WO2021143754A1 - 用于癌症治疗的组合及其应用 - Google Patents

用于癌症治疗的组合及其应用 Download PDF

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WO2021143754A1
WO2021143754A1 PCT/CN2021/071685 CN2021071685W WO2021143754A1 WO 2021143754 A1 WO2021143754 A1 WO 2021143754A1 CN 2021071685 W CN2021071685 W CN 2021071685W WO 2021143754 A1 WO2021143754 A1 WO 2021143754A1
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Prior art keywords
cancer
group
combination
salt
present
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PCT/CN2021/071685
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English (en)
French (fr)
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邱紫文
韩鸿志
林欣荣
李睿豪
刘人玮
林思吟
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长弘生物科技股份有限公司
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Priority to JP2022543427A priority Critical patent/JP2023511072A/ja
Priority to US17/792,468 priority patent/US20230092846A1/en
Priority to CN202180008932.9A priority patent/CN114945364A/zh
Publication of WO2021143754A1 publication Critical patent/WO2021143754A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to the field of cancer treatment, in particular to the application of combining the compound of formula (I) and/or its pharmaceutically acceptable salt with anticancer drugs in the treatment of cancer, in particular, the combination is used to enhance the resistance of cancer cells
  • the combination is used to enhance the resistance of cancer cells
  • cancer drug sensitivity lowering the dosage of anti-cancer drugs, reducing the side effects of anti-cancer drugs, reversing the immunosuppression caused by anti-cancer drugs and/or alleviating the cachexia symptoms of cancer individuals:
  • A is a C1-C8 aliphatic hydrocarbon group containing a carbonyl group as required; X is H or OH; Y is O; and R 1 is H or not present, provided that when R 1 is not present, Y bonds with A The knot forms a five-membered ring.
  • Tumor refers to abnormal cell pathology in medicine. This type of pathology is caused by various carcinogenic factors that cause cells in local tissues of the body to lose normal regulation of their growth at the genetic level, resulting in Cells proliferate abnormally and aggregate into masses, so they are called “tumors.” Cancer, also known as malignant tumor (malignant tumor), abnormally proliferating cancer cells will not only aggregate into masses, but also spread and metastasize to other tissues or organs of the body. The proliferation and metastasis of cancer cells can cause severe physiological abnormalities and are difficult to cure. Therefore, in recent years, cancer has become the leading cause of human death in the world.
  • the common clinical treatments currently include surgical treatment, chemotherapy, radiotherapy, targeted therapy, immunotherapy and other treatment methods.
  • chemotherapy is the use of chemical drugs (such as topoisomerase inhibitors, microtubule polymerization inhibitors, platinum-based reagents, antimetabolites) to kill fast-growing cancer cells.
  • drugs such as topoisomerase inhibitors, microtubule polymerization inhibitors, platinum-based reagents, antimetabolites
  • most drugs used in chemotherapy also act on normal cells and affect the growth of normal cells, causing serious side effects to cancer patients, including nausea, vomiting, anorexia, hair loss, fatigue, bleeding, anemia, leukopenia, etc. , Not only affects the patient’s quality of life, but may also cause cachexia, infection or heart failure and lead to the risk of death.
  • cancer cachexia is a comprehensive metabolic syndrome, which is related to reduced calorie intake, increased static energy expenditure, and abnormal protein, fat, and carbohydrate metabolism in the body. It is characterized by weight loss, weakness, anorexia, fatigue, etc., and Even if the food intake or nutritional intake of cancer patients is increased, it cannot prevent or stop the continuous weight loss.
  • cancer cells bind to and induce their surface antigens (eg, programmed death receptor-ligand 1, cytotoxic T cell-associated protein-4) Immune cells initiate a "suppress immune response", making immune cells unable to activate.
  • programmed death-ligand 1 Programmed death-ligand 1, PD-L1
  • cytotoxic T lymphocyte associated protein-4 cytotoxic T lymphocyte associated protein 4, CTLA-4
  • other cancer cell surface antigens are also called It is the "immune checkpoint antigen”.
  • the inventors of the present case have discovered that, compared with the use of anticancer drugs alone, the combined use of the compound of formula (I) or its salt of the present invention and anticancer drugs can enhance the sensitivity of cancer cells to anticancer drugs and effectively reduce the anticancer drugs.
  • the dosage of the drug can further reduce the side effects of the anti-cancer drugs, reverse the immunosuppression caused by the anti-cancer drugs, and alleviate the cachexia symptoms of cancer individuals.
  • an object of the present invention is to provide an active ingredient used in the preparation and combined use of anti-cancer drugs in cancer treatment to reduce the dosage of anti-cancer drugs, reduce the side effects of anti-cancer drugs, and reverse the immunosuppressive properties caused by anti-cancer drugs. And/or use of a pharmaceutical composition for alleviating cachexia symptoms in a cancer individual, wherein the active ingredient is selected from the group consisting of: a compound of formula (I), a pharmaceutically acceptable salt thereof, and the foregoing combination,
  • A is a C1-C8 aliphatic hydrocarbon group containing a carbonyl group as required; X is H or OH; Y is O; and R 1 is H or not present, provided that when R 1 is not present, Y bonds with A
  • the knot forms a five-membered ring, and the anti-cancer drug is selected from the group consisting of topoisomerase inhibitors, microtubule assembly inhibitors, and platinum-based reagents. -based agent), antimetabolite, and combinations of the foregoing.
  • Another object of the present invention is to provide a use of a first active ingredient and a second active ingredient in the preparation of a pharmaceutical composition for the treatment of cancer, wherein the first active ingredient is selected from the group consisting of Group: compounds of formula (I), pharmaceutically acceptable salts thereof, and combinations of the foregoing,
  • A is a C1-C8 aliphatic hydrocarbon group containing a carbonyl group as required; X is H or OH; Y is O; and R 1 is H or not present, provided that when R 1 is not present, Y bonds with A
  • the knot forms a five-membered ring, and wherein the second active ingredient is selected from the group consisting of topoisomerase inhibitors, microtubule polymerization inhibitors, platinum-based reagents, antimetabolites, and combinations of the foregoing.
  • Another object of the present invention is to provide a combination comprising a first component and a second component, wherein the first component is selected from the group consisting of: a compound of formula (I), its medicine The acceptable salt, and the combination of the foregoing,
  • A is a C1-C8 aliphatic hydrocarbon group containing a carbonyl group as required;
  • X is H or OH;
  • Y is O;
  • R 1 is H or not present, and the condition is that when R 1 is not present, Y and A bond to form a five-membered ring, and wherein the second component is selected from the group consisting of: topological isomerism Enzyme inhibitors, microtubule polymerization inhibitors, platinum-based reagents, antimetabolites, and combinations of the foregoing.
  • the combination is in the form of a pharmaceutical composition or kit. Among them, in a specific embodiment of the combination provided according to the present invention, the combination is used for cancer treatment.
  • Another object of the present invention is to provide a method for treating cancer, which comprises administering a combination as described above to an individual in need.
  • the compound of formula (I) is preferably wherein A is a C1-C6 aliphatic hydrocarbon group, R 1 is not present, and more preferably, A is a C5 alkyl group or alkene. Or wherein A is a C1-C6 aliphatic hydrocarbon group containing a carbonyl group, and R 1 is H, more preferably, A is a C5 alkyl or alkenyl group containing a carbonyl group.
  • the pharmaceutically acceptable salt of the compound of formula (I) is preferably at least one of the following: lithium salt, Sodium salt, potassium salt, magnesium salt, calcium salt, and zinc salt.
  • the anti-cancer drug, the second active ingredient, or the second component is preferably selected from the group consisting of: irinotecan, Topotecan, etoposide, mitoxantrone, teniposide, azacitidine, 5-fluorouracil (5-FU) , Tegafur (tegafur), tiggio (TS-1), 6-mercaptopurine (6-mercaptopurine, 6-MP), azathioprine (azathioprine), capecitabine (capecitabine), cladribine ( cladribine, clofarabine, cytosine arabinoside (Ara-C), decitabine, floxuridine, fludarabine, gemcitabine Gemcitabine, hydroxyurea, methotrexate, nelarabine, pemetrexed, pentostatin, pralatrexate, Thioguanine, trifluridine/tipiracil
  • the cancer involved is preferably at least one of the following: colorectal cancer, colorectal cancer, lung cancer, pancreatic cancer, bladder cancer, cholangiocarcinoma, rectal cancer, breast cancer, multiple Myeloma, gynecological tumors, brain cancer, testicular cancer, leukemia, lymphoma, pleural mesothelioma, gastric cancer, and liver cancer.
  • Figure 1 shows a photograph of the expression levels of CD44ICD protein, PD-L1 protein, and GAPDH protein in Panc02 cells treated with different concentrations of Z-butylenephthalide by Western blotting.
  • Figure 2 shows a photograph of pancreatic tumors in each group of mice taken on the 15th day after Panc02 cells were injected into mice (the circled part shown by the dotted line is the tumor), including the "Control” group and the "Control” group.
  • LD low dose
  • HD high dose
  • Gem glycoside
  • LD+Gem LD+Gem
  • TS-1 LD+TS-1
  • Figure 3 shows a bar graph analyzing the size of the tumor in the circled part shown by the dotted line in Figure 2 (* means p value ⁇ 0.05 compared to the control group; ** means p value ⁇ 0.005 compared to the control group) .
  • Figure 4 shows the tumor size (expressed in Photon Flux) measured on days 1, 15 and 22 when Panc02 cells were injected into mice, including the "Cisplatin” group and "Z-BP" +Cisplatin” group result.
  • 5A to 5D are graphs showing the survival rate of pancreatic cancer mice treated with different treatments.
  • Figure 6 shows the expression of CD44 protein, CD44ICD protein, PD-1 protein, PD-L1 protein, p-Akt protein, Akt protein, and GAPDH protein in pancreatic tumor tissue of pancreatic cancer mice with different treatments The amount of photo illustration.
  • Response rate is defined as the proportion of patients who respond to treatment during any period of the observation period, and the response size (referring to the degree of tumor shrinkage) can be divided into complete response (tumor elimination) and partial response (The tumor is eliminated by at least 50%).
  • a certain anti-cancer drug has a "response rate of 40%", which means that the drug can produce an anti-cancer effect in 40% of patients treated with the drug, and the said effect includes reducing tumors by at least 50% or even disappearing completely.
  • the combination of the compound of the present invention ie, the compound of formula (I)
  • anticancer drugs can enhance the sensitivity of cancer cells to anticancer drugs, and is effective Reduce the dosage of anti-cancer drugs, thereby achieving the purpose of reducing the side effects of anti-cancer drugs, reversing the immunosuppression caused by anti-cancer drugs, and alleviating the cachexia symptoms of cancer individuals.
  • the present invention relates to the application of the compound of formula (I) and/or its pharmaceutically acceptable salt in the treatment of cancer:
  • A is a C1-C8 aliphatic hydrocarbon group containing a carbonyl group as required; X is H or OH; Y is O; and R1 is H or not present, and the condition is that when R1 is not present, Y and A bond to form A five-membered ring.
  • the aforementioned applications include: (i) using the compound of formula (I) and/or its pharmaceutically acceptable salt in the preparation of an anticancer drug for use in cancer treatment to increase the sensitivity of cancer cells to anticancer drugs and reduce anticancer drugs Dosage, use of a pharmaceutical composition for reducing the side effects of anticancer drugs, reversing immunosuppression caused by anticancer drugs and/or alleviating cachexia symptoms of cancer individuals, (ii) using the compound of formula (I) as the first active ingredient, and / Or the use of a pharmaceutically acceptable salt thereof and an anticancer drug as the second active ingredient in the preparation of a pharmaceutical composition for the treatment of cancer, (iii) a combination comprising the formula (I) as the first component ) A compound and/or a pharmaceutically acceptable salt thereof, and an anticancer drug as the second component, and (iv) a method of treating cancer, comprising administering the aforementioned combination to an individual in need.
