KR100983318B1 - Use in anti-cancer agent of [(meso-Bis(o-hydroxyphenyl)bis(o-Hydroxy)salen, 3,3'-(1E,1'E)-((1R,2S)-1,2-bis(2-hydroxyphenyl)ethane-1,2-diyl)bis(azan-1-yl-1-ylidene)bis(methan-1-yl-1-ylidene)dibenzene-1,2-diol)] - Google Patents

Abstract

The present invention provides meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen [(meso-Bis (o-hydroxyphenyl) bis (o-Hydroxy) salen, 3,3 '-(1E, 1'E) )-((1R, 2S) -1,2-bis (2-hydroxyphenyl) ethane-1,2-diyl) bis (azan-1-yl-1-ylidene) bis (methan-1-yl-1-ylidene (dibenzene-1,2-diol)] compound as an anticancer agent, and more particularly, inhibits proliferation of cancer cells by activating poly ADP-ribose polymerase-1 (PARP-1) cleavage and p21 expression. Meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen compound of formula 1 to induce apoptosis and the compound or a pharmaceutically acceptable salt thereof for the prevention and treatment of cancer diseases It relates to a pharmaceutical composition.

[Formula 1]

Meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen of the present invention effectively cleaves PARP-1 protein of cancer cells and inhibits cell growth by activating p21 expression, a cell cycle progression inhibitor Since it has a suppression of the proliferation of cancer cells and induces apoptosis can be usefully used as a pharmaceutical composition for cancer prevention and treatment.

Anticancer agent, PARP-1, p21, apoptosis, meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen

Description

Use of anti-cancer agent of [(meso-Bis (o-hydroxyphenyl) bis (o-Hydroxy) salen, 3, as the anticancer agent of meso-bis (ortho-hydroxyphenyl) bisene 3 '-(1E, 1'E)-((1R, 2S) -1,2-bis (2-hydroxyphenyl) ethane-1,2-diyl) bis (azan-1-yl-1-ylidene) bis ( methan-1-yl-1-ylidene) dibenzene-1,2-diol)]}

The present invention provides meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen [(meso-Bis (o-hydroxyphenyl) bis (o-Hydroxy) salen, 3,3 '-(1E, 1'E) )-((1R, 2S) -1,2-bis (2-hydroxyphenyl) ethane-1,2-diyl) bis (azan-1-yl-1-ylidene) bis (methan-1-yl-1-ylidene (dibenzene-1,2-diol)] compound as an anticancer agent, and more particularly, inhibits proliferation of cancer cells by activating poly ADP-ribose polymerase-1 (PARP-1) cleavage and p21 expression. Meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen compound of formula 1 to induce apoptosis and the compound or a pharmaceutically acceptable salt thereof for the prevention and treatment of cancer diseases It relates to a pharmaceutical composition.

Poly ADP-ribose polymerase-1 (PARP-1) converts nicotinamide to nicotinamide by using nicotinamide adenine dinucleotide as a substrate. It is an enzyme that catalyzes the poly ADP-ribosyl action, a kind of post-translational modification of proteins.

When the DNA is severely damaged, its expression increases to activate poly ADP-ribosyl proteins. DNA lyase (Dnase) also is one of the protein, calcium ²⁺ / Mg ²⁺ through the process - to inhibit the operation of the dependent DNA lyase ^{Ⅰ (Ca 2+ / Mg 2+ -dependent} Dnase Ⅰ).

That is, when PARP-1 is increased, the activity of DNAase I is inhibited. Conversely, when PARP-1 is cleaved and loses its activity, it induces the activation of DNAase I, which is involved in DNA degradation. This leads to cleavage of chromosomal DNA, which induces apoptosis (Genes to Cell, 9 , 1103, 2004; Cell Death Differentiation, 14 , 992, 2007).

Apoptosis is a form of dying, in which cells are controlled by genes, where the dying cells develop an immune response and cause no adverse effects on surrounding cells, such as fragmentation of the nucleus, fragmentation of chromosomal DNA, changes in cell membranes, blisters and Resulting in various morphological changes associated with the dorsal cell.

Unlike cell death caused by sudden cell damage caused by the influx of radiation or poisons, apoptosis is beneficial to the individual's life history in relation to proper regulation of cell numbers.

