WO2021197333A1 - 药物组合及其用途 - Google Patents

药物组合及其用途 Download PDF

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WO2021197333A1
WO2021197333A1 PCT/CN2021/084008 CN2021084008W WO2021197333A1 WO 2021197333 A1 WO2021197333 A1 WO 2021197333A1 CN 2021084008 W CN2021084008 W CN 2021084008W WO 2021197333 A1 WO2021197333 A1 WO 2021197333A1
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inhibitor
ascorbic acid
therapeutic agent
derivative
signaling pathway
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PCT/CN2021/084008
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English (en)
French (fr)
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许诺
林坚
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浙江养生堂天然药物研究所有限公司
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Priority to EP21780063.0A priority Critical patent/EP4129283A4/en
Priority to US17/915,275 priority patent/US20230130144A1/en
Priority to CN202180023639.XA priority patent/CN115361945A/zh
Publication of WO2021197333A1 publication Critical patent/WO2021197333A1/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/609—Amides, e.g. salicylamide
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • This application relates to the field of biomedicine, in particular to a drug combination and its use.
  • the current drugs used to treat osteosarcoma are high-dose methotrexate, ifosfamide, doxorubicin, cisplatin, etc., or two or two
  • methotrexate ifosfamide, doxorubicin, cisplatin, etc.
  • colorectal cancer accounts for 10.2% of the total incidence of cancer and 9.2% of the deaths, that is, about 185 colorectal cancers each year 10,000 new cases and 880,000 deaths.
  • the clinical treatment of colorectal cancer is mainly oxaliplatin.
  • This application provides a drug combination and its use or administration method, which mainly includes Notch signaling pathway inhibitor, HH signaling pathway inhibitor, Porcupine inhibitor, RXR ⁇ inhibitor, Niclosamide, CK1a inhibitor and/or Frizzled receptor
  • the therapeutic agent of the inhibitor is combined with ascorbic acid or its derivatives as a drug for the treatment of tumors, or the therapeutic agent containing Notch signaling pathway inhibitor, HH signaling pathway inhibitor, RXR ⁇ inhibitor and/or Wnt signaling pathway inhibitor is combined with ascorbic acid or
  • the combination of its derivatives to treat tumors has at least one of the following technical effects:
  • the drug combination can be used as an alternative therapy to traditional chemotherapy drugs to avoid the side effects of traditional chemotherapy on the human body.
  • the drug combination can be combined with traditional chemotherapy drugs to reduce the dose of chemotherapy drugs, thereby reducing the side effects of traditional chemotherapy drugs.
  • the combination of drugs has an unexpected inhibitory effect on tumors, significantly reduces the dose of a single drug with the same effect, and improves the safety of medication.
  • the application provides a drug combination, which comprises:
  • a second therapeutic agent selected from the group consisting of Notch signaling pathway inhibitors, HH signaling pathway inhibitors, Porcupine inhibitors, RXR ⁇ inhibitors, Niclosamide, CK1a inhibitors and Frizzled receptor inhibitors Agent.
  • the RXR ⁇ inhibitor comprises berberine or a pharmaceutically acceptable salt thereof.
  • the Notch signaling pathway inhibitor comprises a gamma-secretase inhibitor.
  • the ⁇ -secretase inhibitor comprises MK0752, RO4929097 and/or PF-03084014.
  • the HH signaling pathway inhibitor comprises an SMO inhibitor.
  • the SMO inhibitor comprises Vismodegib, Sonidegib, and/or Glasdegib.
  • the Porcupine inhibitor comprises LGK974 and/or ETC-159.
  • the CK1a inhibitor comprises Pyrvinium.
  • the Frizzled receptor inhibitor comprises Foxy-5.
  • the inhibitor comprises Fervenulin, 3-Methyltoxoflavin and/or Walrycin B.
  • the ascorbic acid derivative comprises a pharmaceutically acceptable salt of ascorbate.
  • the pharmaceutically acceptable ascorbate salt comprises sodium ascorbate.
  • the ratio of the effective amount of the second therapeutic agent to the effective amount of the ascorbic acid or derivative thereof is about 1:10 to about 1:5000.
  • the mass ratio of the second therapeutic agent to the ascorbic acid or derivative thereof is about 1:10 to about 1:5000.
  • the second therapeutic agent and the ascorbic acid or derivative thereof are each in a different container.
  • the pharmaceutical combination includes a first formulation and a second formulation
  • the first formulation includes the ascorbic acid or a derivative thereof and a pharmaceutically acceptable first carrier
  • the second formulation includes The second therapeutic agent and a pharmaceutically acceptable second carrier.
  • the pharmaceutical combination includes a pharmaceutical composition
  • the pharmaceutical composition includes the second therapeutic agent and the ascorbic acid or derivative thereof.
  • the content of the second therapeutic agent in the pharmaceutical composition is about 5% to about 20% (w/w).
  • the content of the ascorbic acid or its derivative in the pharmaceutical composition is about 80% to about 95% (w/w).
  • the present application also provides a kit, which includes the drug combination described in the present application.
  • the present application also provides the use of the combination of ascorbic acid or its derivative and a second therapeutic agent in the preparation of a medicament for the prevention and/or treatment of tumors, wherein the second therapeutic agent is selected from: Notch signaling pathway inhibitor, HH signaling pathway inhibitor, RXR ⁇ inhibitor and Wnt signaling pathway inhibitor.
  • the Wnt signaling pathway inhibitor comprises a Porcupine inhibitor, a Dvl-2 inhibitor, a CK1a inhibitor and/or a Frizzled receptor inhibitor.
  • the Porcupine inhibitor comprises LGK974 and/or ETC-159.
  • the Dvl-2 inhibitor comprises Niclosamide and/or Sulindac.
  • the CK1a inhibitor comprises Pyrvinium.
  • the Frizzled receptor inhibitor comprises Foxy-5.
  • the RXR ⁇ inhibitor comprises berberine or a pharmaceutically acceptable salt thereof.
  • the Notch signaling pathway inhibitor comprises a gamma-secretase inhibitor.
  • the ⁇ -secretase inhibitor comprises MK0752, RO4929097 and/or PF-03084014.
  • the HH signaling pathway inhibitor comprises an SMO inhibitor.
  • the SMO inhibitor comprises Vismodegib, Sonidegib, and/or Glasdegib.
  • the tumor includes solid tumors and non-solid tumors.
  • the solid tumor includes osteosarcoma and/or colon cancer.
  • the non-solid tumor includes lymphoma.
  • the ascorbic acid derivative comprises a pharmaceutically acceptable salt of ascorbate.
  • the pharmaceutically acceptable ascorbate salt comprises sodium ascorbate.
  • the second therapeutic agent and the ascorbic acid or derivative thereof are configured to be administered to the subject simultaneously.
  • the second therapeutic agent and the ascorbic acid or derivative thereof are configured to be administered to the subject separately.
  • the medicament is configured such that the second therapeutic agent is administered at a dose of about 1 mg/kg to about 100 mg/kg.
  • the medicament is configured such that the ascorbic acid or derivative thereof is administered at a dose of about 0.05 g/kg to about 2.5 g/kg.
  • the medicament is configured such that the second therapeutic agent and the ascorbic acid or derivative thereof are administered in a mass ratio of about 1:5 to about 1:5000.