  • the compound of formula (I) is preferably in which A is a C1-C6 aliphatic hydrocarbon group (more preferably A is C5 alkyl or alkenyl) and R 1 is absent, or where A is A C1-C6 aliphatic hydrocarbon group containing a carbonyl group (more preferably A is a C5 alkyl group or alkenyl group containing a carbonyl group) and R 1 is H.
  • the compound of formula (I) involved is Z-butylenephthalide, E-butylenephthalide, 2-pentanoylbenzoic acid, or butylphthalide .
  • examples of the pharmaceutically acceptable salt of the compound of formula (I) include: lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, and zinc salt.
  • the pharmaceutically acceptable salt of the compound of formula (I) in question is a sodium salt, for example: sodium 2-pentanoylbenzoate.
  • the compound of formula (I) and the pharmaceutically acceptable salt thereof can be obtained commercially or prepared by synthetic methods known in the field of the present invention.
  • anti-cancer drugs examples include topoisomerase inhibitors, microtubule assembly inhibitors, platinum-based agents, and antimetabolites (antimetabolite), and the aforementioned combination.
  • it is selected from the group consisting of: irinotecan, topotecan, etoposide, mitoxantrone, teniposide ), azacitidine (azacitidine), 5-fluorouracil (5-fluorouracil, 5-FU), tegafur (tegafur), teggio (TS-1; namely, compound containing 5-FU prodrug tegafur Drugs), 6-mercaptopurine (6-mercaptopurine, 6-MP), azathioprine (ie, the prodrug of 6-MP), capecitabine, cladribine, chlorine Clofarabine (clofarabine), cytosine arabinoside (Ara-C), decitabine (decitabine), deoxyfluridine (floxuridine), flu
  • the anti-cancer drug involved is one of erenoxine, 5-fluorouracil, tigeo, gemcitabine, cisplatin, oxaliplatin, and paclitaxel or Multiple.
  • the combination provided according to the present invention can be a pharmaceutical composition or a set.
  • the combination is used for cancer treatment.
  • the combination provided according to the present invention is a set
  • Cancer drugs are usually packaged separately, stored in different containing spaces (such as plastic bags, plastic bottles, glass bottles, ampoules), and can be shipped or sold separately, or they can be delivered and sold as a set.
  • the kit may additionally include an instruction manual, so that the user can mix the ingredients on-site for processing and application according to the procedures and procedures drawn up in it during use.
  • examples of cancers involved include: colorectal cancer, colorectal cancer, lung cancer (such as non-small cell lung cancer), pancreatic cancer, bladder cancer, cholangiocarcinoma, rectal cancer, breast cancer, multiple myeloma , Gynecological tumors (such as cervical cancer, ovarian cancer, uterine cancer, vulvar cancer), brain cancer (such as glioblastoma), testicular cancer, leukemia (such as acute myeloid leukemia), lymphoma, pleural mesothelioma, Stomach cancer, and liver cancer.
  • lung cancer such as non-small cell lung cancer
  • pancreatic cancer bladder cancer
  • cholangiocarcinoma rectal cancer
  • breast cancer multiple myeloma
  • Gynecological tumors such as cervical cancer, ovarian cancer, uterine cancer, vulvar cancer
  • brain cancer such as glioblastoma
  • testicular cancer such as leukemia (such as acute myeloid leuk
  • the components of the pharmaceutical composition or kit provided according to the present invention can be used for systemic administration or local administration, and can be delivered through various drug delivery systems (DDS). Suitable drug delivery systems include oral administration. Oral drug delivery system, transdermal drug delivery system, injectable drug delivery system, inhalation drug delivery system, and transmucosal drug delivery System (transmucosal drug delivery system), etc.
  • the medical composition or the components of the kit provided by the present invention can be made of liposomes, microcapsules, nanoparticles, and microparticles. Systems such as a microneedle are used for delivery to achieve the effects of improving bioavailability, controlling drug release speed, accurately administering drugs to the lesion, and reducing drug side effects.
  • the pharmaceutical composition or the components of the kit provided according to the present invention can be in any suitable form without any special restrictions, and the corresponding suitable dosage form can be presented depending on the intended use; for example, but not limited to this.
  • the components of the pharmaceutical composition or kit can be taken orally, transdermally (such as patches, ointments, etc.), corticospinal tract injection, intrathecal injection, intracerebral injection, intravenous injection (including Infusion and rapid injection), intramuscular injection, subcutaneous injection, arterial injection, intraperitoneal injection, subcutaneous implantation, interstitial implantation, trans-respiratory (e.g. sprays, nasal drops, etc.), transmucosal (e.g. oral tablets, etc ) Is administered to individuals in need.
  • transdermally such as patches, ointments, etc.
  • corticospinal tract injection such as patches, ointments, etc.
  • intrathecal injection intracerebral injection
  • intravenous injection including Infusion and rapid injection
  • a pharmaceutically acceptable carrier can be selected to provide the components of the pharmaceutical composition or kit, wherein the carrier is known in the art and includes excipients, diluents, etc. Agents, adjuvants, stabilizers, absorption promoters, disintegrating agents, solubilizers, emulsifiers, antioxidants, binders, binding agents, tackifiers, dispersants, suspending agents, lubricants, moisture absorbents, etc.
  • any convenient method can be used to provide the pharmaceutical composition or the components of the kit in a dosage form suitable for oral administration, wherein the liquid dosage form suitable for oral administration includes syrups, oral liquids, and suspensions.
  • solid dosage forms suitable for oral administration include powders, granules, lozenges, sugar-coated tablets, enteric-coated tablets, chewable tablets, foaming tablets, film-coated tablets, capsules, and long-acting sustained-release tablets.
  • the pharmaceutical composition or the components of the kit provided according to the present invention may contain any anti-cancer drugs and/or at least one of the compounds of formula (I) and their pharmaceutically acceptable salts.
  • examples of the pharmaceutically acceptable carrier of the aforementioned liquid dosage form include: water, saline, dextrose, glycerin, ethanol or the like, oil (such as olive oil, Castor oil, cottonseed oil, peanut oil, corn oil, and germ oil), glycerin, polyethylene glycol, and combinations of the foregoing;
  • examples of pharmaceutically acceptable carriers of the foregoing solid dosage forms include: cellulose, starch, and kaolin (kaolinite), bentonite (bentonite), sodium citrate, gelatin, agar, carboxymethyl cellulose, acacia gum, seaweed gum, glyceryl monostearate, calcium stearate, and The aforementioned combination.
  • the pharmaceutically acceptable carrier for the desired benefits of the drug for example: water, mineral oil, propylene glycol, polyethylene oxide, liquid paraffin, sorbitan monostearate, and polysorbate 60.
  • any suitable method can be used to provide the pharmaceutical composition or the components of the kit in a dosage form suitable for transdermal administration, such as emulsion, cream, oil, gel (e.g., hydrogel), paste It is provided in the form of (for example, dispersion cream, ointment), lotion, spray, and patch (for example, microneedle patch), but not limited to this.
  • a dosage form suitable for transdermal administration such as emulsion, cream, oil, gel (e.g., hydrogel), paste It is provided in the form of (for example, dispersion cream, ointment), lotion, spray, and patch (for example, microneedle patch), but not limited to this.
  • Injections or drips suitable for injection may contain one or more such as isotonic solutions, salt buffers (such as phosphate buffer or phosphate buffer) in the pharmaceutical composition or kit components provided by the present invention.
  • Citrate buffer such as phosphate buffer or phosphate buffer
  • solubilizer such as phosphate buffer or phosphate buffer
  • emulsifier such as phosphate buffer or phosphate buffer
  • 5% sugar solution such as phosphate buffer or phosphate buffer
  • other carriers and other ingredients as intravenous infusion, emulsion intravenous infusion, dry powder injection, suspension injection, or dry powder suspension injection, etc.
  • the dosage form provides the components of the pharmaceutical composition or kit.
  • the pharmaceutical composition or the components of the kit can be prepared as a pre-injection solid, and the pre-injection solid can be dissolved or emulsified in other solutions or suspensions before being administered to an individual in need. Provide the desired injections.
  • the pharmaceutical composition or kit provided by the present invention may additionally contain one or more such as excipients, stabilizers, and buffers.
  • the pharmaceutical composition or kit may additionally contain one or more such as excipients, stabilizers, and buffers.
  • other carriers, etc. are provided in dosage forms such as wafers, tablets, pills, capsules, etc., so that the components of the medical composition or kit can be implanted into a body for slow and sustained release
  • At least one of the anti-cancer drug and/or the compound of formula (I) and its pharmaceutically acceptable salt is contained in the tissue around the administration site to achieve a local stable high-dose effect of killing cancer cells.
  • a biocompatible polymer may be included in the components of the medical composition or kit provided by the present invention, so that the components of the medical composition or kit present a subcutaneous Chip dosage form implanted or implanted between tissues.
  • the aforementioned biocompatible polymer may be commercially available or prepared by synthetic methods known in the art of the present invention.
  • a polyanhydride for example, "p(CPP-SA) copolymer”
  • p(CPP-SA) copolymer provided by bis(p-carboxyphenoxy)propane and sebacic acid can be used as the biocompatible polymer.
  • any suitable method can be used to aerosolize the pharmaceutical composition or the components of the kit as necessary to facilitate the use of the pharmaceutical composition or kit.
  • the components enter the respiratory tract.
  • the pharmaceutical composition or the components of the kit can be administered via a nebulizer or a pressurized container (such as a nasal spray).
  • the pharmaceutical composition or the components of the kit can be prepared as a nasal drop.
  • the medical composition or the components of the kit for transmucosal administration may contain one or more penetrating agents, surfactants, and viscosity regulators.
  • the medicine is provided in the form of eye drops, ophthalmic ointments, oral tablets, suppositories, nasal sprays, nasal drops, etc., including ingredients, pH regulators, preservatives, stabilizers, osmotic pressure regulators, and other carriers.
  • the components of a composition or set are examples of a composition or set.
  • the pharmaceutical composition or the components of the kit provided according to the present invention may further contain additives in a suitable amount, for example, to improve the toner and coloring of the composition or kit during use.
  • additives for example, to improve the toner and coloring of the composition or kit during use.
  • Agents, etc., as well as buffers, preservatives, preservatives, antibacterial agents, antifungal agents, etc. that can improve the stability and storage properties of the composition or kit.
  • the components of the pharmaceutical composition or kit provided according to the present invention may additionally contain one or more other active ingredients as needed to further enhance the efficacy of the composition or kit or increase the flexibility and formulation of formulations As long as the other active ingredients do not adversely affect the benefits of at least one of the anticancer drugs and/or the compound of formula (I) and pharmaceutically acceptable salts thereof contained in the pharmaceutical composition or kit of the present invention.
  • the pharmaceutical composition provided according to the present invention contains at least about 0.0001, 0.0002, 0.0003, 0.0004, 0.0005, 0.001, 0.0015, 0.002, 0.0025, 0.003, 0.0035, 0.004, 0.0045, 0.005, based on the total weight of the composition, 0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100% by weight of the compound of formula (I) and At least one of its pharmaceutically acceptable salts, and a useful range can be selected from any two of the aforementioned values, for example: about 0.0001% by weight to about 90% by weight, about 0.001% by weight to about 25% by weight, about 0.01
  • the pharmaceutical composition or kit provided according to the present invention can be administered at different frequencies such as once a day, multiple times a day, or once a few days, depending on the individual's needs, age, weight, and health status and the purpose of administration. different.
  • the content of at least one of the anti-cancer drugs and/or the compound of formula (I) and pharmaceutically acceptable salts thereof in the pharmaceutical composition or kit provided according to the present invention can also be adjusted according to actual application requirements, for example: To the amount that should be taken daily or for external use.
  • the method of administration, frequency of administration, and dosage range of the pharmaceutical composition or kit are as described above.
  • Human pancreatic cancer cell line Mia-PaCa2 cells (purchased from Bioresource Collection and Research Center; website: https://www.bcrc.firdi.org.tw/wwwbcrc/index.do ); BCRC 60319), PANC-1 cells (purchased from the Biological Resources Conservation and Research Center; BCRC 60284), AsPC-1 cells (purchased from the Biological Resources Conservation and Research Center; BCRC 60494).