In addition to PARP-1, p21 is known to be involved in apoptosis. p21 is a Cyclin Dependent Kinase Inhibitor 1A, a cyclin / CDK complex such as Cyclin-Cyclin-CDK2, or Cyclin-Cyclin-Dependent Kinase 4 (Cyclin-CDK4) It is a protein that inhibits activity. It is known to be mainly related to cell cycle inhibitory activity, although its mechanism is not clear yet, but it has been reported that p21 overexpression is closely related to induction of apoptosis (Mol. Cancer Ther., 1 , 639, 2002). ).

On the other hand, since cancer cells are cells that are not properly regulated in self-apoptosis function unlike normal cells, it is possible to suppress the proliferation of cancer cells through induction of self-apoptosis function. In addition, induction of apoptosis in cancer cells may have a positive effect on the interaction between cancer cells and patients, in particular immune responses, in addition to the direct reduction effect of cancer cells.

Therefore, cutting PARP-1 and increasing the expression level of p21 as a cancer inhibitor through induction of apoptosis is very important to search for new cancer inhibitors that are more target specific than conventional cancer inhibitors.

The present inventors can inhibit the proliferation of cancer cells by cleaving poly ADP-ribose polymerase-1 (PARP-1), a protein involved in inducing apoptosis, and overexpressing p21 to induce cell death. As a result of diligent efforts to find a substance, it was confirmed that a new salen ligand having stereospecificity effectively cleaves PARP-1 and activates the expression of p21 protein, thereby completing the present invention.

Finally, the present invention provides meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen [(meso-Bis (o-hydroxyphenyl) bis (o-) having activity of increasing PARP-1 cleavage and p21 expression. Hydroxy) salen, 3,3 '-(1E, 1'E)-((1R, 2S) -1,2-bis (2-hydroxyphenyl) ethane-1,2-diyl) bis (azan-1-yl- 1-ylidene) bis (methan-1-yl-1-ylidene) dibenzene-1,2-diol)] and its use as an anticancer agent.

In order to achieve the above object, the present invention produces a poly ADP-ribose polymerase-1 (PARP-1) fragment, and by inhibiting the proliferation of cancer cells and induces apoptosis by activating p21 expression meso -Bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen [(meso-Bis (o-hydroxyphenyl) bis (o-Hydroxy) salen, 3,3 '-(1E, 1'E)-(( 1R, 2S) -1,2-bis (2-hydroxyphenyl) ethane-1,2-diyl) bis (azan-1-yl-1-ylidene) bis (methan-1-yl-1-ylidene) dibenzene-1 , 2-diol)].

[Formula 1]

The present invention also provides a use of the meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen compound as an anticancer agent.

Specifically, the present invention provides a pharmaceutical composition for the prevention and treatment of cancer diseases including the meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen or a pharmaceutically acceptable salt thereof.

The cancer disease includes a general cancer disease caused by abnormalities of the p21 gene, preferably gastric cancer, colon cancer, breast cancer, lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or eye melanoma , Uterine cancer, ovarian cancer, rectal cancer, anal muscle cancer, fallopian tubes, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, Adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, 1 One or more diseases selected from primary CNS lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, and the like.

Meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen [(meso-Bis (o-hydroxyphenyl) bis (o-Hydroxy) salen, 3,3 '-(1E, 1'E) )-((1R, 2S) -1,2-bis (2-hydroxyphenyl) ethane-1,2-diyl) bis (azan-1-yl-1-ylidene) bis (methan-1-yl-1-ylidene ) dibenzene-1,2-diol)] effectively inhibits cancer cell proliferation and apoptosis by effectively cutting the PARP-1 protein of cancer cells and activating p21 expression, a cell cycle inhibitor. By inducing it can be usefully used as a pharmaceutical composition for cancer prevention and treatment.

Hereinafter, the present invention will be described in more detail.

The present invention provides a poly ADP-ribose polymerase-1 (PARP-1) fragment and inhibits proliferation of cancer cells and induces apoptosis by activating p21 expression. Meso-Bis (o-hydroxyphenyl) bis (o-Hydroxy) salen, 3,3 '-(1E, 1'E)-((1R, 2S) -1, 2-bis (2-hydroxyphenyl) ethane-1,2-diyl) bis (azan-1-yl-1-ylidene) bis (methan-1-yl-1-ylidene) dibenzene-1,2-diol)] compound To provide.

[Formula 1]

In the present invention, the meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen of the formula (1) can be prepared by a synthesis method well known in the art according to the following scheme. However, the method for preparing the compound of Formula 1 is not limited to the following scheme, and may be variously prepared using other known organic synthesis reactions.

The present invention also provides a pharmaceutical composition for the prevention and treatment of cancer diseases comprising the meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen compound or a pharmaceutically acceptable salt thereof. do.