  • the medicament is configured such that the second therapeutic agent and the ascorbic acid or derivative thereof are administered in a mass ratio of about 1:5 to about 1:5000.
  • this application also provides a method for preventing and/or treating tumors, which comprises administering to a subject in need:
  • a second therapeutic agent wherein the second therapeutic agent is selected from the group consisting of Notch signaling pathway inhibitors, HH signaling pathway inhibitors, RXR ⁇ inhibitors, and Wnt signaling pathway inhibitors.
  • the Wnt signaling pathway inhibitor comprises a Porcupine inhibitor, a Dvl-2 inhibitor, a CK1a inhibitor and/or a Frizzled receptor inhibitor.
  • the Porcupine inhibitor comprises LGK974 and/or ETC-159.
  • the Dvl-2 inhibitor comprises Niclosamide and/or Sulindac.
  • the CK1a inhibitor comprises Pyrvinium.
  • the Frizzled receptor inhibitor comprises Foxy-5.
  • the RXR ⁇ inhibitor comprises berberine or a pharmaceutically acceptable salt thereof.
  • the Notch signaling pathway inhibitor comprises a gamma-secretase inhibitor.
  • the ⁇ -secretase inhibitor comprises MK0752, RO4929097 and/or PF-03084014.
  • the HH signaling pathway inhibitor comprises an SMO inhibitor.
  • the SMO inhibitor comprises Vismodegib, Sonidegib, and/or Glasdegib.
  • the tumor includes solid tumors and non-solid tumors.
  • the solid tumor includes osteosarcoma and/or colon cancer.
  • the non-solid tumor includes lymphoma.
  • the ascorbic acid derivative comprises a pharmaceutically acceptable salt of ascorbate.
  • the pharmaceutically acceptable ascorbate salt comprises sodium ascorbate.
  • the second therapeutic agent and the ascorbic acid or derivative thereof are configured to be administered to the subject simultaneously.
  • the second therapeutic agent and the ascorbic acid or derivative thereof are configured to be administered to the subject separately.
  • the medicament is configured such that the second therapeutic agent is administered at a dose of about 1 mg/kg to about 100 mg/kg.
  • the medicament is configured such that the ascorbic acid or derivative thereof is administered at a dose of about 0.05 g/kg to about 2.5 g/kg.
  • the medicament is configured such that the second therapeutic agent and the ascorbic acid or derivative thereof are administered in a mass ratio of about 1:5 to about 1:5000.
  • the medicament is configured such that the second therapeutic agent and the ascorbic acid or derivative thereof are administered in a mass ratio of about 1:5 to about 1:5000.
  • this application also provides a method for monitoring the response of the subject to the drug, and the method includes:
  • the Wnt signaling pathway inhibitor comprises a Porcupine inhibitor, a Dvl-2 inhibitor, a CK1a inhibitor and/or a Frizzled receptor inhibitor.
  • the Porcupine inhibitor comprises LGK974 and/or ETC-159.
  • the Dvl-2 inhibitor comprises Niclosamide and/or Sulindac.
  • the CK1a inhibitor comprises Pyrvinium.
  • the Frizzled receptor inhibitor comprises Foxy-5.
  • the RXR ⁇ inhibitor comprises berberine or a pharmaceutically acceptable salt thereof.
  • the Notch signaling pathway inhibitor comprises a gamma-secretase inhibitor.
  • the ⁇ -secretase inhibitor comprises MK0752, RO4929097 and/or PF-03084014.
  • the HH signaling pathway inhibitor comprises an SMO inhibitor.
  • the SMO inhibitor comprises Vismodegib, Sonidegib, and/or Glasdegib.
  • the tumor includes solid tumors and non-solid tumors.
  • the solid tumor includes osteosarcoma and/or colon cancer.
  • the non-solid tumor includes lymphoma.
  • the ascorbic acid derivative comprises a pharmaceutically acceptable salt of ascorbate.
  • the pharmaceutically acceptable ascorbate salt comprises sodium ascorbate.
  • the second therapeutic agent and the ascorbic acid or derivative thereof are configured to be administered to the subject simultaneously.
  • the second therapeutic agent and the ascorbic acid or derivative thereof are configured to be administered to the subject separately.
  • the medicament is configured such that the second therapeutic agent is administered at a dose of about 1 mg/kg to about 100 mg/kg.
  • the medicament is configured such that the ascorbic acid or derivative thereof is administered at a dose of about 0.05 g/kg to about 2.5 g/kg.
  • the medicament is configured such that the second therapeutic agent and the ascorbic acid or derivative thereof are administered in a mass ratio of about 1:5 to about 1:5000.
  • the medicament is configured such that the second therapeutic agent and the ascorbic acid or derivative thereof are administered in a mass ratio of about 1:5 to about 1:5000.
  • Figure 1 shows the effects of different concentrations of berberine described in this application on 143B cells and HOS cells.
  • Figure 2 shows the inhibitory effect of the combination of berberine and sodium ascorbate described in this application on 143B cells and HOS cells.
  • Figure 3 shows the effects of different concentrations of Foxy-5 described in this application on 143B cells and HOS cells.
  • Figure 4 shows the inhibitory effect of the combination of Foxy-5 and sodium ascorbate described in this application on 143B cells and HOS cells.
  • Figure 5 shows the inhibitory effect of the combination of Pyrvinium and sodium ascorbate described in this application on 143B cells and HOS cells.
  • Figure 6 shows the inhibitory effect of Niclosamide combined with sodium ascorbate described in this application on 143B cells and HOS cells.
  • Figure 7 shows the inhibitory effect of the combination of ETC-159 and sodium ascorbate described in this application on 143B cells and HOS cells.
  • Figure 8 shows the inhibitory effect of LGK974 combined with sodium ascorbate described in this application on 143B cells and HOS cells.
  • Figure 9 shows the effects of Sonidegib at different concentrations described in this application on 143B cells and HOS cells.
  • Figure 10 shows the inhibitory effect of Sonidegib combined with sodium ascorbate as described in this application on 143B cells and HOS cells.
  • Figure 11 shows the inhibitory effect of Vismodegib and sodium ascorbate described in this application on 143B cells and HOS cells.
  • Figure 12 shows the effects of different concentrations of PF-03084014 described in this application on 143B cells and HOS cells.
  • Figure 13 shows the inhibitory effect of PF-03084014 combined with sodium ascorbate described in this application on 143B cells and HOS cells.
  • Figure 14 shows the inhibitory effect of RO4929097 combined with sodium ascorbate described in this application on 143B cells and HOS cells.
  • Figure 15 shows the inhibitory effect of the combination of MK0752 and sodium ascorbate described in this application on 143B cells and HOS cells.
  • Figure 16 shows the effects of Sulindac at different concentrations described in this application on 143B cells and HOS cells.
  • Figure 17 shows the inhibitory effect of the combination of Sulindac and sodium ascorbate described in this application on 143B cells and HOS cells.
  • Figure 18 shows the inhibitory effect of the combination of Niclosamide and sodium ascorbate described in this application on MC38 cells.
  • Figure 19 shows the inhibitory effect of different concentrations of Niclosamide and sodium ascorbate on DB cells as described in this application.
  • Notch signaling pathway generally refers to a cell signaling pathway mediated by Notch receptors.
  • the Notch signaling pathway is a highly conserved cell signal transduction system that exists in most multicellular organisms.