  • Mouse pancreatic cancer cell line Panc02 cells (provided by Everfront Biotech Inc.).
  • Lung cancer cell line A549 cells (purchased from the Biological Resources Preservation and Research Center; BCRC 60074).
  • Brain cancer cell line DBTRG-05MG cells (purchased from the Biological Resources Conservation and Research Center; BCRC 60380).
  • Colorectal cancer cell line HT-29 cells (purchased from the Biological Resources Preservation and Research Center; BCRC 67003).
  • Liver cancer cell line HepG2 cells (purchased from the Biological Resources Preservation and Research Center; BCRC 60177).
  • PANC-1 cell culture medium DMEM-HG culture medium containing 10% fetal bovine serum and 1% penicillin/streptomycin.
  • AsPC-1 cell culture medium containing 10% fetal bovine serum, 1% penicillin/streptomycin, 10 millimolar concentration (mM) HEPES (purchased from Biomedicals; product number: 194549), and 1 millimolar RPMI1640 culture medium (purchased from HyClone) with a concentration of sodium pyruvate.
  • Panc02 cell culture medium RPMI1640 culture medium containing 10% fetal bovine serum and 1% penicillin/streptomycin.
  • A549 cell culture medium DMEM culture medium containing 10% fetal bovine serum.
  • DBTRG-05MG cell culture medium RPMI1640 culture medium containing 10% fetal bovine serum and 1 millimolar sodium pyruvate.
  • HT-29 cell culture medium RPMI1640 culture medium containing 10% fetal bovine serum.
  • HepG2 cell culture medium DMEM culture medium containing 10% fetal bovine serum.
  • Z-butylidenephthalide ((Z)-n-butylidenephthalide, Z-BP): provided by Changhong Biotech; purity 99.8%.
  • E-butylidenephthalide ((E)-n-butylidenephthalide, E-BP): provided by Changhong Biotech; purity 98.01%.
  • BP-OH 2-pentanolybenzoic acid
  • BPONa Sodium 2-pentanoylbenzoate
  • butylphthalide (butylphthalide): provided by Changhong Biotechnology; purity ⁇ 97%.
  • Irinotecan (CPT-11) purchased from Sigma; product number: I1406.
  • Cisplatin purchased from Sigma; product number: C2210000.
  • Oxaliplatin purchased from Sigma; product number: 61825-94-3.
  • MTT thiazole blue, 3-[4,5-dimethylthiahiazo-2-y1]-2,4-dipheny-tetrazolium bromide: purchased from ALFA Aesar TM ; product number: L11939-000000-16AF.
  • ELISA reader purchased from Thermo Fisher Scientific; model number: 22662.
  • C57BL/6J mice (weight: 18-22 grams): purchased from the Experimental Animal Center (No.99, Lane130, Section 1, Academia Road, Nangang District, Taipei City, Taiwan, China).
  • Antibodies used in Western Blotting anti-Akt antibody (purchased from Cell Signaling Technology; product number: #9272); anti-phospho-Akt (Ser473) antibody (purchased from Cell Signaling Technology; product number: #9271); anti-CD44 antibody (purchased from Abcam; product number: #ab24504); anti-PD-L1 antibody (purchased from Abcam; product number: #ab238697); anti-PD-1 antibody (purchased from BioLegend; product Code: #367402); anti-GAPDH antibody (purchased from Genetex; product code: GTX100118).
  • Example 1 The lethal effect of the compound of the present invention and different anti-cancer drugs on cancer cells
  • This example uses MTT (thiazole blue, 3-[4,5-dimethylthiahiazo-2-y1]-2,4-dipheny-tetrazolium bromide) cell survival analysis method to study the effects of the compounds of the present invention and different anticancer drugs on cancer cells The lethal effect.
  • MTT thiazole blue, 3-[4,5-dimethylthiahiazo-2-y1]-2,4-dipheny-tetrazolium bromide
  • Culture lung cancer cell lines (A549 cells), liver cancer cell lines (HepG2 cells), colorectal cancer cell lines (HT-29 cells), and brain cancer cell lines (DBTRG-05MG cells) in each well of a 96-well microwell plate ( Culture 1 ⁇ 10 4 cells per well; the 96-well microwell plate is placed in an incubator at 37° C. and 5% CO 2 for 24 hours. Thereafter, the aforementioned cell strains were cultured in a culture medium containing 5-fluorouracil, Z-butylenephthalide, and 2-pentanoylbenzoic acid, respectively, for 24, 48, and 72 hours.
  • MTT solution (0.5 mg/ml) was added to each well of the 96-well microwell plate, and placed in an incubator at 37° C. and 5% CO 2 for 1.5 hours. After aspirating the culture medium, add 100 microliters of dimethyl sulfoxide, and then use an ELISA reader to measure its absorbance at a wavelength of 595 nanometers. Based on this, calculate the survival rate of the cells, and calculate 5-fluorouracil and Z-butylene phthalide, and 2-valeryl acid concentration reaches 50% lethality (IC 50) for each cancer cell line. The results are shown in Table 2.
  • Example 2 The effect of the compound of the present invention in combination with anticancer drugs
  • Culture pancreatic cancer cell lines PANC-1, Mia-PaCa2, and AsPC-1
  • lung cancer cell lines A549 cells
  • liver cancer cell lines HepG2 cells
  • colorectal cancer cells in each well of a 96-well microwell plate Strains (HT-29 cells)
  • brain cancer cell lines DBTRG-05MG cells
  • (D)1 and (D)2 respectively represent the IC 50 of drug 1 and drug 2 when used in combination
  • (Dx)1 and (Dx)2 respectively represent the IC 50 of the two drugs when used alone . If the drug combination index (CI) is less than 1, it means that the combination of the two drugs has a synergistic effect.
  • Table 3 CI value of Z-butylenephthalide and 5-fluorouracil used to kill cancer cells
  • Example 2-1 Comparing the method of Example 2-1, combined use of Z-butylenephthalide and other anti-cancer drugs to treat pancreatic cancer cells, and calculate experimental data to obtain the aforementioned CI value used to kill pancreatic cancer cells. The results are shown in Table 4.
  • Table 4 CI value of Z-butylenephthalide (Z-BP) and other anticancer drugs used to kill pancreatic cancer cells
  • Example 2-1 Comparing the method of Example 2-1, combined use of E-butylenephthalide and oxaliplatin, paclitaxel, gemcitabine, 5-fluorouracil and other anticancer drugs to treat pancreatic cancer cells, and calculate the experimental data to Obtain the aforementioned CI value used to kill pancreatic cancer cells.
  • the results are shown in Table 5 to Table 7.
  • E-BP E-butylenephthalide
  • oxaliplatin or paclitaxel used to poison the pancreas
  • E-BP E-butylenephthalide
  • 5-fluorouracil used to kill pancreatic cancer cells
  • Example 2-1 Comparing the method of Example 2-1, combined use of 2-pentanoylbenzoic acid (BP-OH) and 5-fluorouracil, gemcitabine, oxaliplatin, paclitaxel and other anticancer drugs to treat pancreatic cancer cell lines (PANC-1, Mia-PaCa2, AsPC-1, and Panc02), lung cancer cell line (A549 cell), liver cancer cell line (HepG2 cell), colorectal cancer cell line (HT-29 cell), and brain cancer cell line (DBTRG-05MG cells), and calculate the experimental data to obtain the aforementioned CI value used to kill each cancer cell. The results are shown in Table 8 to Table 11.
  • Table 8 CI value of 2-pentanoyl benzoic acid (BP-OH) and 5-fluorouracil used to kill cancer cells
  • Table 9 CI value of 2-pentanoyl benzoic acid (BP-OH) and gemcitabine used to kill pancreatic cancer cells
  • Table 10 CI value of 2-pentanoyl benzoic acid (BP-OH) and oxaliplatin used to kill pancreatic cancer cells
  • Table 11 CI value of 2-pentanoyl benzoic acid (BP-OH) and paclitaxel used to kill pancreatic cancer cells
  • Example 2-1 Comparing the method of Example 2-1, combined use of 2-pentanoyl benzoate (BPONa) and oxaliplatin, gemcitabine, 5-fluorouracil, paclitaxel and other anti-cancer drugs to treat pancreatic cancer cells, and calculate The experimental data is used to obtain the aforementioned CI value used to kill pancreatic cancer cells. The results are shown in Table 12 to Table 14.
  • Table 12 CI value of 2-pentanoyl benzoate (BPONa) and oxaliplatin used to kill pancreatic cancer cells
  • Table 13 CI value of 2-pentanoyl benzoate (BPONa) and gemcitabine used to kill pancreatic cancer cells
  • Table 14 CI value of 2-pentanoyl benzoate (BPONa) and 5-fluorouracil or paclitaxel used to kill pancreatic cancer cells
  • the combination of the compound of formula (I) or its salt of the present invention and anticancer drugs can increase the sensitivity of cancer cells to anticancer drugs and effectively reduce anticancer drugs
  • the dosage of the drug further achieves the purpose of reducing the side effects of the anti-cancer drug, reversing the immunosuppression caused by the anti-cancer drug, and alleviating the cachexia symptoms of the cancer individual.
  • Example 3 The effect of the compound of the present invention on reducing the expression of CD44 and PD-L1 in cancer cells
  • CD44 and CD44ICD will promote the performance of PD-L1, and the downregulation of CD44 will inhibit the growth of cancer cells. See, for example: CD44 promotes PD-L1 expression and its tumor-intrinsic function in breast and lung cancers. Cancer Research .2020 Feb 1; 80(3):444-457., the full text of this document is incorporated here for reference.
  • Panc02 cells pancreatic cancer cell line
  • 37.5 and 75 micrograms/ml ( ⁇ g/ml) of Z-butylenephthalide were cultured with 37.5 and 75 micrograms/ml ( ⁇ g/ml) of Z-butylenephthalide, respectively, for 6 hours (during the period of 3 hours of culture, one portion is collected Copies of cells).
  • the protein of the cells was extracted, and the expression of CD44 intracellular domain (CD44ICD) protein and PD-L1 protein of cancer cells treated with Z-butylenephthalide was detected by Western blotting. .
  • the performance of GAPDH protein was tested as an internal control. The results are shown in Figure 1.
  • Example 4 Combined use of the compound of the present invention and anti-cancer drugs to treat cancer
  • mice were kept in the Experimental Animal Center of Donghua University until they were eight to ten weeks old. Then, the stably constructed Panc02 cells (1 ⁇ 10 6 cells/0.02 ml/each mouse) transfected with Luc-eGFP were injected into the mouse pancreas in situ. Then, the tumor size of the mouse pancreas was analyzed through the results of animal imaging, and then the mice were divided into nine groups according to the average tumor size, and they were treated under the following conditions, which lasted three to four weeks:
  • TS-1 "TS-1" group (5 animals): After oral administration of 100 mg/kg body weight of Tiggio (TS-1) daily for five consecutive days, the oral administration was suspended for two days.
  • LD+TS-1 "LD+TS-1" group (2 animals): 12.5 mg/kg body weight of Z-butylenephthalide was administered orally every day, and 50 mg/kg body weight was administered orally every day for five consecutive days After the administration of Tiggio (TS-1), the oral administration of TS-1 was suspended for two days.
  • Z-BP+Cisplatin group (3 animals): daily oral administration of 6.25 mg/kg body weight of Z-butylenephthalide, and intraperitoneal injection of 1.25 mg/kg body weight of cisplatin every 7 days (cisplatin).
  • pancreatic tumor in situ After the stably constructed Panc02 cells transfected with Luc-eGFP were injected in situ into each group of mice in Example 4-1, and the growth of the pancreatic tumor in situ was confirmed, the drug treatment was started for 14 days (ie, Day 15), during a T2-weighted magnetic resonance imaging (T 2 -weighted MRI) analytical observed pancreatic tumors of mice in each group, and record pictures, the results shown in FIG. The size of the tumor (the circled part shown by the dotted line) of each group of mice in FIG. 2 was analyzed with amide software.
  • T2-weighted magnetic resonance imaging T 2 -weighted MRI
  • Gemcitabine (GEM) and Tiggio (TS-1) are clinically used drugs for cancer treatment.
