JP6243850B2 - Prevention, treatment or alleviation of peripheral neuropathy with anticancer drugs - Google Patents

Description

  The present invention relates to an agent for preventing, treating or alleviating peripheral neuropathy with an anticancer agent.

  Today, in the treatment of cancer (malignant tumors), surgery, radiation, and chemotherapy are used individually or in combination as appropriate. Of these, anti-cancer agents (anti-neoplastic agents) used in chemotherapy are inherently cytotoxic or cytotoxic, and include not only cancer (malignant tumor) cells but also human normal cells. Since side effects due to injury occur, it is important to administer to patients so that sufficient anticancer (anti-malignant tumor) effects are exhibited while preventing or reducing such side effects as much as possible.

  Side effects associated with the administration of anticancer agents include hematological disorders, gastrointestinal disorders, and neurological disorders. Recently, acute or chronic neurological disorders have attracted attention in recent years. This is because neuropathy is often the main side effect of new anticancer drugs that exert significant anticancer effects, the effects of multidrug therapy, which is the center of recent treatment, and blood disorders This is thought to be due to the improvement in side effects of gastrointestinal disorders and gastrointestinal disorders. Nerve cells are difficult to regenerate and neuropathy is an important therapeutic issue because once it develops, there are no effective measures, which can cause serious symptoms or irreversible damage. Yes.

  In addition to the central nervous system, autonomic nervous system, and peripheral nervous system, neuropathy associated with the administration of anticancer agents is also observed in sensory organs such as taste. Among them, the frequency of occurrence is relatively high, and problems such as fulminant pain or burning pain, numbness of the extremities of the extremities, abnormal perception such as burning sensation, hypersensitivity such as hypersensitivity to a cold sensation, Peripheral nervous system neuropathy such as sensory abnormalities such as loss of sensation, numbness and discomfort, sensory ataxia, and weakness. Peripheral nervous system lesions caused by administration of this anticancer agent are thought to be mainly due to axonal degeneration. Microtubules in axons play an important role in maintaining the normal function of cells, such as the formation of spindles during cell division, the arrangement of intracellular organelles and mass transport, but paclitaxel and docetaxel. Taxane drugs such as vincristine, vinplastin, vindesine, vinorelbine, and other vinca alkaloid drugs act by targeting microtubules in the axon, thereby suppressing the growth of malignant tumor cells. It is believed that neuronal microtubules are also damaged and cause neuropathy. In addition, platinum preparations such as oxaliplatin, carboplatin, cisplatin and nedaplatin and proteasome inhibitors such as portezomib are considered to cause secondary axonal damage as a result of directly damaging neurons.

  However, neuropathy caused by anticancer drugs is an area where research has not progressed much, and no method for preventing / symptoming neuropathy has been established. For this reason, vitamin preparations such as mecobalamin and Kampo-Kakjin-gan are used to relieve numbness, and antidepressants (amitriptine hydrochloride), antiepileptic drugs (carbamazepine), and antiarrhythmic drugs for pain. (Mexiletine hydrochloride) and corticosteroids are used, but at present, there is no established cure or prevention method, and stopping or reducing the dose of the drug is the only certainty to stop neuropathy (However, neuropathy may persist or worsen after treatment is discontinued).

  Furthermore, in recent years, cancer chemotherapy combining several types of injections has become mainstream. In addition to administering a plurality of anticancer agents, it is a burden on the patient to intravenously or intravenously administer a therapeutic agent for peripheral neuropathy, and it is difficult to design the administration timing. In addition, recently, there are many patients who receive cancer chemotherapy at home, and a drug that can be easily taken at home is desirable as a drug that reduces peripheral neuropathy. In view of such circumstances, there is a demand for a treatment for peripheral neuropathy caused by cancer chemotherapy that is effective, safe and easy to take.

  So far, it has been reported that peripheral neuropathy in rats administered with oxaliplatin, a platinum-based drug, has been improved by intracerebroventricular administration of a PKC inhibitor (calphostin C) (Non-patent Document 1). In addition, administration of compounds that inhibit the MEK / ERK pathway (farnesylthiosalicylic acid and GW5074) into the subarachnoid space has improved peripheral neuropathy in rats administered with the pin alkaloid drug vincristine. It has been reported (Non-Patent Document 2). However, even by the methods of these documents, the improvement effect declined after 2 to 3 hours from the administration, and the continuous improvement could not be performed. The degree of improvement was also slight. Furthermore, the administration is performed by a specialized surgical technique, and is performed by a method that cannot be easily performed on a daily basis. Thus, there is still no practical preventive, therapeutic or alleviating agent for peripheral neuropathy resulting from the administration of anticancer agents.

  Although Non-Patent Document 1 mentions not only PKC but also ERK, the experimental result shows that the tendency of ERK phosphorylation is different from the tendency of PKC phosphorylation. The relationship with the reduction of peripheral neuropathy has not been studied. Non-Patent Document 2 describes that farnesyl thiosalicylic acid and GW5074 are inhibitors of the Ras / Raf / MEK / ERK2 signaling pathway, but these are described to inhibit Ras and c-Raf-1. No mention is made of the relationship between inhibition of MEK or ERK and reduction of peripheral neuropathy.

Pain, 146, 141-147, 2009 Food and chemical toxicology, 50, 1295-1301, 2012

  Accordingly, an object of the present invention is to prevent, treat or alleviate peripheral neuropathy caused by an anticancer agent sufficiently and continuously.

  The present inventors show that non-local administration of a PKC inhibitor or a MEK / ERK pathway inhibitor can sufficiently and continuously suppress peripheral neuropathy caused by an anticancer agent. I found it. In the prior art, the PKC inhibitor or MEK / ERK pathway inhibitor was locally administered into the ventricle or the intrathecal space, etc., and the improvement effect was not sustained, and this finding was partial. It is groundbreaking. Since non-local administration can be performed by a simple method such as oral administration, it is possible to prevent, treat, or alleviate by a simple method in a daily environment such as home. It is groundbreaking.