  • the Notch signaling pathway is mainly composed of Notch receptor, Notch ligand (DSL protein), CSL (CBF-1, Su(H), Lag collective name) DNA binding protein, Notch regulatory molecules and other effectors.
  • CBF-1, Su(H), Lag1 are the different names of this protein in mammals, fruit flies, and nematodes. In 1917, Morgan and his colleagues discovered the Notch gene in mutated fruit flies.
  • Notch The gene's partial function loss caused a notch (Notch) on the edge of the fruit fly's wings. Mammals have 4 Notch receptors (Notch1, Notch2, Notch3, Notch4) and 5 Notch ligands (Delta-like 1, Delta-like 3, Delta-like 4, Jagged 1 and Jagged 2). Studies have shown that the generation of Notch signal can interact with the receptor through Notch ligands in neighboring cells. Notch protein undergoes three shearing (for example, shearing mediated by ⁇ -secretase) and is released from the intracellular segment (NICD).
  • Notch protein undergoes three shearing (for example, shearing mediated by ⁇ -secretase) and is released from the intracellular segment (NICD).
  • NICD/CSL transcription activation complex thereby activating basic helix-loop-helix (bHLH) transcriptional inhibition such as HES, HEY, and HERP
  • bHLH basic helix-loop-helix
  • the term "functional variant” generally means that the functional variant may include amino acid modifications (such as group substitutions, etc.) on the original protein sequence or the insertion, substitution, and substitution of one or more amino acids in the original protein sequence. / Or missing, but retain the original sequence of the function of the molecule.
  • the functional variant may have better biological activity (function) than the original sequence.
  • the reservation need not be a complete reservation.
  • the functional variant may basically retain the original sequence function, for example, retain the original sequence at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99% functionality.
  • ⁇ -secretase generally refers to an intramembrane proteolytic enzyme composed of four subunits, which can cleave transmembrane proteins at residues in the transmembrane domain.
  • the gamma secretase complex generally consists of four separate protein subunits or functional variants thereof: presenilin-1, nicastrin, APH-1 and presenilin enhancer 2 ( presenilin enhancer 2)
  • presenilin enhancer 2 presenilin enhancer 2
  • the main role of Nicastrin can be to maintain the stability of the complex and regulate the transport of intracellular proteins;
  • PEN-2 associates with the complex by binding to the transmembrane domain of presenilin, among other possible effects
  • presenilin proteolysis produces activated N-terminal and C-terminal fragments, PEN-2 helps to stabilize the complex; APH-1 is necessary for proteolytic activity, and it interacts with the conserved ⁇ -helix interaction motif.
  • ⁇ -secretase is involved in the processing of ⁇ -amyloid precursor (APP) and several other type I membrane proteins (such as Notch, ErbB4, E-cadherin, N-cadherin, ephrin-B2 and/or CD44).
  • Presenilin as a catalytic subunit is an aspartyl protease.
  • HH signaling pathway generally refers to a cell signaling pathway mediated by Hedgeho (Hh) signaling molecules.
  • Hedgehog signaling pathway controls cell proliferation and differentiation. When this signaling pathway is abnormally activated, it may cause the occurrence and development of tumors.
  • Hedgehog signaling molecule is a local protein ligand secreted by signaling cells.
  • SHH Sonic Hedgehog
  • IHH Indian Hedgehog
  • DHH Desert Hedgehog
  • Hh-N amino-terminal domain
  • Hh-C carboxy-terminal domain
  • Hh-N has the signal activity of Hh protein
  • Hh-C has its own Proteolytic enzyme activity and cholesterol transferase function.
  • Hh signal transmission is controlled by two receptors on the target cell membrane, Patched (Ptc) and Smoothened (Smo).
  • the receptor Ptc is encoded by the tumor suppressor gene Patched, which is composed of a single peptide chain of 12 transmembrane regions, which can directly bind to the ligand and exert a negative regulatory effect on Hh signaling;
  • Smo is the receptor required for Hedgeho (Hh) signaling. body.
  • SMO generally refers to the receptor or functional variants thereof required for Hedgeho (Hh) signaling in the HH signaling pathway.
  • the receptor Smo is encoded by the proto-oncogene Smothened and is homologous to the G protein-coupled receptor. It is composed of a single peptide chain with 7 transmembrane regions. The N-terminus is located outside the cell, and the C-terminus is located in the cell. The amino acid sequence of the transmembrane region is high. Conservatively, the C-terminal serine and threonine residues are phosphorylation sites, which bind to phosphate groups when catalyzed by protein kinases.
  • the members of this protein family can function as a transcription promoter when they maintain their full length to initiate the transcription of downstream target genes; when the carboxyl end is hydrolyzed by the proteasome, a transcription repressor is formed to inhibit the transcription of downstream target genes. According to reports, in the absence of Hh and Ptc, activation of Smo may lead to the activation of Hh target genes; when the gene Smo is mutated, the same characteristics as the Hh gene mutation may appear.
  • Wnt signaling pathway generally refers to a cell signaling pathway mediated by Wnt protein.
  • Wnt signaling pathways Three Wnt signaling pathways have been identified: canonical Wnt pathway, non-canonical Wnt/planar cell polarization pathway (PCP) and non-canonical Wnt/calcium ion pathway (noncanonical Wnt) /calcium pathway). All three Wnt signaling pathways are activated by the binding of Wnt protein ligands to its receptor Frizzled receptor (Frizzled receptor).
  • the canonical Wnt signaling pathway can participate in the regulation of gene expression
  • the non-classical planar cell polarization pathway can regulate the cytoskeleton to control cell shape
  • the non-canonical Wnt/calcium pathway can regulate the concentration of intracellular calcium ions.
  • the Wnt signaling pathway can often be used for communication between adjacent cells (paracrine) or the same cell itself (autocrine). The Wnt signaling pathway is highly conserved in animals.
  • Dvl-2 generally refers to a member of the dishevelled (dsh) protein family or a functional variant thereof.
  • the Dvl-2 protein is encoded by the DVL2 gene. This gene encodes a 90kD protein, which is phosphorylated after translation to form a 95kD cytoplasmic protein, which may play a role in a variety of Wnt protein-mediated signal transduction pathways.
  • Vertebrate dsh protein has about 40% amino acid sequence similarity with Drosophila dsh.
  • each active ingredient/therapeutic agent can each be prepared into an independent formulation (solid, liquid, gel, etc.), in some embodiments, each active ingredient/therapeutic agent can be present in different containers, It can also be formulated into desired preparations when needed simultaneously or separately with a suitable carrier; in some embodiments, each active ingredient/therapeutic agent can be from different sources (for example, manufactured or sold by different merchants); in some In an embodiment, each active ingredient/therapeutic agent may form a pharmaceutical composition in a mixed form.
  • casein kinase 1 ⁇ usually refers to a member of the casein kinase 1 family (EC 2.7.11.1) or a functional variant thereof, which belongs to the serine/threonine kinase ( In some cases, tyrosine residues are also phosphorylated).
  • casein kinase 1 is known as ⁇ , ⁇ 1, ⁇ 1, ⁇ 2, ⁇ 3, ⁇ , and ⁇ . It is known that these subtypes activate or inactivate or stabilize or destabilize the function of various substrate proteins by phosphorylation of various substrate proteins, thereby participating in the regulation of various biological functions.