  • the mice in the "Gem” group and the "TS-1" group On the contrary, the tumor size was larger than the unadministered "Control” group (also known as "'Ctl' group”).
  • gemcitabine (GEM) and tigeo (TS-1) can cause immunosuppression in the tumor microenvironment (TME), leading to the resistance of cancer cells to the immune system.
  • Figure 3 also shows that the tumor size of the "LD+Gem” group was significantly smaller than that of the "Gem” group, and the tumor size of the "LD+TS-1” group was significantly smaller than that of the "TS-1” group. From the foregoing results, it can be seen that the combined use of the compound or its salt of the present invention and anti-cancer drugs can effectively reverse the immunosuppressive properties caused by anti-cancer drugs and more effectively inhibit tumor growth.
  • mice in Example 4-1 On the 1, 15 and 22 days after the stably constructed Panc02 cells transfected with Luc-eGFP were injected into each group of mice in Example 4-1 in situ, the "Cisplatin” group and the “Cisplatin” group were detected by IVIS imaging system. Tumor size of mice in Z-BP+Cisplatin” group (by measuring Photon Flux; unit: photon/sec/cm2/steradian (ph/s/cm 2 /sr)), the results are shown in Figure 4.
  • pancreatic cancer mice were established according to the method of Example 4-1, and the survival conditions of the mice in each group were observed and recorded daily. The results are shown in Table 15 and FIGS. 5A to 5D.
  • mice of each group were sacrificed and their pancreatic tumor tissues were taken. Then, protein extraction was performed, and the expression of CD44 protein, CD44ICD protein, PD-1 protein, PD-L1 protein, p-Akt protein, and Akt protein in each tissue protein sample was detected by Western blotting. In addition, the performance of GAPDH protein was tested as an internal control. The results are shown in Figure 6.
  • Figure 6 also shows that the expression levels of CD44 protein, CD44ICD protein, PD-1 protein and PD-L1 protein in the "LD+Gem” group were significantly lower than those in the "Gem” group, and the CD44 protein, The expression levels of CD44ICD protein, PD-1 protein and PD-L1 protein were significantly lower than those of the "TS-1" group.
  • Z-butylenephthalide has the effect of inhibiting the CD44 protein and CD44ICD protein of cancer cells, thereby inhibiting the expression of immune checkpoint antigens such as PD-1 protein and PD-L1 protein, so it can block cancer cells and immune cells.
  • the foregoing results once again show that the combined use of the compound or its salt of the present invention and anti-cancer drugs can effectively reverse the immunosuppression caused by the anti-cancer drugs, and help to improve the efficacy of the anti-cancer drugs.

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Abstract

一种组合，其包含一第一组分与一第二组分，其中该第一组分选自以下所组成的群组：式(I)化合物、其医药上可接受的盐、及前述的组合，其中， A为视需要含有羰基的C1-C8脂肪族烃基；X为H或OH；Y为O；以及 R 1为H或不存在，其条件为，当R 1不存在时，Y与A键结形成一五元环, 且其中，该第二组分选自以下所组成的群组：拓扑异构酶抑制剂、微小管聚合抑制剂、铂基试剂、抗代谢药物、及前述的组合。

Description

用于癌症治疗的组合及其应用 技术领域
本发明是关于癌症治疗的领域，尤其是关于将式(I)化合物及/或其医药上可接受的盐与抗癌药物并用在癌症治疗的应用，特别是通过该并用以提升癌细胞对抗癌药物的敏感性、降低抗癌药物投药量、减少抗癌药物副作用、逆转抗癌药物引起的免疫抑制性及/或减缓癌症个体的恶病质症状的应用：
Figure PCTCN2021071685-appb-000001
其中，A为视需要含有羰基的C1-C8脂肪族烃基；X为H或OH；Y为O；以及R 1为H或不存在，其条件为，当R 1不存在时，Y与A键结形成一五元环。
背景技术
肿瘤(tumor)在医学上是指细胞的异常病变，此种病变是在各种致瘤因素(carcinogenic factor)作用下，使身体局部组织的细胞在基因层次上失去对其生长的正常调控，导致细胞异常增生且集结成为肿块，因而称为“肿瘤”。癌症，又名恶性肿瘤(malignant tumor)，异常增生的癌细胞除了会集结成为肿块，更会扩散、转移至身体其他组织或器官。癌细胞的增生以及转移会导致严重的生理功能异常且难以治愈，故近年来癌症已成为全球人类死因之首。
关于癌症的治疗，目前临床上常见治疗方式有外科手术治疗、化学疗法、放射线疗法、标靶治疗、免疫疗法等治疗方式。其中，化学疗法是使用化学药物(例如拓扑异构酶抑制剂、微小管聚合抑制剂、铂基试剂、抗代谢药物)对生长快速的癌细胞进行毒杀作用。然而，多数化学疗法所使用的药物也会作用于正常细胞，影响正常细胞的生长，对癌症患者造成严重的副作用，此包括恶心、呕吐、厌食、脱发、倦态、出血、贫血、白血球减少等，不仅会影响到患 者的生活质量，更可能造成恶病质、感染或心脏衰竭而导致死亡的危险。其中，癌症恶病质为一种综合性的代谢症候群，与卡路里摄取减少、静态能量消耗增加、及体内蛋白质、脂肪及碳水化合物的代谢异常有关，其特征为体重减轻、虚弱、厌食、疲劳等，且纵使增加癌症患者的进食量或营养摄取，也无法预防或阻止体重持续下降。
研究显示，癌细胞的免疫抑制作用也与癌症的发展相关，某些癌细胞会通过其表面抗原(例如：程序性死亡受体-配体1、细胞毒性T细胞相关蛋白-4)结合并诱导免疫细胞启动“抑制免疫反应”，使免疫细胞无法活化。前述程序性死亡受体-配体1(Programmed death-ligand 1，PD-L1)、细胞毒性T细胞相关蛋白-4(cytotoxic T lymphocyte associated protein 4，CTLA-4)等癌细胞的表面抗原又称为“免疫检查点(immune checkpoint)抗原”。也有研究显示，部分抗癌药物(例如gemcitabine)反而会引起肿瘤微环境(tumor microenvironment，TME)中的免疫抑制性，导致癌细胞对免疫系统产生抗药性，此可参见例如：Gemcitabine treatment promotes immunosuppressive microenvironment in pancreatic tumors by supporting the infiltration,growth,and polarization of macrophages.Scientific reports.2018 Aug 10；8(1):1-10.，该文献的全文并于此处以供参考。
因此，业界仍致力于癌症的治疗药物及治疗方法的研究。若能有效提升癌细胞对抗癌药物的敏感性、降低抗癌药物的投药量，将可减少抗癌药物副作用，从而降低患者负担、减缓患者的恶病质症状。此外，若能逆转抗癌药物引起的免疫抑制性，将可进一步提升抗癌药物的药效，有助于治疗。
发明内容
本案发明人研究发现，相比于单独使用抗癌药物，将本发明式(I)化合物或其盐与抗癌药物并用，可提升癌细胞对抗癌药物的敏感性，有效降低抗癌药物的投药量，进而达到减少抗癌药物副作用、逆转抗癌药物引起的免疫抑制性、 以及减缓癌症个体的恶病质症状的目的。
因此，本发明的一目的，在于提供一种使用一活性成分于制备一与抗癌药物并用在癌症治疗以降低抗癌药物投药量、减少抗癌药物副作用、逆转抗癌药物引起的免疫抑制性及/或减缓癌症个体的恶病质症状的医药组成物的用途，其中该活性成分选自以下所组成的群组：式(I)化合物、其医药上可接受的盐、及前述的组合，
Figure PCTCN2021071685-appb-000002
其中，A为视需要含有羰基的C1-C8脂肪族烃基；X为H或OH；Y为O；以及R 1为H或不存在，其条件为，当R 1不存在时，Y与A键结形成一五元环，且其中，该抗癌药物选自以下所组成的群组：拓扑异构酶抑制剂(topoisomerase inhibitor)、微小管聚合抑制剂(microtubule assembly inhibitor)、铂基试剂(platinum-based agent)、抗代谢药物(antimetabolite)、及前述的组合。