  In addition, the present inventors have found that the sufficient and sustained suppression effect found in PKC inhibitors or MEK / ERK pathway inhibitors is due to inhibition of MEK or ERK. In the conventional prior art documents, there are descriptions of PKC inhibition and MEK / ERK pathway inhibition, but there is no mention of MEK or ERK inhibition, and the findings of the present inventors are novel.

  Furthermore, since the PKC inhibitor or MEK / ERK pathway inhibitor for which sufficient and sustained inhibitory effect has been observed is an anticancer agent, the present inventors have been able to prevent peripheral neuropathy caused by administration of the anticancer agent. It has been found that prevention, treatment or alleviation can be carried out sufficiently and continuously with another anticancer agent. This finding is an epoch-making in that peripheral neuropathy caused by the administration of anticancer drugs is adequately and sustainedly prevented, treated, or reduced by devising combinations of anticancer drugs in combination therapy. It provides ideas.

  That is, the present invention provides a preventive, therapeutic or alleviating agent for non-local administration of peripheral neuropathy caused by an anticancer agent, which contains a PKC inhibitor or a MEK / ERK pathway inhibitor as an active ingredient.

  Furthermore, the present invention provides a preventive, therapeutic or alleviating agent for peripheral neuropathy caused by an anticancer agent, which contains a MEK inhibitor or ERK inhibitor as an active ingredient.

  Moreover, this invention provides the said prevention, treatment, or relief agent whose MEK inhibitor or ERK inhibitor is an anticancer agent.

  The present invention also provides the aforementioned preventive, therapeutic or alleviating agent, wherein the ERK inhibitor is an ERK phosphorylation inhibitor.

  In addition, the present invention provides the prevention, treatment, wherein the ERK inhibitor is a phosphorylation inhibitor of a phosphorylation site selected from the group consisting of ERK1 Thr202, ERK1 Tyr204, ERK2 Thr185, and ERK2 Tyr187, Or provide a mitigation agent.

  The present invention also provides the preventive, therapeutic or alleviating agent described above, wherein the peripheral neuropathy is caused by a platinum preparation.

  Furthermore, the present invention includes a step for evaluating PKC inhibition or MEK / ERK pathway inhibition by a subject, a preventive, therapeutic or alleviating agent for non-local administration of peripheral neuropathy by an anticancer agent, A method for selecting an active ingredient is provided.

  The present invention also provides a method for selecting an active ingredient for prevention, treatment, or alleviation of peripheral neuropathy with an anticancer agent, comprising the step of evaluating MEK inhibition or ERK inhibition by a test subject. To do.

  In still another aspect, the present invention relates to a method for preventing, treating or alleviating peripheral neuropathy with an anticancer agent, characterized by non-locally administering a PKC inhibitor or a MEK / ERK pathway inhibitor. Is to provide.

  The present invention also provides a method for preventing, treating or alleviating peripheral neuropathy with an anticancer agent, which comprises administering a MEK inhibitor or an ERK inhibitor.

  Furthermore, the present invention provides the prevention, treatment or alleviation method described above, wherein the MEK inhibitor or ERK inhibitor is an anticancer agent.

  Furthermore, the present invention provides the prevention, treatment or alleviation method described above, wherein the ERK inhibitor is an ERK phosphorylation inhibitor.

  Furthermore, the present invention relates to the prevention, treatment, or treatment described above, wherein the ERK inhibitor is a phosphorylation inhibitor of a phosphorylation site selected from the group consisting of ERK1 Thr202, ERK1 Tyr204, ERK2 Thr185, ERK2 Tyr187, or It provides a mitigation method.

  Furthermore, the present invention provides the above-described prevention, treatment or alleviation method, wherein the peripheral neuropathy is caused by a platinum preparation.

  In another aspect, the present invention provides a use of a PKC inhibitor or a MEK / ERK pathway inhibitor for producing a preventive, therapeutic, or alleviating agent for non-local administration of peripheral neuropathy caused by an anticancer agent. Is to provide.

  Furthermore, the present invention provides the use of a MEK inhibitor or an ERK inhibitor for producing an agent for preventing, treating or alleviating peripheral neuropathy with an anticancer agent.

  Furthermore, the present invention provides the use as described above, wherein the MEK inhibitor or ERK inhibitor is an anticancer agent.

  The present invention also provides the use described above, wherein the ERK inhibitor is an ERK phosphorylation inhibitor.

  The present invention also provides the use as described above, wherein the ERK inhibitor is a phosphorylation inhibitor of a phosphorylation site selected from the group consisting of ERK1 Thr202, ERK1 Tyr204, ERK2 Thr185, ERK2 Tyr187. It is.

  The present invention also provides the use as described above, wherein the peripheral neuropathy is caused by a platinum preparation.

  Furthermore, in another aspect, the present invention provides a non-topical use of a PKC inhibitor or MEK / ERK pathway inhibitor for the prevention, treatment or alleviation of peripheral neuropathy by an anticancer agent. It is.

  The present invention also provides use of a MEK inhibitor or ERK inhibitor for the prevention, treatment, or alleviation of peripheral neuropathy caused by an anticancer agent.

  Moreover, this invention provides said use whose MEK inhibitor or ERK inhibitor is an anticancer agent.

  The present invention also provides the use described above, wherein the ERK inhibitor is an ERK phosphorylation inhibitor.

  The present invention also provides the use as described above, wherein the ERK inhibitor is a phosphorylation inhibitor of a phosphorylation site selected from the group consisting of ERK1 Thr202, ERK1 Tyr204, ERK2 Thr185, ERK2 Tyr187. It is.

  The present invention also provides the use as described above, wherein the peripheral neuropathy is caused by a platinum preparation.