  • the gene encoding casein kinase 1 ⁇ can be found in HGNC:2451.
  • Frizzled receptor is also called “frizzled receptor”, usually refers to a family of G protein-coupled receptors or functional variants thereof, which can be used as Wnt signaling pathways and other signaling pathways.
  • the receptor In general, when it is activated, it can cause the activation of downstream proteins (for example, Dishevelled) in the intracellular signaling pathway.
  • Frizzled receptor proteins usually contain a cysteine-rich domain, which is commonly found in proteins such as receptor tyrosine kinases. In humans, Frizzled receptors can include eight members of Frizzled receptors 1-8.
  • the term "Porcupine” generally refers to a protein or a functional variant thereof that can participate in secretion or endoplasmic reticulum transport in humans, and it participates in Wnt signaling pathway transduction.
  • mom-1 In Caenorhabditis elegans, its homologue mom-1 has a similar function in promoting the secretion of Wnt protein Mom-2.
  • Porcupine shares some homology with the o-acyltransferase family and may be involved in the modification of Wnt protein.
  • the coding gene can be found in HGNC:17652.
  • RXR ⁇ is also referred to as NR2B1 (nuclear receptor subfamily 2, group B, member 1) and generally refers to a nuclear receptor or a functional variant thereof. In humans, it is encoded by the RXRA gene, and the coding sequence can be found in MGI:98214.
  • the term "pharmaceutical composition” generally refers to a mixture comprising at least two active ingredients administered to a subject to treat a specific disease or condition affecting the individual. It allows the active ingredient to be in an effective form and does not contain additional components that have unacceptable toxicity to the subject to which the composition is to be administered.
  • This composition may be sterile, or it may contain a pharmaceutically acceptable carrier.
  • the term "inhibitor” generally refers to the ability to completely or partially hinder or reduce the physiology of one or more specific biological molecules (for example, proteins, polypeptides, lipopolysaccharides, glycoproteins, ribonucleoprotein complexes, etc.) Functional compound/substance or composition.
  • the reduction of the physiological function of one or more specific proteins may include a reduction in the activity of the protein itself (for example, the ability to bind to other molecules, etc.) or a reduction in the amount of the protein itself.
  • the inhibitor may exist as different crystals, amorphous substances, pharmaceutically acceptable salts, hydrates, and solvates.
  • the inhibitor can hinder the activation of cell signaling pathways.
  • ascorbic acid derivatives generally refers to compounds that release ascorbic acid (vitamin C) in vivo or in vitro, and solvates, hydrates and salts thereof.
  • the term also includes ascorbic acid analogs, in which one or more hydroxyl groups of ascorbic acid are replaced by another moiety, and in which the ascorbic acid analog substantially maintains the stable activity of ascorbic acid in vitro or in vivo.
  • the term “effective amount” or “effective dose” generally refers to an amount sufficient to achieve or at least partially achieve the desired effect.
  • the "therapeutically effective dose” or “therapeutically effective dose” of a drug or therapeutic agent is usually used alone or in combination with another therapeutic agent to promote the regression of the disease (this is achieved by reducing the severity of disease symptoms and the frequency of the asymptomatic period of the disease). Increase in degree and duration, or prevention of damage or disability due to disease).
  • the “prophylactically effective dose” or “prophylactically effective dose” of a drug generally refers to the amount of the drug that inhibits the development or recurrence of the disease when administered to a subject at risk of disease development or disease recurrence, alone or in combination with another therapeutic agent .
  • a variety of methods known to those skilled in the art can be used to evaluate the ability of the therapeutic or preventive agent to promote the regression of the disease or inhibit the development or recurrence of the disease, such as in a human subject during a clinical trial, in an animal model system Predict the efficacy on humans or determine the activity of the agent in an in vitro assay.
  • prevention generally refers to preventive administration of the combination to healthy subjects to prevent the occurrence of a certain disease or condition. It may also include prophylactic administration of the combination to patients in the pre-stage of the allergic disease to be treated. "Prevention” does not require 100% elimination of the possibility of occurrence of a disease or condition. In other words, “prevention” generally means that the probability or degree of occurrence of a disease or condition is reduced in the presence of the administration combination.
  • treatment generally refers to clinical intervention for changing the natural course of the treated individual or cell in the clinical pathological process. This may include improving the state of the disease, eliminating the focus of the disease, or improving the prognosis.
  • the term "administration" generally refers to the introduction of the drug combination into the body of a subject through any route of introduction or delivery. Any method known to those skilled in the art for contacting cells, organs or tissues with the drug combination can be used. Including but not limited to intra-arterial, intranasal, intra-abdominal, intravenous, intramuscular, subcutaneous transdermal or oral administration.
  • the daily dose can be divided into one, two or more suitable form doses to be administered at one, two or more times during a certain period of time.
  • tumor generally refers to neoplasms or solid lesions formed by abnormal cell growth.
  • the tumor can be a solid tumor or a non-solid tumor.
  • a tangible mass that can be detected by clinical examinations such as X-ray film, CT scan, B-ultrasound, or palpation can be called a solid tumor.
  • X-ray, CT scan, B-ultrasound and palpation cannot Tumors seen or palpated, such as leukemia, can be called non-solid tumors.
  • subject generally refers to human or non-human animals, including but not limited to cats, dogs, horses, pigs, cows, sheep, rabbits, mice, rats, or monkeys.
  • preparation which can also be referred to as a pharmaceutical preparation, generally refers to a drug that is made to meet the needs of treatment or prevention and can be provided to subjects for use in accordance with certain dosage form requirements.
  • the formulation may contain the active ingredient and a carrier.
  • carrier generally refers to any substance other than the active ingredient.
  • pharmaceutically acceptable substances for example, pharmaceutically acceptable substances, compositions or vehicles that carry or transport chemical agents.
  • buffers for example, surfactants, stabilizers, preservatives, absorption enhancers for enhancing bioavailability, liquid or solid fillers, diluents, excipients, solvents, encapsulating materials and/or other conventional enhancements Solvent or dispersant, etc.
  • the term “container” generally refers to any vessel or device suitable for holding medicines.
  • medicine box medicine bottle
  • medicine bag blister
  • tube tube
  • syringe etc.
  • the term "about” generally refers to a range of 0.5%-10% above or below the specified value, such as 0.5%, 1%, 1.5%, 2%, 2.5%, above or below the specified value. Variation within the range of 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%.
  • the application provides a drug combination, which includes:
  • a second therapeutic agent selected from the group consisting of Notch signaling pathway inhibitors, Hh signaling pathway inhibitors, Porcupine inhibitors, RXR ⁇ inhibitors, Niclosamide, CK1a inhibitors and Frizzled receptor inhibitors Agent.
  • the present application also provides the use of the combination of ascorbic acid or its derivative and a second therapeutic agent in the preparation of a medicament for the prevention and/or treatment of tumors, wherein the second therapeutic agent is selected from: Notch signaling pathway inhibitor, HH signaling pathway inhibitor, RXR ⁇ inhibitor and Wnt signaling pathway inhibitor.
  • the second therapeutic agent may include a Notch signaling pathway inhibitor.
  • the second therapeutic agent may include an SHH signaling pathway inhibitor.
  • the second therapeutic agent may include an RXRa inhibitor.