In the present invention, the meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen compound controls PA cell-1 by inhibiting its function and increasing the expression of p21 to control the proliferation of cancer cells. It features.

In addition, the meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen compound of the present invention can be synthesized through the synthesis and fractionation of conventional substituents (Herbert O. House, Modern Synthetic Reactions, 2nd). Ed., The Benjamin / Cummings Publishing Co., 1972).

In addition, the compounds of the present invention can be prepared with pharmaceutically acceptable salts and solvates according to methods conventional in the art.

As the pharmaceutically acceptable salt, acid addition salts formed by free acid are useful. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and acid or alcohol (eg, glycol motomethylether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.

In this case, organic acids and inorganic acids may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like may be used as the inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like.

In addition, bases can be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. In this case, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salt, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

Pharmaceutically acceptable salts of the compounds of the invention include salts of acidic or basic groups which may be present in the compounds of the invention, unless otherwise noted. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. It can be prepared through.

Compounds of the present invention obtained by the above method was tested to determine the effect of inhibiting the proliferation of cancer cells and induce apoptosis, can confirm the PARP-1 cleavage activity and the expression activity of p21.

Pharmaceutical compositions comprising a compound of formula 1 according to the invention may further comprise a suitable carrier, excipient or diluent according to conventional methods. Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The composition according to the invention can be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral formulations, external preparations, suppositories or sterile injectable solutions according to conventional methods.

Specifically, when formulated, it may be formulated using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like that are commonly used. Formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient in the compound, such as starch, calcium carbonate, sucrose. ), Lactose, gelatin and the like can be mixed. In addition to the simple excipients, lubricants such as magnesium stearate, talc and the like may also be used. Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Preferred dosages of the compounds according to the invention vary depending on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention may be administered in an amount of 0.0001 to 100 mg / kg, preferably 0.001 to 100 mg / kg, divided once or several times a day. In the compositions of the present invention the compound of formula 1 should be present in an amount of 0.001 to 50% by weight, preferably 0.01 to 50% by weight relative to the total weight of the total composition.

Pharmaceutical dosage forms of the compounds according to the invention can also be used in the form of their pharmaceutically acceptable salts, or can be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.

The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, humans, etc. by various routes, and all modes of administration can be expected, for example, oral, rectal or intravenous, muscle, subcutaneous, It can be administered by intrauterine dural or intracerebroventricular injection.

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

However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

Example. Preparation of meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen compound

Meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen according to the present invention was prepared according to conventional synthetic methods (Chem. Ber., 109 , 1, 1976; Agric. Chem. Biotechnol., 45 , 23, 2002).

Specifically, to the acetonitrile solution containing 1.5 mmol of diamine suspension was added salicylic aldehyde substituted with 3 mmol of nitro (-NO ₂ ) functional group, and stirred well at room temperature until a clear solution was obtained. After 2 hours, a yellow precipitate formed in the reaction mixture was filtered and dried to obtain meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen in a yield of 86 to 92%.

¹ H NMR (400 MHz, DMSO) δ 13,48 (br, OH), 9.61 (br, OH), 8.89 (br, OH), 8.30 (s, H), 7.31 (dd, J = 1.0, 8.0Hz , H), 7.03 (td, J = 1.0, 7.8 Hz, H), 6.78 (m, H), 6.77 (m, H), 6.76 (m, H), 6.76 (m, H), 6.70 (dd, J = 1.5, 7.8 Hz, H), 6.57 (t, J = 7.8 Hz, H), 5.52 (s, H)

¹³ C NMR (400 MHz, DMSO) d 165.4, 155.1, 150.9, 145.7, 128.8, 128.3, 125.9, 121.9, 119.0, 118.2, 117.7, 117.6, 115.3, 69.6

Experimental Example 1. Confirmation of PARP-1 cleavage effect of meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen compound

In the present invention, Western blot assay was performed to observe the PARP-1 cleavage effect of meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen prepared in the above example.

Specifically, human cervical cancer HeLa cells were treated with meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen at a concentration of 20 μg / ml and the cells were harvested after 24 hours. Harvested cells were treated with 20 mM HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) buffer + 1% Triton X-100 + 10% glycerol + 150 mM NaCl + 10 μg / μL Leupeptin + 1 mM PMSF ( After dissolving in phenylmethylsulfonyl fluoride buffer, the intracellular residues were separated by high-speed centrifugation, and the same amount of protein was separated by electrophoresis on SDS-polyacrylamide gel. Transfer to nitrocellulose filter (Bovine albumin serum) dissolved in PBS soaked at room temperature for 1 hour and washed with PBS (Phosphate buffered saline). The antibody to PARP was reacted and reacted with the addition of a secondary antibody, followed by addition of an Enhanced Chemiluminescence (ECL) solution, followed by exposure to an X-ray film to confirm the amount of protein change.