  According to the present invention, peripheral neuropathy caused by an anticancer agent can be prevented, treated, or alleviated extremely highly and continuously. That is, by administering the preventive, therapeutic, or alleviating agent of the present invention, limb numbness, extremity pain, deep tendon reflex reduction, muscle strength reduction, allodynia, hyperalgesia, fingers It is possible to prevent, treat, or alleviate dexterous dysfunction, gait disturbance, whispering, falling, flexion disorder (difficult or impossible of sitting, cross-legged, side-sitting or chair-sitting), or paralysis of the extremities. In the past, in order to deal with peripheral neuropathy, it was necessary to reduce the amount of anticancer drugs or to interrupt cancer chemotherapy, but if the preventive, therapeutic, or alleviating agent of the present invention is used, it is appropriate. Cancer treatment can be continued, leading to early recovery from cancer. In addition, the preventive, therapeutic, or alleviating agent of the present invention can be administered non-locally by oral administration or the like, and can easily prevent or treat peripheral neuropathy caused by an anticancer agent in a daily environment such as home. Or can be reduced. This improves the quality of life for patients who receive home-treated anticancer drug treatment. Further, when an anticancer agent different from the anticancer agent causing peripheral neuropathy is used as the active ingredient of the preventive, therapeutic or alleviating agent of the present invention, prevention, treatment or improvement of peripheral neuropathy is performed. This can be easily performed in combination therapy with anticancer agents. In addition, if an active ingredient is selected using an indicator that it is an anticancer drug, it can be used in combination with multiple drugs without requiring long-term clinical trials by using existing information on effective dose, effective administration method, side effects, etc. Peripheral neuropathy prophylactic, therapeutic or alleviating agents that can be used clinically in therapy can be easily and rapidly manufactured.

FIG. 1 shows the results of examining the alleviation effect of a test drug on hypersensitivity caused by oxaliplatin administration in the von Frey test. FIG. 2 shows the results of examining the reducing effect of the test drug on the sensory abnormality caused by oxaliplatin administration in the cold plate test. FIG. 3 shows the results of examining the inhibitory effect of the test drug on the increased expression of phosphorylated ERK and phosphorylated PKC in the spinal cord on the 14th day after oxaliplatin administration. The figure shows the results of one representative experiment of at least three independent experiments. FIG. 4 shows the results of examining the alleviation effect of the test drug on the hypersensitivity caused by oxaliplatin administration in the von Frey test. FIG. 5 shows the results of examining the reducing effect of the test drug on the sensory abnormality caused by oxaliplatin administration in the cold plate test. FIG. 6 shows the results of examining the inhibitory effect of the test drug on the increased expression of phosphorylated ERK and phosphorylated PKC in the spinal cord on the 14th day after oxaliplatin administration.

  A PKC inhibitor is an active ingredient of the preventive, therapeutic, or alleviating agent of the present invention. PKC is also referred to as protein kinase C. Examples of PKC include PKC-α, PKC-β1, PKC-β2, PKC-γ, PKC-δ, PKC-υ, PKC-ν, PKC-λ, PKC-μ, PKC-θ, and PKC-ζ. It is done. A PKC inhibitor is a substance having an action of inhibiting PKC. As an effect | action which inhibits PKC, the effect | action which inhibits phosphorylation of PKC is mentioned. The action of inhibiting PKC phosphorylation is preferably an action of reducing the expression level of phosphorylated PKC without substantially reducing the expression level of PKC. A substance having an action of inhibiting PKC phosphorylation can be referred to as a PKC phosphorylation inhibitor. Examples of the phosphorylation site of PKC include Ser638 for PKC-α and Ser643 and Thr505 for PKC-δ. The PKC inhibitor may be cell permeable. The PKC inhibitor may be an inorganic compound or an organic compound, and examples of the organic compound include organic compounds having 10 to 100 carbon atoms.

  As PKC inhibitors, 3,4-bis (3-indolyl) maleimide, bisindolylmaleimide I, bisindolylmaleimide II, bisindolylmaleimide III, bisindolylmaleimide IV, bisindolylmaleimide V, bisin Drillmaleimide VI, bisindolylmaleimide VII, bisindolylmaleimide VIII, bisindolylmaleimide X, calphostin C, cardiotoxin, CGP41351, CGP53353, chelerythrine chloride, decalinium chloride, 5- (2,5-dihydroxybenzylamino) 2-hydroxybenzoic acid, ellagic acid, Go 6976, Go 6983, Go 7874, H-7, 2,2 ', 3,3', 4,4'-hexahydroxy-1,1'-biphenyl-6 6'-Dimethanone Dimethyl ether, Hispidin, Hypericin, 1- (5-Isoquinolinesulfonyl) -3-methylpiperazine dihydrochloride, Iso-H-7, K-252a, K-252b, K-252c, KN-62, KN-93, KT5823 , Melittin, NGIC-I, 7-oxostaurosporine, phloretin, piceatanol, PKC 20-28, polymyxin B, Ro-31-7549, Ro-31-8220, Ro-31-8425, Ro-32-0432, Lotrelin, saphingol, sangivamycin, schitonemin, staurosporine, sterettamid A, STO-609, tamoxifen, (Z) -4-hydroxy tamoxifen, TER14687, UCN-01, UCN-02, vitamin E succinate, 4 -Hydroxytam Xifene, endoxifen, clomiphene, toremifene, and derivatives thereof, pharmaceutically acceptable salts, and the like.

  The MEK / ERK pathway inhibitor is an active ingredient of the preventive, therapeutic, or alleviating agent of the present invention. MEK is also referred to as mitogen activated protein kinase kinase. ERK is also referred to as extra cellular signal regulated kinase. Examples of MEK include MEK1 and MEK2. ERK includes ERK1, ERK2, and ERK1 / 2. ERK1 / 2 is a complex consisting of ERK1 and ERK2. The MEK / ERK pathway inhibitor is a substance having an action of inhibiting the MEK / ERK pathway. The MEK / ERK pathway is a signal transduction pathway involving MEK and ERK. Examples of MEK / ERK pathway inhibitors include MEK inhibitors such as MEK1 inhibitors and MEK2 inhibitors; ERK inhibitors such as ERK1 inhibitors and ERK2 inhibitors. The ERK1 inhibitor and the ERK2 inhibitor may be an ERK1 / 2 inhibitor that is an inhibitor of a complex composed of ERK1 and ERK2. The MEK / ERK pathway inhibitor may be cell permeable. The MEK / ERK pathway inhibitor may be an inorganic compound or an organic compound, and examples of the organic compound include organic compounds having 10 to 100 carbon atoms.