  • the second therapeutic agent may include a Wnt signaling pathway inhibitor.
  • this application also provides a method for preventing and/or treating tumors, which comprises administering to a subject in need:
  • a second therapeutic agent wherein the second therapeutic agent is selected from the group consisting of Notch signaling pathway inhibitors, HH signaling pathway inhibitors, RXR ⁇ inhibitors, and Wnt signaling pathway inhibitors.
  • this application also provides a method for monitoring the response of the subject to the drug, and the method includes:
  • the present application also provides a kit, which includes the drug combination described in the present application.
  • the pharmaceutical combination of the present application comprises: a) a prophylactic and/or therapeutically effective amount of ascorbic acid or derivatives thereof described in the present application; and b) a prophylactic and/or therapeutically effective amount of the first described in the present application selected from the group consisting of Two therapeutic agents: Notch signaling pathway inhibitor, HH signaling pathway inhibitor, Porcupine inhibitor, RXR ⁇ inhibitor, Niclosamide, CK1a inhibitor and Frizzled receptor inhibitor.
  • the ascorbic acid or its derivatives may include ascorbic acid, ascorbic acid derivatives and any combination thereof.
  • the second therapeutic agent may include any one of Notch signaling pathway inhibitor, HH signaling pathway inhibitor, Porcupine inhibitor, RXR ⁇ inhibitor, Niclosamide, CK1a inhibitor, Frizzled receptor inhibitor, or any of several The combination.
  • the second therapeutic agent may include a Notch signaling pathway inhibitor.
  • the second therapeutic agent may include an HH signaling pathway inhibitor.
  • the second therapeutic agent may include a Porcupine inhibitor.
  • the second therapeutic agent may include an RXRa inhibitor.
  • the second therapeutic agent may include Niclosamide.
  • the second therapeutic agent may include a CK1a inhibitor.
  • the second therapeutic agent may include a Frizzled receptor inhibitor.
  • the ratio of the effective amount of the second therapeutic agent to the effective amount of the ascorbic acid or derivative thereof is about 1:1 to about 1:5000.
  • the ratio of the effective amount of the second therapeutic agent to the effective amount of the ascorbic acid or derivative thereof is about 1:10 to about 1:5000.
  • the ratio of the effective amount of the second therapeutic agent to the effective amount of the ascorbic acid or its derivative is about 1:1, 1:5, 1:7, 1:10, 1:12, 1 :15, 1:17, 1:20, 1:25, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75 , 1:80, 1:85, 1:90, 1:100, 1:120, 1:150, 1:180, 1:200, 1:220, 1:250, 1:280, 1:300, 1 :320, 1:350, 1:380, 1:400, 1:420, 1:450, 1:480, 1:500, 1:550, 1:600, 1:650, 1:700, 1:750 , 1:800, 1:850, 1:900, 1:950, 1:1000, 1:1100, 1:1200, 1:1300, 1:1400, 1:1500, 1:1600, 1:1700, 1 :1800, 1:1900, 1:2000, 1:2100, 1:2200, 1:2300, 1:2400, 1:2500, 1:1
  • the effective amount ratio may include an effective amount mole ratio and/or an effective amount mass ratio.
  • the mass ratio of the second therapeutic agent to the ascorbic acid or its derivative is about 5000:1 to about 1:5000.
  • the mass ratio of the second therapeutic agent to the ascorbic acid or its derivative is about 20:1 to 1:1, about 20:1 to about 5:1, about 20:1 to about 10:1, about 25:1 to about 10:1, about 50:1 to about 10:1, about 100:1 to about 10:1, about 150:1 to about 10:1, about 200:1 to about 10:1, about 250:1 to about 10:1, about 300:1 to about 10:1, about 400:1 to about 10:1, about 450:1 to about 10:1, about 10:1 to about 500:1, about 10:1 to about 550:1, about 10:1 to about 600:1, about 10:1 to about 650:1, about 700:1 to about 10:1, about 800:1 to about 10:1, about 900:1 to about 10:1, about 1000:1 to about 10:1, about 1500:1 to about 10:1, about 2000:1 to about 10:1, about 3000:1 to about 10:1, about 4000:1 to about 10:1, about 5000:1 to about 10:1, about 20:1
  • the mass ratio of the second therapeutic agent to the ascorbic acid or its derivative is about 1:10 to about 1:5000.
  • each of the second therapeutic agent and the ascorbic acid or its derivatives may be from different sources, for example, manufactured or sold by different merchants.
  • the ascorbic acid or its derivatives prepared, produced or sold need not be single-component or pure, as long as it contains a compound or solvate, hydrate, or salt thereof that can release ascorbic acid (vitamin C) in vivo or in vitro,
  • analogs containing ascorbic acid for example, where one or more hydroxyl groups of ascorbic acid are replaced by another moiety, and where the ascorbic acid analog basically maintains the stable activity of ascorbic acid in vitro or in vivo
  • the present application Within range.
  • the second therapeutic agent prepared, produced or sold need not be single-component or pure, as long as it contains any one or more of the second therapeutic agents described in the application that can be released in vivo or in vitro , Or its solvates, hydrates, salts, and/or analogs containing any one or more of the second therapeutic agent (for example, it contains group modification or substitution, and the analog It is within the scope of the present application to substantially maintain the stable activity of any second therapeutic agent in vitro or in vivo.
  • the second therapeutic agent and the ascorbic acid or derivative thereof are each in a different container.
  • the second therapeutic agent and the ascorbic acid or its derivative are each in a different container, and the amount of the second therapeutic agent and the amount of the ascorbic acid or its derivative can be set according to their effective amount ratio. , Or not set according to its effective ratio.
  • the second therapeutic agent may be present in 1 or more containers, such as 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more.
  • the ascorbic acid or its derivatives may be present in 1 or more containers, such as 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more , 8 or more, 9 or more, 10 or more, 11 or more, 12 or more.
  • the container may include a medicine box, a medicine box, a medicine bottle, a medicine bag, a blister, a tube, a syringe, etc.;
  • the medicine bottle may include a sealed glass ampoule, a test tube, a vial, a flask, a bottle, etc.;
  • the container can be made of glass, polycarbonate, polystyrene and other organic polymers or ceramics, metals, composite films, cellophane, aluminum or alloy and other foil lined packaging materials, and can generally be used to hold Any other appropriate materials and other components of the reagent.
  • the second therapeutic agent and the ascorbic acid or a derivative thereof may each be present in different containers, and may be formulated into preparations with a suitable carrier at the same time or separately when needed.
  • the second therapeutic agent is mixed with the ascorbic acid or its derivative to prepare a suitable preparation.
  • the second therapeutic agent and the ascorbic acid or its derivative are each formulated into different suitable preparations.
  • the second therapeutic agent and the ascorbic acid or a derivative thereof may each be present in different containers in the form of preparations.
  • the pharmaceutical combination includes a first preparation and a second preparation
  • the first preparation includes the ascorbic acid or a derivative thereof and a pharmaceutically acceptable first carrier
  • the second preparation includes the second treatment Agent and a pharmaceutically acceptable second carrier.
  • first preparation and the second preparation may be the same dosage form or may be different dosage forms.
  • the first preparation and the second preparation may both be pills, powders, tablets, granules, gels, hard capsules, soft capsules, syrups, mixtures, lotions, injections, aerosols.