本发明的另一目的，在于提供一种使用一第一活性成分与一第二活性成分在制备一用于治疗癌症的医药组成物的用途，其中该第一活性成分选自以下所组成的群组：式(I)化合物、其医药上可接受的盐、及前述的组合，
Figure PCTCN2021071685-appb-000003
其中，A为视需要含有羰基的C1-C8脂肪族烃基；X为H或OH；Y为O；以及R 1为H或不存在，其条件为，当R 1不存在时，Y与A键结形成一五元环，且其中，该第二活性成分选自以下所组成的群组：拓扑异构酶抑制剂、微小管聚合抑制剂、铂基试剂、抗代谢药物、及前述的组合。
本发明的又一目的，在于提供一种组合，其包含一第一组分与一第二组分，其中该第一组分选自以下所组成的群组：式(I)化合物、其医药上可接受的盐、及前述的组合，
Figure PCTCN2021071685-appb-000004
其中，A为视需要含有羰基的C1-C8脂肪族烃基；X为H或OH；Y为O；以及
R 1为H或不存在，其条件为，当R 1不存在时，Y与A键结形成一五元环，且其中，该第二组分选自以下所组成的群组：拓扑异构酶抑制剂、微小管聚合抑制剂、铂基试剂、抗代谢药物、及前述的组合。较佳地，该组合呈一医药组成物或套组的形式。其中，于根据本发明所提供的组合之一具体实施方案，该组合用于癌症治疗。
本发明的再一目的，在于提供一种治疗癌症的方法，其包含对一有需要的个体投予如上述的组合。
于上述根据本发明的用途、组合或方法中，所涉式(I)化合物较佳为其中A为C1-C6脂肪族烃基，R 1为不存在，更佳地，A为C5烷基或烯基；或者其中A为含有羰基的C1-C6脂肪族烃基，且R 1为H，更佳地，A为含有羰基的C5烷基或烯基。
于上述根据本发明的用途、组合或方法中，若所涉为式(I)化合物的医药上可接受的盐，则该医药上可接受的盐较佳是以下的至少一者：锂盐、钠盐、钾盐、镁盐、钙盐、及锌盐。
于上述根据本发明的用途、组合或方法中，所涉抗癌药物、第二活性成分、或第二组分较佳是选自以下所组成的群组：依瑞诺丁(irinotecan)、托普迪肯(topotecan)、依托泊苷(etoposide)、双羟蒽醌(mitoxantrone)、替尼泊苷(teniposide)、阿扎胞苷(azacitidine)、5-氟尿嘧啶(5-fluorouracil，5-FU)、替加氟(tegafur)、替吉奥(TS-1)、6-巯基嘌呤(6-mercaptopurine，6-MP)、 硫唑嘌呤(azathioprine)、卡培他滨(capecitabine)、克拉屈滨(cladribine)、氯法拉滨(clofarabine)、阿糖胞苷(cytosine arabinoside，Ara-C)、地西他滨(decitabine)、脱氧氟尿苷(floxuridine)、氟达拉滨(fludarabine)、吉希他滨(gemcitabine)、羰基脲(hydroxyurea)、氨甲蝶呤(methotrexate)、奈拉滨(nelarabine)、培美曲塞(pemetrexed)、喷司他丁(pentostatin)、普拉曲沙(pralatrexate)、硫鸟嘌呤(thioguanine)、三氟胸苷/替吡嘧啶组成(trifluridine/tipiracil combination)、顺铂(cisplatin)、奥沙利铂(oxaliplatin)、太平洋紫杉醇(paclitaxel)、欧洲紫杉醇(docetaxel)、及前述的组合。
于上述根据本发明的用途、组合或方法中，所涉癌症较佳是以下的至少一种：大肠直肠癌、大肠癌、肺癌、胰脏癌、膀胱癌、胆管癌、直肠癌、乳癌、多发性骨髓瘤、妇科肿瘤、脑癌、睪丸癌、白血病、淋巴瘤、胸膜间皮瘤、胃癌、及肝癌。
附图说明
图1所示为，以西方墨点法(Western Blotting)分析经不同浓度的Z-亚丁基苯酞处理的Panc02细胞的CD44ICD蛋白、PD-L1蛋白、及GAPDH蛋白的表现量的照片图。
图2所示为，在将Panc02细胞注射到小鼠体内第15天所拍摄的各组小鼠的胰脏肿瘤的照片图(虚线所示圆圈部分即为肿瘤)，包括“Control”组、“LD”组(low dose)、“HD”组(high dose)、“Gem”组(gemcitabine)、“LD+Gem”组、“TS-1”组及“LD+TS-1”的结果。
图3所示为，分析图2中虚线所示圆圈部分的肿瘤大小的长条图(*表示相比于控制组的p值<0.05；**表示相比于控制组的p值<0.005)。
图4所示为，在将Panc02细胞注射到小鼠体内第1、15及22天所测得的肿瘤大小(以光子通量(Photon Flux)表示)，包括“Cisplatin”组及 “Z-BP+Cisplatin”组的结果。
图5A至图5D所示为，经不同处理的胰脏癌小鼠的存活率的曲线图。
图6所示为，经不同处理的胰脏癌小鼠的胰脏肿瘤组织中CD44蛋白、CD44ICD蛋白、PD-1蛋白、PD-L1蛋白、p-Akt蛋白、Akt蛋白、及GAPDH蛋白的表现量的照片图。
具体实施方式
本发明的详细技术内容及部分具体实施方案，将描述于以下内容中，以供本发明所属领域技术人员据以明了本发明的特征；但，在不背离本发明精神下，本发明尚可以多种不同形式的方案来实践，不应将本发明保护范围解释为限于说明书所具体陈述者。
除非文中有另外说明，于本说明书中(尤其是在后述专利申请范围中)所使用的“一”、“该”及类似用语应理解为包含单数及复数形式；所谓“个体”指人类或非人的哺乳动物(例如：狗、猫)。
“反应率(response rate)”的定义为在观察期的任一时段内，对治疗出现反应的病人比例，而反应大小(指肿瘤缩小的程度)可分为完全反应(肿瘤消除)、部分反应(肿瘤消除至少50％)。举例来说，某抗癌药物其“反应率40％”，表示此药物可以使四成接受此药物治疗的病人产生抗癌效果，而所称效果包括使肿瘤缩小至少50％，甚至完全消失。
临床研究显示，部分病患在接受化学疗法后，会有低药物反应率及高细胞/组织毒性的问题。本案发明人研究发现，相比于单独使用抗癌药物，将本发明化合物(即，式(I)化合物)或其盐与抗癌药物并用，可以提升癌细胞对抗癌药物的敏感性，有效降低抗癌药物的投药量，进而达到减少抗癌药物副作用、逆转抗癌药物引起的免疫抑制性、以及减缓癌症个体的恶病质症状的目的。
因此，本发明是关于式(I)化合物及/或其医药上可接受的盐在癌症治疗的应用：
Figure PCTCN2021071685-appb-000005
其中，A为视需要含有羰基的C1-C8脂肪族烃基；X为H或OH；Y为O；以及R1为H或不存在，其条件为，当R1不存在时，Y与A键结形成一五元环。
前述应用包括：(i)使用式(I)化合物及/或其医药上可接受的盐于制备一与抗癌药物并用在癌症治疗以提升癌细胞对抗癌药物的敏感性、降低抗癌药物投药量、减少抗癌药物副作用、逆转抗癌药物引起的免疫抑制性及/或减缓癌症个体的恶病质症状的医药组成物的用途、(ii)使用作为第一活性成分的式(I)化合物及/或其医药上可接受的盐与作为第二活性成分的抗癌药物在制备一用于治疗癌症的医药组成物的用途、(iii)一种组合，包含作为第一组分的式(I)化合物及/或其医药上可接受的盐、以及作为第二组分的抗癌药物、以及(iv)一种治疗癌症的方法，包含对一有需要的个体投予前述组合。
于根据本发明的应用中，所涉式(I)化合物较佳为其中A为C1-C6脂肪族烃基(更佳A为C5烷基或烯基)且R 1为不存在、或其中A为含有羰基的C1-C6脂肪族烃基(更佳A为含有羰基的C5烷基或烯基)且R 1为H。举例言之，于根据本发明应用的部分具体实施方案中，所涉式(I)化合物是Z-亚丁基苯酞、E-亚丁基苯酞、2-戊酰基苯甲酸、或丁基苯酞。
于根据本发明的应用中，所涉式(I)化合物的医药上可接受的盐的例子包括：锂盐、钠盐、钾盐、镁盐、钙盐、及锌盐。于根据本发明应用的部分具体实施方案中，所涉式(I)化合物的医药上可接受的盐是钠盐，例如：2-戊酰基苯甲酸钠。
于根据本发明的应用中，所涉式(I)化合物及其医药上可接受的盐可以为由商业上购得或经由本发明领域所知的合成方法制备而得者。
适用于本发明的应用以作为抗癌药物的例子包括：拓扑异构酶抑制剂 (topoisomerase inhibitor)、微小管聚合抑制剂(microtubule assembly inhibitor)、铂基试剂(platinum-based agent)、抗代谢药物(antimetabolite)、及前述的组合。较佳地，选自以下所组成的群组：依瑞诺丁(irinotecan)、托普迪肯(topotecan)、依托泊苷(etoposide)、双羟蒽醌(mitoxantrone)、替尼泊苷(teniposide)、阿扎胞苷(azacitidine)、5-氟尿嘧啶(5-fluorouracil，5-FU)、替加氟(tegafur)、替吉奥(TS-1；即，含5-FU前体药物tegafur的复合药物)、6-巯基嘌呤(6-mercaptopurine，6-MP)、硫唑嘌呤(azathioprine；即，6-MP的前体药物)、卡培他滨(capecitabine)、克拉屈滨(cladribine)、氯法拉滨(clofarabine)、阿糖胞苷(cytosine arabinoside，Ara-C)、地西他滨(decitabine)、脱氧氟尿苷(floxuridine)、氟达拉滨(fludarabine)、吉希他滨(gemcitabine)、羰基脲(hydroxyurea)、氨甲蝶呤(methotrexate)、奈拉滨(nelarabine)、培美曲塞(pemetrexed)、喷司他丁(pentostatin)、普拉曲沙(pralatrexate)、硫鸟嘌呤(thioguanine)、三氟胸苷/替吡嘧啶组成(trifluridine/tipiracil combination)、顺铂(cisplatin)、奥沙利铂(oxaliplatin)、太平洋紫杉醇(paclitaxel)、欧洲紫杉醇(docetaxel)、及前述的组合。于根据本发明应用的部分具体实施方案中，所涉抗癌药物是依瑞诺丁、5-氟尿嘧啶、替吉奥、吉希他滨、顺铂、奥沙利铂、与太平洋紫杉醇之一或多个。
根据本发明所提供的组合可以是一医药组成物或一套组。于根据本发明所提供的组合之一具体实施方案中，该组合用于癌症治疗。当根据本发明所提供的组合是一套组，该(1)作为第一组分的式(I)化合物及/或其医药上可接受的盐、以及(2)作为第二组分的抗癌药物通常是分开包装、各自储存于不同的容纳空间(例如塑料袋、塑胶瓶、玻璃瓶、安瓿(ampoule))中，且可各自分开运送或销售，也可组合成套一起配送与销售。此外，该套组可另包含一使用说明书，以利使用者在使用时，可根据其中所拟定的程序与流程，于现场才 混合各成分以进行处理及施用。
于根据本发明的应用中，所涉癌症的例子包括：大肠直肠癌、大肠癌、肺癌(例如非小细胞肺癌)、胰脏癌、膀胱癌、胆管癌、直肠癌、乳癌、多发性骨髓瘤、妇科肿瘤(例如子宫颈癌、卵巢瘤、子宫癌、外阴癌)、脑癌(例如脑胶质母细胞瘤)、睪丸癌、白血病(例如急性骨髓白血病)、淋巴瘤、胸膜间皮瘤、胃癌、及肝癌。
根据本发明所提供的医药组成物或套组的组分可用于全身性投药或局部性投药，且可通过各种药物传递系统(drug delivery system，DDS)进行传递，合宜的药物传递系统包括口服药物传递系统(oral drug delivery system)、经皮药物传递系统(transdermal drug delivery system)、注射药物传递系统(injectable drug delivery system)、吸入性药物传递系统(inhalation drug delivery system)、以及经黏膜药物传递系统(transmucosal drug delivery system)等。举例言之，但不以此为限，根据本发明所提供的医药组成物或套组的组分可以借由微脂体(liposome)、微胶囊(microcapsule)、奈米微粒(nanoparticle)、微针(microneedle)等系统进行传递，以达到提高生物利用率、控制药物释放速度、针对病灶精准投药、减少药物副作用等效果。