  MEK / ERK pathway inhibitors include AG 126, apigenin, FR180204, 5-iodotubercidine, 5-nitro-2- (3-phenylpropylamino) benzoic acid, PD98059, U0125, U0126, and derivatives thereof. Pharmaceutically acceptable salts, and the like.

  The MEK inhibitor is an active ingredient of the preventive, therapeutic or alleviating agent of the present invention. The MEK inhibitor is a substance having an action of inhibiting MEK. Examples of MEK inhibitors include ATP competitive MEK inhibitors, non-ATP competitive MEK inhibitors, and ATP non-competitive MEK inhibitors. As an effect | action which inhibits MEK, the effect | action which inhibits phosphorylation of MEK is mentioned. The action of inhibiting the phosphorylation of MEK is preferably the action of reducing the expression level of phosphorylated MEK without substantially reducing the expression level of MEK. A substance having an action of inhibiting MEK phosphorylation can be referred to as MEK phosphorylation inhibitor. There may be one or more phosphorylation sites that the phosphorylation inhibitor of MEK inhibits. MEK inhibitors include substances that inhibit MEK in the spinal cord of animals. Examples of the spinal cord include the lumbar spinal cord. The MEK inhibitor is more preferable because it can inhibit the MEK / ERK pathway more specifically and does not affect other signal transduction pathways, and thus has few side effects. In addition, MEK inhibitors are preferable in that they can suppress peripheral neuropathy.

  Examples of the MEK inhibitor include a benzimidazole derivative MEK inhibitor, a benzamide derivative MEK inhibitor, a pyridazine derivative MEK inhibitor, a benzopyran derivative MEK inhibitor, and the like. More specifically, examples of the MEK inhibitor include, for example, trametinib, selumetinib, refametinib, pimasertib, MEK162 / ARRY-162, AZD8330 / ARRY-4704, RG7420, GDC-0623 / RG7421 / XL518, CIF / RG7167 / RO497655, CK127 / RG7304 / RO5126766, E6201, TAK-733, PD-0325901, AS703888 / MSC2015103B, WX-554, and derivatives thereof, pharmaceutically acceptable And the like, and the like.

  An ERK inhibitor is an active ingredient of the preventive, therapeutic, or alleviating agent of the present invention. An ERK inhibitor is a substance having an action of inhibiting ERK. As an effect | action which inhibits ERK, the effect | action which inhibits the phosphorylation of ERK is mentioned. The action of inhibiting the phosphorylation of ERK is preferably the action of reducing the expression level of phosphorylated ERK without substantially reducing the expression level of ERK. A substance having an action of inhibiting ERK phosphorylation can be referred to as an ERK phosphorylation inhibitor. There may be one or more phosphorylation sites that are inhibited by an ERK phosphorylation inhibitor. Examples of the phosphorylation site of ERK include Thr202 and Tyr204 for ERK1, and Thr185 and Tyr187 for ERK2. Examples of the phosphorylation inhibitor of ERK include phosphorylation inhibitors of phosphorylation sites selected from the group consisting of ERK1 Thr202, ERK1 Tyr204, ERK2 Thr185, and ERK2 Tyr187. ERK inhibitors include substances that inhibit ERK in the spinal cord of animals. Examples of the spinal cord include the lumbar spinal cord.

  The PKC inhibitor, MEK / ERK pathway inhibitor, MEK inhibitor, or ERK inhibitor may be an anti-estrogen agent. Antiestrogens include steroidal antiestrogens and nonsteroidal antiestrogens. An anti-estrogen agent is a substance that binds to an estrogen receptor and exerts an antagonistic action against estrogen. Mepithiostan is a steroidal antiestrogen. Tamoxifen is a non-steroidal anti-estrogen agent.

  The PKC inhibitor, MEK / ERK pathway inhibitor, MEK inhibitor, or ERK inhibitor may be an analog of tamoxifen (also referred to as a tamoxifen analog). Tamoxifen analogs include non-steroidal antiestrogens such as clomiphene and toremifene; selective estrogen modulators such as raloxifene, bazedoxifene, arzoxifene, and lasofoxifene; tamoxifen such as 4-hydroxytamoxifen and endoxifen Active metabolites.

  The PKC inhibitor, MEK / ERK pathway inhibitor, MEK inhibitor, or ERK inhibitor includes a drug having a function as an anticancer agent. In the preventive, therapeutic, or alleviating agent of the present invention, a PKC inhibitor, MEK / ERK pathway inhibitor, MEK inhibitor, or ERK inhibitor that is an anticancer agent may be used as an active ingredient. In that case, it is possible to easily prevent, treat, or reduce peripheral neuropathy caused by anticancer drugs by devising combinations of anticancer drugs in combination therapy using multiple anticancer drugs. In addition, clinical use can be rapidly started by using information such as known side effects, dosage, administration method, pharmacological test data, etc., regarding the anticancer agent to be used.

  The active ingredient of the preventive, therapeutic, or alleviating agent of the present invention may contain only one PKC inhibitor, MEK / ERK pathway inhibitor, MEK inhibitor, or ERK inhibitor, or two or more PKC inhibitors Agents, MEK / ERK pathway inhibitors, MEK inhibitors, or ERK inhibitors may be included.

  Accompanying administration of anticancer agents by non-local administration of PKC inhibitors or MEK / ERK pathway inhibitors, or by inhibiting MEK or ERK, as described in the Examples below It has been found that peripheral neuropathy is highly and persistently suppressed. Therefore, by using a PKC inhibitor, MEK / ERK pathway inhibitor, MEK inhibitor, or ERK inhibitor as an active ingredient, peripheral neuropathy caused by an anticancer agent can be prevented, treated, or reduced.

