2227), which is known as a marker of oncogenes or cancer stem cells, ) c-met showed decreased protein expression when 0.5 μM CG200745 was additionally administered in triplicate, compared with the combination of gemcitabine and cisplatin. In addition, BAX, cleaved Caspase 3, and cleaved PARP, which are related to apoptosis, were significantly increased in triple combination administration. In addition, the phospho-AKT protein, an active form of AKT associated with cell survival, was found to be reduced in each of the bile duct cancer cell lines when the triple combination was administered, as compared to the combination therapy. The protein of phospho-ERK, which is an active state of ERK related to cell proliferation, was also decreased in the SNU1196 cell line compared to the combination treatment when the triple combination was administered.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the scope of the present invention is not limited to the disclosed exemplary embodiments, but various changes and modifications may be made without departing from the scope of the invention. It will be obvious to those who have knowledge of

Claims (18)

A pharmaceutical composition for enhancing the anticancer therapeutic effect of biliary cancer or gallbladder cancer, which is used in combination with an anticancer agent,
(E) -N1- ((E) -N- (3- (dimethylamino) propyl) -N8-hydroxy- (Dimethylamino) propyl) -N8-hydroxy-2 - ((naphthalen-1-yloxy) methyl) oct-2-enediamide,
Wherein the anticancer agent is at least one of gemcitabine, cisplatin, oxaliplatin and 5-FU. delete delete delete delete The method according to claim 1,
Wherein the anticancer agent is gemcitabine and cisplatin. delete The method according to claim 1,
Wherein said pharmaceutical composition is for enhancing the anticancer therapeutic effect of bile duct cancer. (E) -N1- ((E) -N- (3- (dimethylamino) propyl) -N8-hydroxy- 1-yloxy) methyl) oct-2-enediamide) and an anticancer agent as active ingredients,
Wherein the anticancer agent is at least one of gemcitabine, cisplatin, oxaliplatin and 5-FU, or a prophylactic or therapeutic agent for biliary cancer or gallbladder cancer. delete delete delete delete 10. The method of claim 9,
Wherein the anticancer agent is gemcitabine and cisplatin. 10. The method of claim 9,
The anticancer agent and the (E) -N1- (3- (dimethylamino) propyl) -N8-hydroxy-2 - ((naphthalen- 1-yloxy) methyl) oct- To 100% by weight of the composition. 15. The method of claim 14,
(E) -N1- (3- (dimethylamino) propyl) -N8-hydroxy-2 - ((naphthalen-1-yloxy) methyl) oct-2- enedamide and gemcitabine and cisplatin are 1 : 0.25 to 2: 0.2 to 5 by weight. delete 10. The method of claim 9,
Wherein said pharmaceutical composition is for the prophylaxis or treatment of bile duct cancer.

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