根据本发明所提供的医药组成物或套组的组分可呈现任何合宜的型式，并无特殊限制，端视所欲的用途而呈现对应的合宜剂型；举例言之，但不以此为限，该医药组成物或套组的组分可以口服、经皮(例如贴片、软膏等)、皮质脊髓注射(corticospinal tract injection)、鞘内注射(intrathecal injection)、脑内注射、静脉注射(包含点滴输注及快速注射)、肌肉注射、皮下注射、动脉注射、腹腔注射、皮下植入、组织间植入、经呼吸道(例如喷剂、鼻滴剂等)、经黏膜(例如口溶锭等)的投药方式施用至有需要的个体上。视使用形式及用途而定，可选用医药上可接受的载剂以提供该医药组成物或套组的组分，其中，该载剂为本领域已知可采用的，包括赋形剂、稀释剂、辅助剂、 安定剂、吸收促进剂、崩散剂、增溶剂、乳化剂、抗氧化剂、黏合剂、结合剂、增黏剂、分散剂、悬浮化剂、润滑剂、吸湿剂等。
以口服剂型为例，可利用任何合宜的方法，将该医药组成物或套组的组分以适于口服投药的剂型提供，其中，适于口服的液态剂型包括糖浆剂、口服液、悬浮液、酏剂等，适于口服的固态剂型则包括粉剂、颗粒剂、口含锭、糖衣锭、肠溶锭、咀嚼锭、发泡锭、膜衣锭、胶囊剂、长效缓释锭等。于根据本发明所提供的医药组成物或套组的组分中可含有任何不会不利地影响抗癌药物及/或式(I)化合物及其医药上可接受的盐的至少一种的所欲效益的医药上可接受的载剂。举例言之，但不以此为限，前述液态剂型的医药上可接受的载剂的例子包括：水、食盐水、葡萄糖(dextrose)、甘油、乙醇或其类似物、油(例如橄榄油、蓖麻油、棉籽油、花生油、玉米油、及胚芽油)、甘油、聚乙二醇、及前述的组合；前述固态剂型的医药上可接受的载剂的例子则包括：纤维素、淀粉、高岭土(kaolinite)、膨润土(bentonite)、柠檬酸钠、明胶、琼脂、羧甲基纤维素、阿拉伯胶、海藻胶、单硬脂酸甘油酯(glyceryl monostearate)、硬脂酸钙(calcium stearate)、及前述的组合。
也可于适于经皮投药的剂型中含有任何不会不利影响本发明医药组成物或套组所含抗癌药物及/或式(I)化合物及其医药上可接受的盐的至少一种的所欲效益的医药上可接受的载剂，例如：水、矿物油、丙二醇、聚氧化乙烯、液体石蜡脂、去水山梨醇单硬脂酸酯、及聚山梨醇酯60。可利用任何合宜的方法，将该医药组成物或套组的组分以适于经皮投药的剂型提供，例如以乳液、乳霜、油状物、凝胶(例如水凝胶)、膏状物(例如分散膏、软膏)、洗剂、喷雾剂、及贴片(例如微针贴片)等形式提供，但不以此为限。
适于注射的针剂或点滴剂，则可于根据本发明所提供的医药组成物或套组的组分中含有一种或多种例如等张溶液、盐类缓冲液(如磷酸盐缓冲液或柠檬酸盐缓冲液)、增溶剂、乳化剂、5％糖溶液、以及其他载剂等成分，以静脉输注 液、乳剂静脉输注液、干粉注射剂、悬液注射剂、或干粉悬液注射剂等剂型提供该医药组成物或套组的组分。或者，可将该医药组成物或套组的组分制备成一注射前固体，并于投予至有需要的个体之前，将该注射前固体溶于其他溶液或悬浮液中或将其乳化，以提供所欲的注射剂。
有关适于皮下植入、或组织间植入的剂型，则可于本发明所提供的医药组成物或套组的组分中另含有一种或多种例如赋形剂、安定剂、缓冲剂、以及其他载剂等成分，以例如芯片(wafer)、锭剂、丸剂、胶囊等剂型提供，从而得以将该医药组成物或套组的组分植入一个体中，以缓慢且持续的释放所含抗癌药物及/或式(I)化合物及其医药上可接受的盐的至少一种至投药部位周围的组织，达到局部稳定高剂量的毒杀癌细胞的功效。举例言之，但不以此为限，可于本发明所提供的医药组成物或套组的组分中含有一生物可兼容聚合物，使医药组成物或套组的组分呈一供皮下植入、或组织间植入的芯片剂型。前述生物可兼容聚合物可以为由商业上购得或经由本发明领域所知的合成方法制备而得者。举例言之，可以由双(对羧基苯氧基)丙烷与癸二酸所提供的聚酸酐(例如“p(CPP-SA)共聚物”)作为该生物可兼容聚合物。
有关经呼吸道投药的医药组成物或套组的组分，视需要地，可使用任何合宜的方法将该医药组成物或套组的组分气雾化，以利该医药组成物或套组的组分进入呼吸道中。举例言之，但不以此为限，该医药组成物或套组的组分可经由雾化器(nebulizer)、或加压容器而施用(例如鼻喷剂)。或者，可将该医药组成物或套组的组分制备成一鼻滴剂。
至于经黏膜投药的医药组成物或套组的组分，则可于根据本发明所提供的医药组成物或套组的组分中含有一种或多种穿透剂、界面活性剂、黏度调节剂、pH调节剂、防腐剂、稳定剂、渗透压调节剂、以及其他载剂等成分，以眼药水、眼药膏、口溶锭、塞剂、鼻喷剂、鼻滴剂等剂型提供该医药组成物或套组的组分。
视需要地，也可于根据本发明所提供的医药组成物或套组的组分中进一步含有合宜用量的添加物，例如可提高该组成物或套组于使用时感受的调色剂、着色剂等，以及可改善该组成物或套组的稳定性及储存性的缓冲剂、保存剂、防腐剂、抗菌剂、抗真菌剂等。
根据本发明所提供的医药组成物或套组的组分可以视需要另外含一中或多种其他活性成分，以进一步加强该组成物或套组的功效或增加制剂配方的运用灵活性与调配度，只要该其他活性成分对本发明医药组成物或套组所含抗癌药物及/或式(I)化合物及其医药上可接受的盐的至少一种的效益没有不利的影响即可。
根据本发明所提供的医药组成物中含有以该组成物的总重量计，至少约0.0001、0.0002、0.0003、0.0004、0.0005、0.001、0.0015、0.002、0.0025、0.003、0.0035、0.004、0.0045、0.005、0.0055、0.006、0.0065、0.007、0.0075、0.008、0.009、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或100重量％的式(I)化合物及其医药上可接受的盐的至少一种，且可自前述数值的任意二者选择有用的范围，例如：约0.0001重量％至约90重量％、约0.001重量％至约25重量％、约0.01重量％至约10重量％、约0.01重量％至约5重量％、约0.05重量％至约1重量％、及约0.05重量％至约0.5重量％。
根据本发明所提供的医药组成物或套组可以一日一次、一日多次、或数日一次等不同频率施用，端视投与个体的需求、年龄、体重、及健康况状及施用目的而异。也可视实际应用需求调整根据本发明所提供的医药组成物或套组中的抗癌药物及/或式(I)化合物及其医药上可接受的盐的至少一种的含量，例如：调整至每日应服用或外用的量。
于根据本发明的方法中，有关医药组成物或套组的施用方式、施用频 率、以及用量范围，均如上述的说明。
现以下列实施例进一步例示说明本发明。其中这些实施例仅提供作为说明，而非用以限制本发明的保护范围。本发明保护范围如权利要求书所示。
实施例
于以下制备实施例中，所使用的物料及器材如下：
1.人类胰脏癌细胞株：Mia-PaCa2细胞(购自生物资源保存及研究中心(Bioresource Collection and Research Center；网址：https://www.bcrc.firdi.org.tw/wwwbcrc/index.do)；BCRC 60319)、PANC-1细胞(购自生物资源保存及研究中心；BCRC 60284)、AsPC-1细胞(购自生物资源保存及研究中心；BCRC 60494)。
2.小鼠胰脏癌细胞株：Panc02细胞(长弘生物科技股份有限公司(长弘生技，Everfront Biotech Inc.)提供)。
3.肺癌细胞株：A549细胞(购自生物资源保存及研究中心；BCRC 60074)。
4.脑癌细胞株：DBTRG-05MG细胞(购自生物资源保存及研究中心；BCRC 60380)。
5.大肠直肠癌细胞株：HT-29细胞(购自生物资源保存及研究中心；BCRC 67003)。
6.肝癌细胞株：HepG2细胞(购自生物资源保存及研究中心；BCRC 60177)。
7.Mia-PaCa2细胞的培养液；含有L-麸酰胺酸(L-glutamine)、丙酮酸钠(sodium pyruvate；购自Thermo Fisher Scientific)、10％胎牛血清(Fetal Calf Serum，FCS；购自Gibco；产品编号：1939760)、1％青霉素/链霉素(penicillin/streptomycin，P/S；购自Simply；产品编号：CC502-0100)、及2.3％马血清(购自Gibco；产品编号：16050122)的DMEM-HG培养液(Dulbecco's modified Eagle's medium-High Glucose)。
8.PANC-1细胞的培养液：含有10％胎牛血清及1％青霉素/链霉素的DMEM-HG培养液。
9.AsPC-1细胞的培养液：含有10％胎牛血清、1％青霉素/链霉素、10毫莫耳浓度(mM)HEPES(购自Biomedicals；产品编号：194549)、及1毫莫耳浓度丙酮酸钠的RPMI1640培养液(购自HyClone)。
10.Panc02细胞的培养液：含有10％胎牛血清及1％青霉素/链霉素的RPMI1640培养液。
11.A549细胞的培养液：含有10％胎牛血清的DMEM培养液。
12.DBTRG-05MG细胞的培养液：含有10％胎牛血清及1毫莫耳浓度丙酮酸钠的RPMI1640培养液。
13.HT-29细胞的培养液：含有10％胎牛血清的RPMI1640培养液。
14.HepG2细胞的培养液：含有10％胎牛血清的DMEM培养液。
15.Z-亚丁基苯酞((Z)-n-butylidenephthalide，Z-BP)：由长弘生技提供；纯度99.8％。
16.E-亚丁基苯酞((E)-n-butylidenephthalide，E-BP)：由长弘生技提供；纯度98.01％。
17.2-戊酰基苯甲酸(2-pentanolybenzoic acid，BP-OH)：由长弘生技提供；纯度99.6％。
18.2-戊酰基苯甲酸钠(sodium 2-pentanoylbenzoate，BPONa)：由长弘生技提供；纯度99.7％。
19.丁基苯酞(butylphthalide)：由长弘生技提供；纯度≥97％。
20.吉希他滨(gemcitabine，GEM)：购自APEXBio；产品编号：A8437。
21.5-氟尿嘧啶(5-fluorouracil，5-FU)：购自Sigma；产品编号：F6627。
22.依瑞诺丁(irinotecan，CPT-11)：购自Sigma；产品编号：I1406。
23.顺铂(cisplatin，CDDP)：购自Sigma；产品编号：C2210000。
24.奥沙利铂(oxaliplatin，OXA)：购自Sigma；产品编号：61825-94-3。
25.太平洋紫杉醇(paclitaxel，PTX)：购自Sigma；产品编号：33069-62-4。
26.替吉奥(TS-1)：由长弘生技提供。
27.MTT(噻唑蓝，3-[4,5-dimethylthiahiazo-2-y1]-2,4-dipheny-tetrazolium bromide)：购自ALFA Aesar TM；产品编号：L11939-000000-16AF。
28.ELISA reader：购自Thermo Fisher Scientific；型号：22662。
[根据细则9.2更正 02.02.2021]　
29.C57BL/6J小鼠（体重：18至22克）：购自实验动物中心（No.99,Lane130，Section1，Academia Road, Nangang District,Taipei City,Taiwan,China）。
30.西方墨点法(Western Blotting)所用抗体：anti-Akt antibody(购自Cell Signaling Technology；产品编号：#9272)；anti-phospho-Akt(Ser473)antibody(购自Cell Signaling Technology；产品编号：#9271)；anti-CD44 antibody(购自Abcam；产品编号：#ab24504)；anti-PD-L1 antibody(购自Abcam；产品编号：#ab238697)；anti-PD-1 antibody(购自BioLegend；产品编号：#367402)；anti-GAPDH antibody(购自Genetex；产品编号：GTX100118)。