  • Any of the dosage forms such as ointment, ointment, film, suppository, dripping pill, etc., can also be any combination of two or two of them.
  • first preparation and the second preparation may be in the form of preparations suitable for the same mode of administration.
  • first preparation and the second preparation may be in the form of preparations suitable for different administration methods.
  • the pharmaceutical combination includes a pharmaceutical composition
  • the pharmaceutical composition includes the second therapeutic agent and the ascorbic acid or a derivative thereof.
  • the content of the second therapeutic agent in the pharmaceutical composition is about 1% to about 50% (w/w).
  • the content of the second therapeutic agent in the pharmaceutical composition is about 5% to about 20% (w/w).
  • the content of the second therapeutic agent is about 5% (w/w) to about 10% (w/w), about 10% (w/w) to about 20% (w/w), about 10% (w/w) to about 15% (w/w), about 10% (w/w) to about 18% (w/w), about 5% (w/w) to about 15% (w/w) .
  • the content of the ascorbic acid or its derivative in the pharmaceutical composition is about 50% to about 95% (w/w).
  • the content of the ascorbic acid or its derivatives is about 50% (w/w) to about 60% (w/w), about 50% (w/w) to about 70% (w/w), about 60% (w/w). %(W/w) to about 80%(w/w), about 50%(w/w) to about 90%(w/w), about 60%(w/w) to about 90%(w/w) ), about 55% (w/w) to about 75% (w/w). About 70% (w/w) to about 90% (w/w), about 80 to about 95% (w/w).
  • the content of the ascorbic acid or its derivative in the pharmaceutical composition is about 80% to about 95% (w/w).
  • the content of the second therapeutic agent is about 80% to about 85% (w/w), about 80% to about 90% (w/w), about 85% to about 95% (w/w), About 85% to about 90% (w/w).
  • the application also provides the use of the combination of ascorbic acid or its derivative and a second therapeutic agent in the preparation of a medicament for the prevention and/or treatment of tumors, wherein the second therapeutic agent is selected from: Notch signaling pathway inhibition Agents, HH signaling pathway inhibitors, RXR ⁇ inhibitors and Wnt signaling pathway inhibitors.
  • This application also provides a method for preventing and/or treating tumors, which comprises administering to a subject in need:
  • the application also provides a method for monitoring the response of a subject to the drug, the method including:
  • the expression level of the gene may include modification and/or mutation of genomic DNA, expression level of mRNA, expression level of protein,
  • the detection can be selected from PCR, real-time quantitative PCR, digital PCR, liquid chip, solid-state chip, in situ hybridization, ordinary sequencing, and high-throughput sequencing to detect the modification and/or mutation of genomic DNA, and the expression level of mRNA .
  • the detection can be selected from liquid chip, solid-state chip, enzyme-linked immunology, radioimmunoassay, chemiluminescence immunoassay, mass spectrometry, high performance liquid chromatography, Western labeling and sequencing to detect the expression level of protein.
  • the ascorbic acid or its derivatives may include ascorbic acid, ascorbic acid derivatives and any combination thereof.
  • the second therapeutic agent may include any one of Notch signaling pathway inhibitor, HH signaling pathway inhibitor, Wnt signaling pathway inhibitor RXR ⁇ inhibitor, or a combination of any of them.
  • the second therapeutic agent may include a Notch signaling pathway inhibitor.
  • the second therapeutic agent may include an HH signaling pathway inhibitor.
  • the second therapeutic agent may include an RXRa inhibitor.
  • the second therapeutic agent may include an HH signaling pathway inhibitor.
  • the tumor includes solid tumors and non-solid tumors.
  • the solid tumor may be selected from the following group: liver cancer, gastric cancer, lung cancer, breast cancer, colon cancer, rectal cancer, renal cell cancer, liver cancer, non-small cell lung cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer , Pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer , Hodgkin's disease, non-Hodgkin's lymphoma, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, childhood solid tumors, bladder cancer, renal or ureteral cancer, renal pelvis Cancer, Central Nervous System (CNS) Tumors, Primary CNS Lymphoma, Tumor Angiogenesis, Spinal Tumors, Brain Stem G
  • the non-solid tumor may be selected from the following group: chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphoid leukemia (ALL), B-cell acute lymphoid leukemia (B-ALL), T-cell acute lymphoid leukemia (T-ALL), Chronic Myeloid Leukemia (CML), Acute Myeloid Leukemia (AML), B-cell Young Lymphocytic Leukemia, Blastoblastic Plasmacytoid Dendritic Cell Tumor, Burkitt Lymphoma, Diffuse Large B-Cell Lymph Tumor, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative disease, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplastic And myelodysplastic syndrome, non-Hodgkin’s lymphoma, Hodgkin’
  • the solid tumor includes osteosarcoma and/or colon cancer.
  • the non-solid tumor includes lymphoma.
  • the second therapeutic agent and the ascorbic acid or derivative thereof are configured to be administered to the subject at the same time.
  • Niclosamide combined with the ascorbic acid or its derivatives can be used to prevent and/or treat tumors.
  • Niclosamide combined with the ascorbic acid or its derivatives can be used to prevent and/or treat lymphoma, osteosarcoma and/or colon cancer.
  • the combination of a Dvl-2 inhibitor and the ascorbic acid or its derivatives can be used to prevent and/or treat lymphoma, osteosarcoma and/or colon cancer.
  • the Wnt signaling pathway inhibitor combined with the ascorbic acid or its derivatives can be used to prevent and/or treat lymphoma, osteosarcoma and/or colon cancer.
  • the simultaneous administration to the subject may include that the time interval between the second therapeutic agent and the administration of the ascorbic acid or its derivative to the subject does not exceed 1 hour.
  • the time interval is 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 8 minutes, 5 minutes, 3 minutes, 2 Minutes, 1 minute, or together in a mixed form.
  • the second therapeutic agent and the ascorbic acid or derivative thereof are configured to be administered to the subject separately.
  • the separate administration to the subject may include the time interval between the second therapeutic agent and the administration of the ascorbic acid or derivative thereof to the subject greater than 1 hour.
  • the time interval is 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 9. Hours, 10 hours, 11 hours, 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or longer.
  • the administration may include oral administration, intravenous administration, intramuscular administration, tumor site in situ administration, inhalation, rectal administration, vaginal administration, transdermal administration, or subcutaneous reservoir administration, etc., any administration methods or combinations thereof .
  • the separate administration to the subject may include alternate administration of the second therapeutic agent and the ascorbic acid or a derivative thereof, for example, administration of the ascorbic acid or a derivative thereof after the second therapeutic agent, or administration
  • the second therapeutic agent is administered after the ascorbic acid or its derivative.
  • the administration of the second therapeutic agent may include one administration.
  • the administration of the second therapeutic agent may include consecutive administrations of 2 or more times, such as 3 or more times, 4 times or more, 5 times or more, 6 times or more, 7 times or more, 8 times or Above, 9 times or more, 10 times or more.
  • the administration of the ascorbic acid or its derivative may include one administration.
  • the administration of the ascorbic acid or its derivative may include consecutive administrations of 2 or more times, such as 3 or more times, 4 times or more, 5 times or more, 6 times or more, 7 times or more, 8 times Or more, 9 times or more, 10 times or more.