As a result, as shown in the upper panel of Figure 3, compared to the control group PARP (116kDa) protein in the experimental group treated with meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen of the present invention Segmented. From the above results, it was found that treatment of meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salene to cancer cells induced apoptosis.

Experimental Example 2 Confirmation of Increased Expression of p21 of Meso-Bis (Osso-Hydroxyphenyl) Bis (Osso-Hydroxy) Salene Compound

In the present invention, to observe the expression activation of p21 of meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen prepared in the above embodiment, 20 ㎍ / ㎖ in the same manner as in Experimental Example 1 The concentration of meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen was treated to human cervical cancer HeLa cells, and the cells were harvested 24 hours later, and Western blot assay was used to determine the expression level of p21 protein. Measured.

As a result, as shown in the lower panel of Figure 3, the expression of p21 protein in the experimental group treated with meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen of the present invention compared to the control time It was confirmed that the increase was dependent.

Examples of the pharmaceutical compositions containing the compounds of the present invention will be described, but the present invention is not intended to be limited thereto, but is intended to be described in detail.

Formulation Example 1 Preparation of Powder

20 mg of the compound of the present invention

Lactose 100 mg

Talc 10 mg

The above ingredients are mixed and filled in an airtight cloth to prepare a powder.

Formulation Example 2 Preparation of Tablet

10 mg of compound of the present invention

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.

Formulation Example 3 Preparation of Capsule

10 mg of compound of the present invention

3 mg of crystalline cellulose

Lactose 14.8 mg

Magnesium Stearate 0.2mg

According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.

Formulation Example 4 Preparation of Injection

10 mg of compound of the present invention

Mannitol 180 mg

Sterile distilled water for injection 2974 mg

Na ₂ HPO ₄ 12H ₂ O 26 mg

According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).

Formulation Example 5 Preparation of Liquid

20 mg of the compound of the present invention

10 g of isomerized sugar

5 g of mannitol

Purified water quantity

According to the conventional method of preparing a liquid solution, each component is added to the purified water to dissolve it, and lemon flavor is added, the above components are mixed, and then, purified water is added to adjust the total amount to 100 ml, and then sterilized by filling into a brown bottle. do.

1 shows hydrogen nuclear magnetic resonance spectroscopy spectra of meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen according to the present invention.

2 shows carbon nuclear magnetic resonance spectroscopy spectra of meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen according to the present invention.

Figure 3 is a Western blot result confirming the effect of PARP-1 cleavage and expression activity for p21 protein of meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen according to the present invention.

Claims (5)

Meso-bis (ortho-hydroxyphenyl) bis of formula (1), which produces a poly ADP-ribose polymerase-1 (PARP-1) fragment and inhibits proliferation of cancer cells and induces apoptosis by activating p21 expression (Orso-hydroxy) salen [(meso-Bis (o-hydroxyphenyl) bis (o-Hydroxy) salen, 3,3 '-(1E, 1'E)-((1R, 2S) -1,2-bis (2-hydroxyphenyl) ethane-1,2-diyl) bis (azan-1-yl-1-ylidene) bis (methan-1-yl-1-ylidene) dibenzene-1,2-diol)] compound. [Formula 1]

A pharmaceutical composition for preventing and treating cancer diseases comprising the meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen compound of claim 1 or a pharmaceutically acceptable salt thereof. 3. The method of claim 2, The meso-bis (ortho-hydroxyphenyl) bis (ortho-hydroxy) salen compound is characterized in that the control of cancer cells by controlling PARP-1 by inhibiting its function and increasing the expression of p21 to control the proliferation of cancer cells Composition. 3. The method of claim 2, The cancer disease is a pharmaceutical composition, characterized in that the cancer caused by abnormalities of the p21 gene. The method according to claim 2 or 4, The cancer diseases include gastric cancer, colon cancer, breast cancer, lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal muscle cancer, fallopian tube death, endometrium Carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penis cancer, prostate cancer, chronic or Acute leukemia, lymphocytic lymphoma, bladder cancer, renal or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma, or pituitary adenoma Pharmaceutical composition.

Images