实施例1：本发明化合物及不同抗癌药物对癌细胞的致死效果
本实施例是使用MTT(噻唑蓝，3-[4,5-dimethylthiahiazo-2-y1]-2,4-dipheny-tetrazolium bromide)细胞存活分析方法来研究本发明化合物及不同抗癌药物对癌细胞的致死效果。
1-1.本发明化合物及不同抗癌药物对胰脏癌细胞的致死效果
于96孔微量孔盘各孔中培养胰脏癌细胞株PANC-1、Mia-PaCa2、AsPC-1、及Panc02(每孔培养1×10 4个细胞；96孔微量孔盘放置于37℃、5％CO 2的培养箱内)，历时24小时。其后，分别以含有吉希他滨、顺铂、5-氟尿嘧啶、依瑞诺丁、奥 沙利铂、太平洋紫杉醇、Z-亚丁基苯酞、E-亚丁基苯酞、2-戊酰基苯甲酸、2-戊酰基苯甲酸钠、及丁基苯酞的培养液培养前述各细胞株，历时24、48及72小时。接着，再于96孔微量孔盘各孔中分别加入MTT(使MTT于各孔培养液中的最终浓度为0.5毫克/毫升)，并将96孔微量孔盘置于37℃、5％CO 2的培养箱内作用1.5小时。将培养液吸出后，加入100微升二甲基亚砜，然后用ELISA reader测量其在595奈米波长下的吸光值，据此计算细胞的存活率，并计算吉希他滨、顺铂、5-氟尿嘧啶、依瑞诺丁、奥沙利铂、太平洋紫杉醇、Z-亚丁基苯酞、E-亚丁基苯酞、2-戊酰基苯甲酸、2-戊酰基苯甲酸钠、及丁基苯酞对各胰脏癌细胞株达到50％致死率的浓度值(IC 50)。结果示于表1。
表1：IC 50(单位：微克/毫升)
Figure PCTCN2021071685-appb-000006
Figure PCTCN2021071685-appb-000007
1-2.本发明化合物及5-氟尿嘧啶对癌细胞的致死效果
于96孔微量孔盘各孔中培养肺癌细胞株(A549细胞)、肝癌细胞株(HepG2细胞)、大肠直肠癌细胞株(HT-29细胞)、及脑癌细胞株(DBTRG-05MG细胞)(每孔培养1×10 4个细胞；96孔微量孔盘放置于37℃、5％CO 2的培养箱内)，历时24小时。其后，分别以含有5-氟尿嘧啶、Z-亚丁基苯酞、及2-戊酰基苯甲酸的培养液培养前述各细胞株，历时24、48及72小时。接着，再于96孔微量孔盘各孔中分别加入MTT溶液(0.5毫克/毫升)，放置在37℃、5％CO 2的培养箱内作用1.5小时。将培养液吸出后，加入100微升二甲基亚砜，然后用ELISA reader测量其在595奈米波长下的吸光值，据此计算细胞的存活率，并计算5-氟尿嘧啶、Z-亚丁基苯酞、及2-戊酰基苯甲酸对各癌细胞株达到50％致死率的浓度值(IC 50)。结果示于表2。
表2：IC 50(单位：微克/毫升)
  A549 HepG2 HT-29 DBTRG-05MG
5-氟尿嘧啶 8.55±0.22 4.44±0.25 20.80±0.91 55.45±6.10
Z-亚丁基苯酞 63.60±0.06 81.10±0.02 52.90±0.01 132.6±0.00
2-戊酰基苯甲酸 795.5±0.02 1141.5±0.01 443.8±0.04 392.8±0.01
实施例2：本发明化合物抗癌药物并用的效果
2-1.Z-亚丁基苯酞与5-氟尿嘧啶
于96孔微量孔盘各孔中培养胰脏癌细胞株(PANC-1、Mia-PaCa2、及AsPC-1)、肺癌细胞株(A549细胞)、肝癌细胞株(HepG2细胞)、大肠直肠癌细胞株(HT-29细胞)、及脑癌细胞株(DBTRG-05MG细胞)(每孔培养1×10 4个细胞；96孔微量孔盘放置于37℃、5％CO 2的培养箱内)，历时24小时。其后，于各细胞的培养液中同时添加Z-亚丁基苯酞与5-氟尿嘧啶。将96孔微量孔盘置于37℃、5％CO 2的培养箱内作用1.5小时之后，将培养液吸出并加入100微升二甲基亚砜，并使用 ELISA reader测量其在595奈米波长下的吸光值，据此计算细胞的存活率，并计算前述处理对各癌细胞株达到50％致死率的浓度值(IC 50)。最后，再经由公式A计算药物合并指数(Combination index，CI)。结果示于表3。
公式A：
Figure PCTCN2021071685-appb-000008
(D)1、(D)2分别表示药物1及药物2在并用的情况下的IC 50，(Dx)1、(Dx)2则分别表示该两种药物在单独使用的情况下的IC 50。若药物合并指数(CI)小于1，则代表该两种药物的并用具有协同效果(synergistic effect)。
表3：Z-亚丁基苯酞与5-氟尿嘧啶的并用于毒杀癌细胞的CI值
细胞株 CI
PANC-1 0.39
Mia-PaCa2 0.27
AsPC-1 0.58
A549 0.34
HepG2 0.46
HT-29 0.26
DBTRG-05MG 0.22
表3结果显示，Z-亚丁基苯酞与5-氟尿嘧啶的并用于毒杀癌细胞的CI值皆小于1，具有协同效果。
2-2.Z-亚丁基苯酞与其他抗癌药物
比照实施例2-1的方式，合并使用Z-亚丁基苯酞与其他抗癌药物以处理胰脏癌细胞，并计算实验数据以获得前述并用于毒杀胰脏癌细胞的CI值。结果示于表4。
表4：Z-亚丁基苯酞(Z-BP)与其他抗癌药物的并用于毒杀胰脏癌细胞的CI值
  PANC-1 Mia-PaCa2 AsPC-1 Panc02
Z-BP+吉希他滨 0.21 0.64 0.44 0.67
Z-BP+顺铂 0.38 0.43 0.50 0.39
Z-BP+依瑞诺丁 0.61 0.36 0.42 0.41
Z-BP+奥沙利铂 0.57 0.90 0.80 0.87
Z-BP+太平洋紫杉醇 0.19 0.54 0.49 0.95
表4结果显示，Z-亚丁基苯酞与其他抗癌药物的并用于毒杀癌细胞的CI值皆小于1，具有协同效果。
2-3.E-亚丁基苯酞与抗癌药物
比照实施例2-1的方式，合并使用E-亚丁基苯酞与奥沙利铂、太平洋紫杉醇、吉希他滨、5-氟尿嘧啶等抗癌药物以处理胰脏癌细胞，并计算实验数据以获得前述并用于毒杀胰脏癌细胞的CI值。结果示于表5至表7。
表5：E-亚丁基苯酞(E-BP)与奥沙利铂或太平洋紫杉醇的并用于毒杀胰脏
癌细胞的CI值
  PANC-1 Mia-PaCa2 Panc02
E-BP+奥沙利铂 0.89 0.96 0.54
E-BP+太平洋紫杉醇 0.69 0.97 0.73
表6：E-亚丁基苯酞与吉希他滨的并用于毒杀胰脏癌细胞的CI值
  PANC-1 Mia-PaCa2
E-BP+吉希他滨 0.95 0.64
表7：E-亚丁基苯酞(E-BP)与5-氟尿嘧啶的并用于毒杀胰脏癌细胞的CI值
  Mia-PaCa2
E-BP+5-氟尿嘧啶 0.79
表5至表7的结果显示，E-亚丁基苯酞与抗癌药物的并用于毒杀癌细胞的CI 值皆小于1，具有协同效果。
2-4. 2-戊酰基苯甲酸(BP-OH)与抗癌药物
比照实施例2-1的方式，合并使用2-戊酰基苯甲酸(BP-OH)与5-氟尿嘧啶、吉希他滨、奥沙利铂、太平洋紫杉醇等抗癌药物以处理胰脏癌细胞株(PANC-1、Mia-PaCa2、AsPC-1、及Panc02)、肺癌细胞株(A549细胞)、肝癌细胞株(HepG2细胞)、大肠直肠癌细胞株(HT-29细胞)、及脑癌细胞株(DBTRG-05MG细胞)，并计算实验数据以获得前述并用于毒杀各癌细胞的CI值。结果示于表8至表11。
表8：2-戊酰基苯甲酸(BP-OH)与5-氟尿嘧啶的并用于毒杀癌细胞的CI值
细胞株 CI
PANC-1 0.57
Mia-PaCa2 0.84
AsPC-1 0.96
Panc02 0.88
A549 0.54
HepG2 0.73
HT-29 0.79
DBTRG-05MG 0.80
表9：2-戊酰基苯甲酸(BP-OH)与吉希他滨的并用于毒杀胰脏癌细胞的CI值
  PANC-1 Mia-PaCa2
BP-OH+吉希他滨 0.93 0.49
表10：2-戊酰基苯甲酸(BP-OH)与奥沙利铂的并用于毒杀胰脏癌细胞的CI值
  PANC-1 Mia-PaCa2 Panc02
BP-OH+奥沙利铂 0.92 0.79 0.23
表11：2-戊酰基苯甲酸(BP-OH)与太平洋紫杉醇的并用于毒杀胰脏癌细胞的CI值
  PANC-1 Panc02
BP-OH+太平洋紫杉醇 0.61 0.52
表8至表11的结果显示，2-戊酰基苯甲酸(BP-OH)与抗癌药物的并用于毒杀癌细胞的CI值皆小于1，具有协同效果。
2-4. 2-戊酰基苯甲酸钠(BPONa)与抗癌药物
比照实施例2-1的方式，合并使用2-戊酰基苯甲酸钠(BPONa)与奥沙利铂、吉希他滨、5-氟尿嘧啶、太平洋紫杉醇等抗癌药物以处理胰脏癌细胞，并计算实验数据以获得前述并用于毒杀胰脏癌细胞的CI值。结果示于表12至表14。
表12：2-戊酰基苯甲酸钠(BPONa)与奥沙利铂的并用于毒杀胰脏癌细胞的CI值
  PANC-1 Mia-PaCa2 AsPC-1 Panc02
BPONa+奥沙利铂 0.70 0.93 0.89 0.22
表13：2-戊酰基苯甲酸钠(BPONa)与吉希他滨的并用于毒杀胰脏癌细胞的CI值
  Mia-PaCa2 AsPC-1 Panc02
BPONa+吉希他滨 0.82 0.93 0.55
表14：2-戊酰基苯甲酸钠(BPONa)与5-氟尿嘧啶或太平洋紫杉醇的并用于毒杀胰脏癌细胞的CI值
  PANC-1 Panc02
BPONa+5-氟尿嘧啶 0.66 0.78
BPONa+太平洋紫杉醇 0.57 0.60
表12至表14的结果显示，2-戊酰基苯甲酸钠(BPONa)与抗癌药物的并用于毒杀癌细胞的CI值皆小于1，具有协同效果。
由本实施例的实验结果可知，相比于单独使用抗癌药物，将本发明式(I)化合物或其盐与抗癌药物并用，可以提升癌细胞对抗癌药物的敏感性，有效降低抗癌药物的投药量，进而达到减少抗癌药物副作用、逆转抗癌药物引起的免疫抑制性、以及减缓癌症个体的恶病质症状的目的。
实施例3：本发明化合物于降低癌细胞表现CD44及PD-L1的效果
已知，癌细胞表面的程序性死亡受体-配体1(Programmed death-ligand 1，PD-L1)会与免疫细胞上的程序性死亡受体-1(Programmed death 1，PD-1)结合，造成免疫细胞死亡。此外，CD44与CD44ICD会促进PD-L1的表现，而CD44的调降会造成癌细胞生长抑制，前述可参见例如：CD44 promotes PD-L1 expression and its tumor-intrinsic function in breast and lung cancers.Cancer Research.2020 Feb 1；80(3):444-457.，该文献的全文并于此处以供参考。
分别以37.5及75微克/毫升(μg/ml)的Z-亚丁基苯酞，对Panc02细胞(胰脏癌细胞株)进行培养，历时6小时(期间于培养经过3小时的时点收取一部份细胞)。接着，萃取细胞的蛋白质，并以西方墨点法(Western Blotting)检测经Z-亚丁基苯酞处理的癌细胞的CD44胞内结构域(CD44 intracellular domain，CD44ICD)蛋白及PD-L1蛋白的表现。此外，检测GAPDH蛋白的表现作为内部控制。结果示于图1。
由图1可知，Panc02细胞的CD44ICD蛋白及PD-L1蛋白的表现皆显著随Z-亚丁基苯酞的浓度提高而下降，其中，于第6小时即达到完全抑制CD44ICD蛋白的效果。前述结果显示，Z-亚丁基苯酞除了可以抑制癌细胞生长以外，更具有抑制癌细胞的CD44ICD蛋白，进而抑制免疫检查点抗原表现的效果，故可阻断癌细胞与免疫细胞的结合，从而逆转抗癌药物引起的免疫抑制性。
实施例4：并用本发明化合物与抗癌药物以治疗癌症
4-1.动物模型的建立