  Examples of anticancer agents that cause peripheral neuropathy include microtubule inhibitors such as anticancer agents that damage microtubules and cause peripheral neuropathy. Examples of such anticancer agents include taxane drugs such as paclitaxel and docetaxel; and vinca alkaloid drugs such as vincristine, vinplastin, vindesine, and vinorelbine. Examples of the anticancer agent that causes peripheral neuropathy include an anticancer agent that causes peripheral neuropathy by causing axonal damage by damaging nerve cells. Examples of such anticancer agents include platinum preparations such as oxaliplatin, carboplatin, cisplatin and nedaplatin; and proteasome inhibitors such as bortezomip.

  Examples of peripheral neuropathy caused by these anticancer agents include hypersensitivity, sensory abnormalities, sensory abnormalities, and acute or chronic pain. More specifically, as hypersensitivity, hyperalgesia such as allodynia caused by mechanical stimulation can be mentioned. Allodynia means severe pain caused by tactile stimuli that do not usually cause pain. More specifically, the abnormal sensation includes abnormal sensation due to low-temperature stimulation, numbness of the extremities, burning sensation and the like. Sensory abnormalities include loss of sensation, numbness, and discomfort. As a site where sensory paralysis occurs, limbs may be mentioned. A limb is mentioned as a site where acute or chronic pain occurs. Pain includes what is called fulminant pain, burning pain. These peripheral neuropathy may cause problems in daily life such as motor dysfunction and a decrease in deep tendon reflexes. Examples of motor dysfunction include muscle weakness and ataxia. Examples of ataxia include finger skillful dysfunction, flexion disorder, and walking disorder. Skillful dysfunction of fingers may be accompanied by obstacles such as difficulty in grasping objects and difficulty in pressing buttons. Examples of the flexion disorder include a state where sitting, cross-legs, side-sitting or chair-sitting is difficult or impossible. Gait disturbance may involve whispering, falling, etc.

  In the present invention, peripheral neuropathy caused by an anticancer agent to be prevented, treated, or alleviated is not only caused by monotherapy using one type of anticancer agent, but also a plurality of different action mechanisms. Also included are peripheral neuropathies that occur in combination therapy in which drugs are administered in combination, and peripheral neuropathies that occur in biochemical modulation therapy. Biochemical modulation therapy is a therapy in which a combination of drugs or a method for administering drugs is devised so that drugs with different mechanisms of action can exert their maximum effectiveness. In addition, peripheral neuropathy that occurs in FOLFOX therapy is also included in the subject of prevention, treatment, or alleviation in the present invention. FOLFOX therapy is a cancer chemotherapy using a combination of fluorouracil, folinic acid, and oxaliplatin, and is one type of chemotherapy for colorectal cancer.

  The present invention can prevent, treat, or alleviate these peripheral neuropathies, where “prevention” includes preventing, suppressing, and delaying the onset of a disease state. Shall be. “Treatment” includes not only the complete cure of the disease state, but also the suppression of the progression or worsening of symptoms that are not completely cured, but the progression of the disease state and the improvement of part or all of the disease state. It shall be included to guide the direction of healing. Further, “relieving” includes alleviating symptoms.

  The preventive, therapeutic, or alleviating agent of the present invention includes, in addition to active ingredients, excipients, binders, lubricants, disintegrants, corrigents, flavoring agents, surfactants, fragrances, coloring agents, and antioxidants. , Additives such as masking agents, antistatic agents, fluidizing agents, wetting agents and the like may be included.

  Examples of excipients include glucose, fructose, maltose, lactose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol, corn starch, potato starch, wheat Starch, rice starch, crystalline cellulose, talc, anhydrous silica, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, dextran (eg, dextran, dextran 40, dextran 70, etc.), pullulan, dextrin, pregelatinized starch, etc. . Examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin, dextrin, etc. These may be used by appropriately blending one or more of these. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol and the like. Examples of the disintegrant include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, hydroxypropyl starch, and corn starch. Examples of the corrigent include sucrose, D-sorbitol, xylitol, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, saccharin sodium, glycyrrhizin dipotassium, sodium glutamate, 5′-sodium inosinate, 5 '-Sodium guanylate, etc. are mentioned. Examples of the flavoring agent include trehalose, malic acid, maltose, potassium gluconate, anise essential oil, vanilla essential oil, and cardamom essential oil. Examples of the surfactant include polysorbate (polysorbate 80 and the like), polyoxyethylene / polyoxypropylene copolymer, sodium lauryl sulfate, and the like. Examples of the fragrances include lemon oil, orange oil, menthol and brackish oil. Examples of the colorant include titanium oxide, edible yellow No. 5, edible blue No. 2, iron sesquioxide, yellow sesquioxide. Examples of the antioxidant include sodium ascorbate, L-cysteine, sodium sulfite, vitamin E and the like. Examples of the concealing agent include titanium oxide. Examples of the antistatic agent include talc and titanium oxide. Examples of the fluidizing agent include light anhydrous silicic acid, talc, hydrous silicon dioxide and the like. Examples of the wetting agent include polysorbate 80, sodium laurate sulfate, sucrose fatty acid ester, macrogol, and hydroxypropyl cellulose (HPC).

  These additives can be mix | blended in the ratio normally used for the target formulation. In addition to the above, additives such as those described in publicly known documents, for example, edited by Yakuji Nippo Co., Ltd., 2000 “Pharmaceutical Additives Dictionary” edited by the Japan Pharmaceutical Additives Association) may be used.

  Examples of the dosage form of the preventive, therapeutic, or alleviating agent of the present invention include, but are not limited to, solid preparations, such as aerosols, liquids, extracts, soft extracts, dry extracts, elixirs, Capsules, hard capsules, soft capsules, granules, pills, eye ointments, transdermal preparations, suspensions, emulsions, suppositories, powders, spirits, tablets, syrups, soaking agents, decoction, Examples include injections, patches, tinctures, eye drops, lozenges, ointments, poultices, fragrances, liniments, limonades, fluid extracts, and lotions.