  • the medicament is configured such that the second therapeutic agent is administered at a dose of about 1 mg/kg to about 100 mg/kg.
  • the second therapeutic agent is at about 10 mg/kg to about 100 mg/kg, 10 mg/kg to about 80 mg/kg, 10 mg/kg to about 50 mg/kg, 20 mg/kg to about 100 mg/kg, 30 mg/kg to About 80mg/kg, 1mg/kg to about 30mg/kg, 1mg/kg to about 20mg/kg, about 1mg/kg to about 5mg/kg, 5mg/kg to about 10mg/kg, 3mg/kg to about 8mg/kg , 5mg/kg to about 30mg/kg, 30mg/kg to about 70mg/kg, 40mg/kg to about 60mg/kg, 20mg/kg to about 50mg/kg, 30mg/kg to about 60mg/kg, 20mg/kg to A dose of about 70 mg/kg is administered.
  • the subject of administration is a mouse.
  • the medicament is configured such that the second therapeutic agent is administered at a dose of about 10 mg/kg to about 100 mg/kg.
  • the subject of administration is a human.
  • the medicament is configured such that the second therapeutic agent is administered at a dose of about 1 mg/kg to about 10 mg/kg.
  • the drug is configured such that the ascorbic acid or derivative thereof is administered at a dose of about 0.05 g/kg to about 2.5 g/kg.
  • the ascorbic acid or its derivative is at a rate of about 0.05 g/kg to about 0.1 g/kg, about 0.1 g/kg to about 0.2 g/kg, about 0.15 g/kg to about 0.25 g/kg, about 0.05 g/kg.
  • a dose of g/kg to about 2.5 g/kg, about 0.1 g/kg to about 2.5 g/kg, about 0.5 g/kg to about 2 g/kg, about 0.05 g/kg to about 0.2 g/kg is administered.
  • the subject of administration is a mouse.
  • the drug is configured such that the ascorbic acid or derivative thereof is administered at a dose of about 0.5 g/kg to about 2.5 g/kg.
  • the subject of administration is a human.
  • the drug is configured such that the ascorbic acid or derivative thereof is administered at a dose of about 0.05 g/kg to about 0.25 g/kg.
  • the drug is configured such that the second therapeutic agent and the ascorbic acid or derivative thereof are administered in a mass ratio of about 1:5 to about 1:5000.
  • the medicament is configured such that the second therapeutic agent and the ascorbic acid or its derivative are in a ratio of about 1:1 to about 1:20, about 1:5 to about 1:20, about 1:10 to about 1:20, about 1:10 to about 1:25, about 1:10 to about 1:50, about 1:10 to about 1:100, about 1:10 to about 1:150, about 1:10 to about 1:200, about 1:10 to about 1:250, about 1:10 to about 1:300, about 1:10 to about 1:400, about 1:10 to about 1:450, about 1:10 to about 1:500, about 1:10 to about 1:550, about 1:10 to about 1:600, about 1:10 to about 1:650, about 1:10 to about 1:700, about 1:10 to about 1:800, about 1:10 to about 1:900, about 1:10 to about 1:1000, about 1:10 to about 1:1500, about 1:10 to about 1:2000, about 1:10 to about 1:3000, about 1:10 to about 1:4000, about 1:10 to about 1:5000, about 1:5 to about 1:20
  • the drug is configured such that the second therapeutic agent and the ascorbic acid or derivative thereof are administered in a mass ratio of about 1:5 to about 1:100.
  • the medicament is configured such that the second therapeutic agent and the ascorbic acid or its derivative are in a ratio of about 1:5 to about 1:20, about 1:10 to about 1:20, about 1:10 to about 1:25, about 1:10 to about 1:50, about 1:10 to about 1:100, about 1:5 to about 1:25, about 1:5 to about 1:35, about 1:5 to about 1:50, about 1:30 to about 1:80, about 1:40 to about 1:80, about 1:20 to about 1:100, about 1:20 to about 1:60, about 1:20 to about
  • the mass ratios of 1:50, about 1:5 to about 1:100, about 1:25 to about 1:50, about 1:25 to about 1:100, and about 1:50 to about 1:100 are applied.
  • the medicament is configured such that the second therapeutic agent and the ascorbic acid or derivative thereof are administered in an effective amount ratio of about 1:5 to about 1:5000.
  • the medicament is configured such that the second therapeutic agent and the ascorbic acid or its derivative are in a ratio of about 1:1 to about 1:20, about 1:5 to about 1:20, about 1:10 to about 1:20, about 1:10 to about 1:25, about 1:10 to about 1:50, about 1:10 to about 1:100, about 1:10 to about 1:150, about 1:10 to about 1:200, about 1:10 to about 1:250, about 1:10 to about 1:300, about 1:10 to about 1:400, about 1:10 to about 1:450, about 1:10 to about 1:500, about 1:10 to about 1:550, about 1:10 to about 1:600, about 1:10 to about 1:650, about 1:10 to about 1:700, about 1:10 to about 1:800, about 1:10 to about 1:900, about 1:10 to about 1:1000, about 1:10 to about 1:1500, about 1:10 to about 1:2000, about 1:10 to about 1:3000, about 1:10 to about 1:4000, about 1:10 to about 1:5000, about 1:5 to about 1:20
  • the medicament is configured such that the second therapeutic agent and the ascorbic acid or derivative thereof are administered in an effective amount ratio of about 1:5 to about 1:100.
  • the medicament is configured such that the second therapeutic agent and the ascorbic acid or its derivative are in a ratio of about 1:5 to about 1:20, about 1:10 to about 1:20, about 1:10 to about 1:25, about 1:10 to about 1:50, about 1:10 to about 1:100, about 1:5 to about 1:25, about 1:5 to about 1:35, about 1:5 to about 1:50, about 1:30 to about 1:80, about 1:40 to about 1:80, about 1:20 to about 1:100, about 1:20 to about 1:60, about 1:20 to about
  • the effective amount ratio is 1:50, about 1:5 to about 1:100, about 1:25 to about 1:50, about 1:25 to about 1:100, about 1:50 to about 1:100.
  • the Notch signaling pathway inhibitor, HH signaling pathway inhibitor, RXR ⁇ inhibitor, and Wnt signaling pathway inhibitor may include small molecule compounds.
  • the Notch signaling pathway inhibitor may include CB-103, FLI-06, JI051, Psoralidin Tangeretin, Carvacrol, Notch inhibitor 1, BMS-906024, IMR-1, IMR-1A, Z-Ile-Leu-aldehyde, ZLDI-8, Semagacestat, Bruceine D, RO4929097, LY-411575, YO-01027, Crenigacestat, Avagacestat, Z-Ile-Leu-aldehyde, MK0752 and/or PF-03084014.
  • the Notch signaling pathway inhibitor may include a gamma secretase (Gamma Secretase) inhibitor, an ADAM-17 inhibitor, a Notch ligand inhibitor, a Notch receptor inhibitor, and/or a CSL-DNA binding protein inhibitor.
  • a gamma secretase Gamma Secretase
  • ADAM-17 ADAM-17 inhibitor
  • Notch ligand inhibitor a Notch ligand inhibitor
  • Notch receptor inhibitor a CSL-DNA binding protein inhibitor
  • the Notch signaling pathway inhibitor may include a Notch ligand inhibitor.