依照东华大学实验动物照护及使用小组(Institutional Animal Care and Use Committee，IACUC)的相关规定，将C57BL/6J小鼠饲养于东华大学实验动物中心，至八至十周龄。然后，将转染有Luc-eGFP的稳定构筑的Panc02细胞(1×10 6个/0.02毫升/每只小鼠)经原位注射到小鼠胰脏。接着，通过动物造影结果分析小鼠胰脏的肿瘤大小，再依平均肿瘤大小将小鼠分成九组，并分别以如下条件进行处理，历时三至四周：
(1)“Control(Ctl.)”组(5只)：未投药，仅每日经口服投予vehicle(不含本发明化合物及其他抗癌药物)。
(2)“LD”组(5只)：每日经口服投予低剂量(12.5毫克/公斤体重)的Z-亚丁基苯酞。
(3)“HD”“组(5只)：每日经口服投予高剂量(25毫克/公斤体重)的Z-亚丁基苯酞。
(4)“Gem”组(5只)：每三日经腹腔注射100毫克/公斤体重的吉希他滨(gemcitabine，GEM)。
(5)“LD+Gem”组(5只)：每日经口服投予12.5毫克/公斤体重的Z-亚丁基苯酞，且每三日经腹腔注射50毫克/公斤体重的吉希他滨(gemcitabine，GEM)。
(6)“TS-1”组(5只)：连续五日每日经口服投予100毫克/公斤体重的替吉奥(TS-1)后，暂停口服两日。
(7)“LD+TS-1”组(2只)：每日经口服投予12.5毫克/公斤体重的Z-亚丁基苯酞、以及连续五日每日经口服投予50毫克/公斤体重的替吉奥(TS-1)后，暂停口服TS-1两日。
(8)“Cisplatin”组(3只)：每七日经腹腔注射2.5毫克/公斤体重的顺铂(cisplatin)。
(9)“Z-BP+Cisplatin”组(3只)：每日经口服投予6.25毫克/公斤体重 的Z-亚丁基苯酞，且每七日经腹腔注射1.25毫克/公斤体重的顺铂(cisplatin)。
4-2.肿瘤大小的观察(T2权重磁振影像)
在将转染有Luc-eGFP的稳定构筑的Panc02细胞经原位注射到实施例4-1各组小鼠体内，并确认原位胰脏肿瘤生长后，开始以药物处理历时14天(即，第15天)，期间以T2权重磁振影像(T 2-weighted MRI)解析观察各组小鼠的胰脏肿瘤，并拍照纪录，结果示于图2。并且以amide软件分析图2中各组小鼠的肿瘤(虚线所示圆圈部分)大小，结果示于图3。
吉希他滨(gemcitabine，GEM)及替吉奥(TS-1)为临床上用于癌症治疗的药物，然而，如图3所显示，“Gem”组与“TS-1”组小鼠的肿瘤大小反而大于未投药的“Control”组(又称“‘Ctl’组”)。由前述结果可知，吉希他滨(gemcitabine，GEM)及替吉奥(TS-1)会引起肿瘤微环境(tumor microenvironment，TME)中的免疫抑制性，导致癌细胞对免疫系统产生抗药性。
图3也显示，“LD+Gem”组的肿瘤大小明显小于“Gem”组，且“LD+TS-1”组的肿瘤大小明显小于“TS-1”组。由前述结果可知，将本发明化合物或其盐与抗癌药物并用，可有效地逆转抗癌药物引起的免疫抑制性，更有效地抑制肿瘤生长。
4-3.肿瘤大小的观察(IVIS影像系统)
在将转染有Luc-eGFP的稳定构筑的Panc02细胞经原位注射到实施例4-1各组小鼠体内之后的第1、15及22天，以IVIS影像系统检测“Cisplatin”组及“Z-BP+Cisplatin”组小鼠的肿瘤大小(借由测量光子通量(Photon Flux)；单位：光子/秒/平方公分/球面度(ph/s/cm 2/sr))，结果示于图4。
由图4可知，相比于“Cisplatin”组，“Z-BP+Cisplatin”组于第22天所测得的光子通量明显较低。换言之，“Z-BP+Cisplatin”组的肿瘤大小明显低于“Cisplatin”组。前述结果再次显示，将本发明化合物或其盐与抗癌药物并用， 可有效提升抗癌药物抑制肿瘤生长的效果。
4-4.存活情形的观察
比照实施例4-1的方式建立胰脏癌小鼠，且每日观察各组小鼠的存活情形并记录，结果示于表15及图5A至图5D。
表15
Figure PCTCN2021071685-appb-000009
由表15及图5A至图5D可知，“LD”组小鼠的存活天数较“Control”组(又称“‘Ctl’组”)及“TS-1”组为高。此外，“LD”组与“Gem”组小鼠的存活天数为“Control”组的1.8倍，“LD+Gem”组小鼠的存活天数则为“Control”组 的2.1倍。
4-5.蛋白质表现的观察
待完成实施例4-2至4-3的观察后，将各组小鼠牺牲，取其胰脏肿瘤组织。接着，进行蛋白质萃取，并以西方墨点法(Western Blotting)检测各组织蛋白质样品中的CD44蛋白、CD44ICD蛋白、PD-1蛋白、PD-L1蛋白、p-Akt蛋白、及Akt蛋白的表现。此外，检测GAPDH蛋白的表现作为内部控制。结果示于图6。
由图6可知，“Gem”组与“TS-1”组小鼠的PD-1蛋白及PD-L1蛋白表现量反而高于未投药的“Control”组(又称“‘Ctl’组”)。前述结果再次显示，吉希他滨(gemcitabine，GEM)及替吉奥(TS-1)会引起肿瘤微环境(tumor microenvironment，TME)中的免疫抑制性，导致癌细胞对免疫系统产生抗药性。
图6也显示，“LD+Gem”组的CD44蛋白、CD44ICD蛋白、PD-1蛋白及PD-L1蛋白表现量明显低于“Gem”组，且“LD+TS-1”组的CD44蛋白、CD44ICD蛋白、PD-1蛋白及PD-L1蛋白表现量明显低于“TS-1”组。前述结果显示，Z-亚丁基苯酞具有抑制癌细胞的CD44蛋白、CD44ICD蛋白，进而抑制PD-1蛋白、PD-L1蛋白等免疫检查点抗原表现的效果，故可阻断癌细胞与免疫细胞的结合，从而逆转抗癌药物引起的免疫抑制性。前述结果再次说明，将本发明化合物或其盐与抗癌药物并用，可有效地逆转抗癌药物引起的免疫抑制性，有助于提升抗癌药物的药效。
此外，由图6也可知，p-Akt蛋白(即，活化形式的Akt蛋白(activated Akt)的表现随着PD-L1蛋白调降而减少。前述结果可验证，PD-L1讯号传递路径被抑制。
由本实施例的动物实验结果可知，将本发明式(I)化合物或其盐与抗癌药物并用于癌症动物的治疗，可提升动物体内癌细胞对抗癌药物的敏感性，有效降低抗癌药物的投药量，进而达到减少抗癌药物副作用、逆转抗癌药物引起的免疫抑制性、以及减缓癌症个体的恶病质症状的目的。

Claims (21)

  1. 一种使用一活性成分于制备一与抗癌药物并用在癌症治疗以提升癌细胞对抗癌药物的敏感性、降低抗癌药物投药量、减少抗癌药物副作用、逆转抗癌药物引起的免疫抑制性及/或减缓癌症个体的恶病质症状的医药组成物的用途，其特征在于，该活性成分选自以下所组成的群组：式(I)化合物、其医药上可接受的盐、及前述的组合，
    Figure PCTCN2021071685-appb-100001
    其中，
    A为视需要含有羰基的C1-C8脂肪族烃基；
    X为H或OH；
    Y为O；以及
    R 1为H或不存在，其条件为，当R 1不存在时，Y与A键结形成一五元环，且其中，该抗癌药物选自以下所组成的群组：拓扑异构酶抑制剂、微小管聚合抑制剂、铂基试剂、抗代谢药物、及前述的组合。
  2. 一种使用一第一活性成分与一第二活性成分在制备一用于治疗癌症的医药组成物的用途，其特征在于，该第一活性成分选自以下所组成的群组：式(I)化合物、其医药上可接受的盐、及前述的组合，
    Figure PCTCN2021071685-appb-100002
    其中，
    A为视需要含有羰基的C1-C8脂肪族烃基；
    X为H或OH；
    Y为O；以及
    R 1为H或不存在，其条件为，当R 1不存在时，Y与A键结形成一五元环，且其中，该第二活性成分选自以下所组成的群组：拓扑异构酶抑制剂、微小管聚合抑制剂、铂基试剂、抗代谢药物、及前述的组合。
  3. 如权利要求1或2的用途，其特征在于，A为C1-C6脂肪族烃基，R 1为不存在。
  4. 如权利要求1或2的用途，其特征在于，A为含有羰基的C1-C6脂肪族烃基，且R 1为H。
  5. 如权利要求3的用途，其特征在于，A为C5烷基或烯基。
  6. 如权利要求4的用途，其特征在于，A为含有羰基的C5烷基或烯基。
  7. 如权利要求4的用途，其特征在于，该医药上可接受的盐是以下的至少一种：锂盐、钠盐、钾盐、镁盐、钙盐、及锌盐。
  8. 如权利要求1的用途，其特征在于，该抗癌药物选自以下所组成的群组：依瑞诺丁、托普迪肯、依托泊苷、双羟蒽醌、替尼泊苷、阿扎胞苷、5-氟尿嘧啶、替加氟、替吉奥、6-巯基嘌呤、硫唑嘌呤、卡培他滨、克拉屈滨、氯法拉滨、阿糖胞苷、地西他滨、脱氧氟尿苷、氟达拉滨、吉希他滨、羰基脲、氨甲蝶呤、奈拉滨、培美曲塞、喷司他丁、普拉曲沙、硫鸟嘌呤、三氟胸苷/替吡嘧啶组成、顺铂、奥沙利铂、太平洋紫杉醇、欧洲紫杉醇、及前述的组合。
  9. 如权利要求2的用途，其特征在于，该第二活性成分选自以下所组成的群组：依瑞诺丁、托普迪肯、依托泊、双羟蒽醌、替尼泊苷、阿扎胞苷、5-氟尿嘧啶、替加氟、替吉奥、6-巯基嘌呤、硫唑嘌呤、卡培他滨、克拉屈滨、氯法拉滨、阿糖胞苷、地西他滨、脱氧氟尿苷、氟达拉滨、吉希他滨、羰基脲、氨甲蝶呤、奈拉滨、培美曲塞、喷司他丁、普拉曲沙、硫鸟嘌呤、三氟胸苷/替吡嘧啶组成、顺铂、奥沙利铂、太平洋紫杉醇、欧洲紫杉醇、及前述的组合。
  10. 如权利要求1或2的用途，其特征在于，该癌症是以下的至少一种：大肠直肠癌、大肠癌、肺癌、胰脏癌、膀胱癌、胆管癌、直肠癌、乳癌、多发性骨髓瘤、妇科肿瘤、脑癌、睪丸癌、白血病、淋巴瘤、胸膜间皮瘤、胃癌、及肝癌。
  11. 一种组合，其包含一第一组分与一第二组分，其中该第一组分选自以下所组成的群组：式(I)化合物、其医药上可接受的盐、及前述的组合，
    Figure PCTCN2021071685-appb-100003
    其中，
    A为视需要含有羰基的C1-C8脂肪族烃基；
    X为H或OH；
    Y为O；以及
    R 1为H或不存在，其条件为，当R 1不存在时，Y与A键结形成一五元环，且其中，该第二组分选自以下所组成的群组：拓扑异构酶抑制剂、微小管聚合抑制剂、铂基试剂、抗代谢药物、及前述的组合。
  12. 如权利要求11的组合，其特征在于，A为C1-C6脂肪族烃基，R 1为不存在。
  13. 如权利要求11的组合，其特征在于，A为含有羰基的C1-C6脂肪族烃基，且R 1为H。
  14. 如权利要求12的组合，其特征在于，A为C5烷基或烯基。
  15. 如权利要求13的组合，其特征在于，A为含有羰基的C5烷基或烯基。
  16. 如权利要求13的组合，其特征在于，该医药上可接受的盐是以下的至少一种：锂盐、钠盐、钾盐、镁盐、钙盐、及锌盐。
  17. 如权利要求11的组合，其特征在于，该第二组分选自以下所组成的群组：依瑞诺丁、托普迪肯、依托泊苷、双羟蒽醌、替尼泊苷、阿扎胞苷、5-氟尿 嘧啶、替加氟、替吉奥、6-巯基嘌呤、硫唑嘌呤、卡培他滨、克拉屈滨、氯法拉滨、阿糖胞苷、地西他滨、脱氧氟尿苷、氟达拉滨、吉希他滨、羰基脲、氨甲蝶呤、奈拉滨、培美曲塞、喷司他丁、普拉曲沙、硫鸟嘌呤、三氟胸苷/替吡嘧啶组成、顺铂、奥沙利铂、太平洋紫杉醇、欧洲紫杉醇、及前述的组合。
  18. 如权利要求11至17中任一项的组合，其特征在于，该组合呈一医药组成物或套组的形式。
  19. 如权利要求11至17中任一项的组合，其特征在于，其用于癌症治疗。
  20. 一种治疗癌症的方法，其包含对一有需要的个体投予如权利要求11至18中任一项的组合。
  21. 如权利要求20的方法，其特征在于，该癌症是以下的至少一种：大肠直肠癌、大肠癌、肺癌、胰脏癌、膀胱癌、胆管癌、直肠癌、乳癌、多发性骨髓瘤、妇科肿瘤、脑癌、睪丸癌、白血病、淋巴瘤、胸膜间皮瘤、胃癌、及肝癌。
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