  The preventive, therapeutic, or alleviating agent of the present invention can be produced by a known method. For example, a granular solid preparation can be produced by granulation using a tumbling granulator, a stirring granulator, a fluidized granulator, a centrifugal tumbling granulator, a dry granulator or the like. . The capsule can be produced by a known method. For example, a hard capsule (for example, a gelatin capsule, a hydroxypropyl methylcellulose (HPMC) capsule, a pullulan, and the like added with additives as necessary to the granules). Capsules, polyvinyl alcohol (PVA) capsules, and the like) using a capsule filling machine. Tablets can also be produced by a known method. For example, the above granules and, if necessary, the additives are mixed evenly, compression-molded by a rotary tableting machine or the like to obtain an uncoated tablet, and the uncoated tablet is used as a tablet as it is, or as necessary Further, a tablet can be produced by coating with a coating base. A tablet can also be produced by preparing a mixed powder containing a drug and the like without granulation and tableting it with a rotary tableting machine or the like. Furthermore, instead of the above granules, the active ingredient and excipient are dissolved in a solvent (for example, water, an organic solvent (for example, ethanol, acetone, etc.), or a mixed solvent thereof), and lyophilized by lyophilization according to a conventional method. You may manufacture a tablet using goods. That is, after freeze-dried products containing active ingredients are pulverized, additives may be added and mixed as necessary, and tablets may be produced by tableting.

  The dose of the active ingredient of the preventive, therapeutic, or alleviating agent of the present invention varies depending on the age, weight, pathological condition, administration method, etc. of the patient receiving the administration. For example, 20-40 mg per administration in the patient receiving the administration This may be administered, for example, once every half day to once every two days. The frequency of administration of the preventive, therapeutic, or alleviating agent of the present invention varies depending on the age, weight, disease state, method of administration, etc. of the patient receiving the administration. For example, the frequency of administration of anticancer agents causing peripheral neuropathy is 3 to 3. 10 times. The dose of the active ingredient of the preventive, therapeutic or alleviating agent of the present invention is such that, for example, the blood concentration of the patient receiving the administration is 100 ng / mL to 800 ng / mL, more specifically 100 ng / mL to The amount is 200 ng / mL.

  The preventive, therapeutic, or alleviating agent of the present invention containing a PKC inhibitor or MEK / ERK pathway inhibitor as an active ingredient is administered to a patient by non-local administration. Local administrations that are excluded in non-local administration include intrathecal administration, such as intraventricular administration, intrathecal administration. Non-local administration includes oral administration, tube feeding, enteral administration such as enema administration; intravenous administration such as intravenous injection and intravenous infusion; transarterial administration; intramuscular administration; subcutaneous administration; Skin administration; transmucosal administration; intraosseous administration may be used. Of these, oral administration and transdermal administration are excellent in that they can be easily used in a daily environment. The administration route of the preventive, therapeutic, or alleviating agent of the present invention containing a MEK inhibitor or ERK inhibitor as an active ingredient includes dermal administration, inhalation administration, enema administration, ear-dropping, nasal administration, and intravaginal administration. Oral administration, tube feeding, enema administration, intravenous administration, transarterial administration, intramuscular administration, intracardiac administration, subcutaneous administration, intraosseous administration, intradermal administration, intrathecal (cavity) administration, intraperitoneal administration, Examples include intravesical administration, transdermal administration, transmucosal administration, epidural administration, and intravitreal administration.

  Patients to whom the preventive, therapeutic or alleviating agent of the present invention is administered include ovarian cancer, non-small cell lung cancer, breast cancer, gastric cancer, endometrial cancer, head and neck cancer, esophageal cancer, leukemia, malignant lymphoma, Childhood tumor, multiple myeloma, malignant astrocytoma, glioma, choriocarcinoma, germ cell tumor, testicular tumor, bladder cancer, renal pelvis tumor, ureteral tumor, prostate cancer, cervical cancer, neuroblast Examples include cancer patients suffering from one or more types of cancer selected from the group consisting of cell tumors, small cell lung cancer, osteosarcoma, malignant pleural mesothelioma, malignant bone tumor, and colon cancer.

  As described in Examples below, the effect of suppressing peripheral neuropathy by an anticancer agent is that a PKC inhibitor or MEK / ERK pathway inhibitor is administered non-locally, or MEK or ERK is inhibited. Has been found to be due to Therefore, peripheral neuropathy caused by an anticancer agent by performing a step of evaluating PKC inhibition or MEK / ERK pathway inhibition by a test substance, or by performing a step of evaluating MEK inhibition or ERK inhibition by a test substance The active ingredient of the preventive, therapeutic or alleviating agent can be selected. That is, the present invention includes the step of evaluating PKC inhibition or MEK / ERK pathway inhibition by a test subject, which is characterized by prevention, treatment, or alleviation for non-local administration of peripheral neuropathy caused by an anticancer agent. A method for selecting an active ingredient of an agent; and selection of an active ingredient for prevention, treatment, or alleviation of peripheral neuropathy by an anticancer agent, comprising the step of evaluating MEK inhibition or ERK inhibition by a subject. A method is also provided.

  A test substance is a substance that is a candidate for an active ingredient to be selected. The test object may be an organic compound or an inorganic compound derived from a natural product, or may be a synthetic organic compound or an inorganic compound.

  The step of evaluating PKC inhibition or MEK / ERK pathway inhibition by a subject and the step of evaluating MEK inhibition or ERK inhibition by a subject may be performed by an in vivo test or an in vitro test. . In vivo testing may be performed, for example, by a test comprising administering a test substance to a model organism and comparing PKC, MEK, or ERK in the model organism before and after administration of the test substance. Among these, the step of comparing PKC, MEK, or ERK in the model organism before and after the administration of the test subject is the step of measuring PKC, MEK, or ERK in the model organism before and after the test subject administration, and the measurement May be performed by comparing PKC, MEK, or ERK before and after administration. Examples of the PKC, MEK, or ERK in the model organism to be measured include the expression level of PKC, MEK, or ERK protein, the degree of phosphorylation of PKC, MEK, or ERK. The degree of phosphorylation of PKC, MEK, or ERK can be measured by using a phosphorylation-specific recognition antibody, for example, the expression level of phosphorylated PKC, MEK, or ERK protein. Examples of phosphorylated PKC, MEK, or ERK protein to be measured include PKC-α protein phosphorylated by Ser638; PKC-δ protein phosphorylated by Ser643 or Thr505; Thr202 or Tyr204 site is phosphorylated ERK1 protein; ERK2 protein phosphorylated at Thr185 or Tyr187 site; phosphorylation site selected from the group consisting of Thr202 of ERK1 protein, Tyr204 of ERK1 protein, Thr185 of ERK2 protein, and Tyr187 of ERK2 protein Examples include ERK1 / 2 protein. The phosphorylation site in phosphorylated PKC, MEK, or ERK protein to be measured may be single or plural. Examples of PKC, MEK, or ERK in the model organism to be measured include PKC, MEK, or ERK in the spinal cord of the model organism, and in particular, PKC, MEK, or ERK in the lumbar spinal cord. Examples of model organisms used in the test include mammals, and examples of mammals include humans and non-human mammals such as rats and mice.

  In the method for selecting an active ingredient in the present invention, the selection of an active ingredient for prevention, treatment, or alleviation of peripheral neuropathy by an anticancer agent is PKC inhibition, MEK / ERK pathway inhibition, MEK inhibition, or ERK by the subject. This is based on the result of evaluating inhibition. The selection of the active ingredient of the preventive, therapeutic, or alleviating agent may be based solely on the results of evaluating PKC inhibition, MEK / ERK pathway inhibition, MEK inhibition, or ERK inhibition by the subject, but depending on the subject It may be based on an evaluation performed by combining the result of evaluating PKC inhibition, MEK / ERK pathway inhibition, MEK inhibition, or ERK inhibition with other information on the test substance. Other information about the subject includes other in vivo or in vitro test results for the subject.

  The method for selecting an active ingredient in the present invention may be performed for a single test substance or may be performed in a high content screening system using a plurality of test objects.

  Hereinafter, although an example explains the present invention in detail, the present invention is not limited to these.

Example 1: Effect of oxaliplatin on mouse peripheral neuropathy:
The test drug is orally administered to mice as described below, and the cold plate test and the von Frey test are performed. The efficacy of the test drug on hypersensitivity and sensory abnormalities in cold stimulation was investigated.

(1) Test drug administration:
6-7 week old Balb / c male mice were used as experimental animals, and there were 3 groups: a control group, an oxaliplatin administration group, and an oxaliplatin and test drug administration group (hereinafter also simply referred to as an oxaliplatin + test drug administration group). It was organized into groups. In the oxaliplatin administration group, once a week intravenous administration of oxaliplatin was continued for 2 weeks, and oxaliplatin was administered twice in total. The single dose of oxaliplatin was 6 mg / kg relative to the body weight of the mouse. In the oxaliplatin + test drug administration group, tamoxifen was orally administered as the test drug 14 times in total, continuously for 2 weeks immediately after oxaliplatin administration. The single dose of tamoxifen was 30 mg / kg relative to the body weight of the mouse. The control group was administered with 5% glucose solution and physiological saline. In addition, the solvent used for administration to the oxaliplatin administration group and the oxaliplatin + test drug administration group was also 5% glucose solution and physiological saline.

(2) von Frey test
About 12 hours after administration of the test drug to the oxaliplatin + test drug administration group, the mice of the three groups (1) above were placed in a cage with a wire net at the bottom and allowed to acclimate for 1 hour. The von Frey filament with a strength of .16 g was pressed perpendicularly to the back of the hind limb until the filament bent, and rested for 6 seconds. The number of times was measured. The avoidance response was measured continuously for 14 days from the start of oxaliplatin administration. The measured avoidance behavior results were scored according to the method of Descoeur et al. (EMBO Molecular Medicine 3, 266-278, 2011) to obtain an avoidance behavior score.

  The results of the above test are shown in FIG. In the oxaliplatin administration group, the avoidance behavior score significantly increased compared to the control group. The oxaliplatin + test drug administration group administered with oxaliplatin in combination with the test drug showed an avoidance behavior score similar to that of the control group, and significantly suppressed the increase in the avoidance behavior score compared to the oxaliplatin administration group . Moreover, in the oxaliplatin + test drug administration group, it was confirmed that the suppression of the decrease in the pain threshold value was continued even after the administration of the test drug was terminated. From the above results, it became clear that the test drug exerts an excellent preventive, therapeutic, or alleviating action continuously against hypersensitivity caused by oxaliplatin.

(3) Cold plate test
A cold plate test was continuously performed from the start date of oxaliplatin administration to the 14th day, and the effect of the test drug on sensory abnormalities in cold stimulation was tested. On the day before the test, the three groups of (1) were placed on a cold plate (Hot / Cold plate Cat, No. 35100 Ugo Basile Biological Research Apparatus) for 30 minutes to fully acclimate. On the day of the test, rats were placed on a cold plate set at 10 ° C., the behavior of the mice was observed for 30 seconds, and the reaction time (latency) until avoiding the hind paw was measured. The latency was measured about 12 hours after administration of the test drug to the oxaliplatin + test drug administration group. In addition, in order to eliminate preconceptions of the experimenter, behavioral observation was performed so that the dose of each mouse group could not be understood. The test was performed three times and averaged, and the average value and standard error were calculated. Comparison between multiple groups was performed by comparing each group by a Tukey-Kramer method after one-way analysis of variance (one-way ANOVA). Stat View (Abacus Concepts, Berkeley, CA, USA) was used for the test, and a risk rate of less than 5% (p <0.05) was considered significant.

  The results of the above test are shown in FIG. On the fourth day of the above test, the latency was significantly shortened in the oxaliplatin administration group in response to the cold stimulation in the cold plate, but in the oxaliplatin + test drug administration group, it was almost the same as the control group, and The latency was recovered continuously. From the above results, it became clear that the test drug exerts an excellent preventive, therapeutic, or alleviating effect continuously against abnormal sensation caused by oxaliplatin (hypersensitivity to a cold sensation).

Test Example 1: Measurement of ERK inhibitory action:
Western blot analysis was performed on lumbar spinal cord samples collected from mice 14 days after the start of the experiment, and the expression levels of ERK protein and phosphorylated ERK protein in the samples were examined. The phosphorylated ERK protein test was performed using an antibody (Phospho-p44 / 42MAPK (ERK1 / 2) that recognizes phosphorylation of a phosphorylation site selected from the group consisting of Thr202 of ERK1, Tyr204 of ERK1, Thr185 of ERK2, and Tyr187 of ERK2. ) (Thr202 / Tyr204) Antibody; Cell Signaling Technology). As a control, β-actin was used.

  The results of the above test are shown in FIG. As shown in FIG. 3, in the sample of the oxaliplatin administration group, the expression level of phosphorylated ERK induced upon hypersensitivity was remarkably increased. On the other hand, the oxaliplatin + test drug administration group administered with oxaliplatin in combination with the test drug showed the same amount of phosphorylated ERK as the control group, and was significantly phosphorylated ERK compared to the oxaliplatin administration group. The expression level was suppressed. Regarding the expression level of ERK, no significant difference was observed between the two groups. From this, it becomes clear that the test drug continuously and significantly prevents, treats, or reduces peripheral neuropathy caused by anticancer agents such as oxaliplatin by inhibiting ERK phosphorylation. It was.

Test Example 2: Measurement of PKC inhibitory action:
The same test as in Test Example 1 was performed to examine the expression levels of phosphorylated PKC-α (Ser638), phosphorylated PKC-γ (Ser643), and phosphorylated PKC-γ (Thr505) in the thoracic spinal cord sample. The results are shown in FIG. As shown in FIG. 3, in the oxaliplatin + test drug administration group administered with oxaliplatin in combination with the test drug, the expression level of phosphorylated PKC was significantly suppressed as compared with the oxaliplatin administration group. From this, it is clear that peripheral neuropathy caused by anticancer agents such as oxaliplatin can be prevented, treated, or alleviated continuously and non-locally by administering a PKC inhibitor. became.

Example 2: Effect of MEK inhibitor:
A von Frey test and a cold plate test were performed in the same manner as in Example 1 except that PD0325901 was used as a test drug. PD0325901 is a MEK inhibitor that selectively binds to MEK and inhibits MEK in a non-ATP competitive manner. MEK is located upstream of ERK in the MEK / ERK pathway. The results are shown in FIGS. 4 and 5, respectively. As shown in FIGS. 4 and 5, as in Example 1, the mechanical stimulus suppression effect and the cold stimulus suppression effect by the test drug were recognized.

  In addition, except that PD0325901 was used as a test drug, the same test as in Test Example 1 was performed to examine the expression level of ERK protein and the expression level of phosphorylated ERK protein in the sample. The results are shown in FIG. As shown in FIG. 6, as in Test Example 1, the effect of suppressing the phosphorylated ERK expression level by the test drug was observed.

  As apparent from the comparison between FIG. 1 and FIG. 4, the comparison between FIG. 2 and FIG. 5, and the comparison between FIG. 3 and FIG. 6, the effect of suppressing mechanical stimulation in the test of Example 2 using a MEK inhibitor, The effect of suppressing cold stimulation and the effect of suppressing the expression level of phosphorylated ERK were almost the same as the effects of Example 1 and Test Example 1 in which ERK was inhibited using a PKC inhibitor. From this, the sustained and prominent prevention, treatment or alleviation effect of peripheral neuropathy observed in Example 1 and Example 2 is due to inhibition of MEK / ERK and inhibition of MEK / ERK pathway. Thus, it has been clarified that inhibition of MEK or ERK provides an effect of preventing, treating, or alleviating persistent and significant peripheral neuropathy.

Test Example 3: Safety measurement:
For the three groups in the test of Example 1 and the three groups in the test of Example 2, changes in body weight of the mice used in the test were measured over time. As a result, there was no significant difference in body weight change in any group, and it was found that the preventive, therapeutic or alleviating agent of the present invention had few side effects and high safety.

  As is clear from the results of these pharmacological tests, the test drug was used as an indicator of peripheral neuropathy, with hypersensitivity such as allodynia caused by mechanical stimulation caused by administration of anticancer agents such as oxaliplatin, and sensory abnormalities caused by cold stimulation. In the oral administration test of mice conducted, it was confirmed that peripheral neuropathy has an excellent preventive, therapeutic or alleviating action continuously. These test drugs, known as PKC inhibitors or MEK inhibitors, inhibit MEK or inhibit phosphorylation of ERK, inhibit ERK, and inhibit the MEK / ERK pathway. It has been observed that it has sustained good preventive, therapeutic, or alleviating effects. Thus, hypersensitivity caused by the administration of anticancer agents such as oxaliplatin by non-local administration of PKC inhibitors or MEK / ERK pathway inhibitors or by inhibiting MEK or ERK It has been shown that peripheral neuropathy, such as abnormalities and sensory abnormalities, can be continually and significantly prevented, treated, or alleviated.

Claims (3)

An agent for preventing, treating, or alleviating peripheral neuropathy with an anticancer agent, containing tamoxifen or PD0325901 as an active ingredient (provided that the anticancer agent is paclitaxel, docetaxel, vincristine, vinblastine, vindesine, vinorelbine, cisplatin and carboplatin) Not included).   The preventive, therapeutic or alleviating agent according to claim 1, which is for non-local administration.   The preventive, therapeutic or alleviating agent according to claim 1 or 2, wherein the peripheral neuropathy is caused by a platinum preparation.

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