  • the Notch ligand inhibitor may include a Delta-like 1 inhibitor, a Delta-like 3 inhibitor, a Delta-like 4 inhibitor, a Jagged 1 inhibitor and/or a Jagged 2 inhibitor.
  • the Jagged 1 inhibitor may include Carvacrol.
  • the Notch signaling pathway inhibitor may include a Notch receptor inhibitor.
  • the Notch receptor inhibitor may include Notch1 receptor inhibitor, Notch2 receptor inhibitor, Notch3 receptor inhibitor, and/or Notch4 receptor inhibitor.
  • the Notch receptor inhibitor may include Tangeretin, Carvacrol, Notch inhibitor 1, BMS-906024, IMR-1, IMR-1A, Z-Ile-Leu-aldehyde, Semagacestat, and/or Bruceine's D.
  • the Notch1 receptor inhibitor may include Tangeretin, Carvacrol and/or Notch inhibitor 1.
  • the Notch3 receptor inhibitor may include Notch inhibitor 1.
  • the ADAM-17 inhibitor may include ZLDI-8.
  • the Notch signaling pathway inhibitor includes a ⁇ -secretase inhibitor.
  • the gamma secretase (Gamma Secretase) inhibitor may include RO4929097, LY-411575, YO-01027, Crenigacestat, Semagacestat, Avagacestat, Z-Ile-Leu-aldehyde, MK0752 and/or PF-03084014.
  • the ⁇ -secretase inhibitor includes MK0752, RO4929097 and/or PF-03084014.
  • the HH signaling pathway inhibitor may include Jervine, Ciliobrevin D, RU-SKI 43 hydrochloride, RU-SKI 43, JK184, Cyclopamine, Mebendazole, Ciliobrevin A, SANT-1, Vismodegib, GANT 61, HhAntag, Saridegib, MRT -83, PF-5274857, 20(S)-Hydroxycholesterol, CUR61414, MK-4101, Vismodegib, Sonidegib and/or Glasdegib.
  • the HH signaling pathway inhibitor may include a hedgehog inhibitor, a Gli inhibitor, and/or a smo inhibitor.
  • the HH signaling pathway inhibitor may include a Hedgehog inhibitor.
  • the Hedgehog inhibitor may include Jervine, Ciliobrevin D, RU-SKI 43 hydrochloride, RU-SKI 43, JK184, Cyclopamine, Mebendazole, Ciliobrevin A, SANT-1, Visitodegib, CUR61414, MK-4101, and/or Dynarestin.
  • the HH signaling pathway inhibitor may include a Gli inhibitor.
  • the Gli inhibitor may include GANT 61 and/or HhAntag.
  • the Smo inhibitor may include Saridegib, MRT-83, Jervine, SANT-1, PF-5274857, 20(S)-Hydroxycholesterol, CUR61414, MK-4101, Vismodegib, Sonidegib, and/or Glasdegib.
  • the HH signaling pathway inhibitor includes an SMO inhibitor.
  • the SMO inhibitor may comprise Vismodegib, Sonidegib, and/or Glasdegib.
  • the Wnt signaling pathway inhibitor may include a Tankyrases inhibitor, a Porcupine inhibitor, a Dvl-2 inhibitor, a DKK inhibitor, a CK1a inhibitor, and/or a Frizzled receptor inhibitor.
  • the Wnt signaling pathway inhibitor may include Porcupine inhibitor, Dvl-2 inhibitor, CK1a inhibitor, and/or Frizzled receptor inhibitor.
  • the Wnt signaling pathway inhibitor may include a Tankyrases inhibitor.
  • the Tankyrases inhibitor may comprise IWR1, XAV939, NVP-TNKS656 and/or JW74.
  • the Wnt signaling pathway inhibitor may include a Porcupine inhibitor.
  • the Porcupine inhibitor may comprise IWP-2, LGK974 and/or ETC-159.
  • the Porcupine inhibitor may include LGK974 and/or ETC-159.
  • the Wnt signaling pathway inhibitor may include a DKK inhibitor.
  • the DKK inhibitor may comprise DKN-01.
  • the Wnt signaling pathway inhibitor may include a CK1a inhibitor.
  • the CK1a inhibitor may comprise Pyrvinium.
  • the Wnt signaling pathway inhibitor may include a Dvl-2 inhibitor.
  • the Dvl-2 inhibitor may comprise NSC668036, J01-017a, Niclosamide and/or Sulindac.
  • the Dvl-2 inhibitor may comprise Niclosamide and/or Sulindac.
  • the Dvl-2 inhibitor may not contain Sulindac.
  • the Wnt signaling pathway inhibitor may include a Frizzled receptor inhibitor.
  • the RXR ⁇ inhibitor comprises berberine or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt may include berberine and R-(+)- ⁇ -organic acid, hydroxycitric acid, eicosapentaenoic acid, docosahexaenoic acid, ursolic acid, Corosolic acid, cinnamic acid, cholic acid, obeticholic acid, ursodeoxycholic acid, oleanolic acid, salicylic acid, betulinic acid, chlorogenic acid, caffeic acid, lindenic acid, acetyl-L-carnitine, S-allylcysteine sulfoxide, S-methylcysteine sulfoxide, pantothenic acid, ascorbic acid, retinoic acid, niacin and biotin .
  • the inhibitor may also include Fervenulin, 3-Methyltoxoflavin and/or Walrycin B.
  • the Notch signaling pathway inhibitor, HH signaling pathway inhibitor, RXR ⁇ inhibitor, Wnt signaling pathway inhibitor may also include antibodies or polypeptides.
  • the interaction of the antibody or polypeptide with its corresponding binding target can reduce or hinder the activation/signal transduction of the Notch signal pathway, the HH signal pathway, and the Wnt signal pathway, and/or reduce or hinder the activity of RXR ⁇ .
  • the antibody or polypeptide may include Gamma Secretase (Gamma Secretase) antibody or binding polypeptide, ADAM-17 antibody or binding polypeptide, Notch ligand antibody or binding polypeptide, Notch receptor antibody or binding polypeptide, CSL -DNA binding protein antibody or binding polypeptide, Hedgehog antibody or binding polypeptide, Gli antibody or binding polypeptide, smo antibody or binding polypeptide, Tankyrases antibody or binding polypeptide, Porcupine antibody or binding polypeptide, Dv1-2 antibody Or binding polypeptide, DKK antibody or binding polypeptide, CK1a antibody or binding polypeptide and/or Frizzled receptor antibody or binding polypeptide.
  • Gamma Secretase Gamma Secretase
  • ADAM-17 antibody or binding polypeptide gamma Secretase
  • Notch ligand antibody or binding polypeptide Notch receptor antibody or binding polypeptide
  • CSL -DNA binding protein antibody or binding polypeptide Hedgehog antibody or binding polypeptide
  • the Frizzled receptor antibody may include OMP18RS (Vantictumab), OMP-54F28 (Ipafricept), OMP131R10 and/or OTSA 101.
  • the Frizzled binding polypeptide may include Fz7-21TFA, Fz7-21 and/or Foxy-5.
  • the Notch signaling pathway inhibitor, HH signaling pathway inhibitor, RXR ⁇ inhibitor, Wnt signaling pathway inhibitor may also include siRNA, shRNA and/or CRISPR/Cas9 system.
  • the siRNA, shRNA and CRISPR/Cas9 system can target the coding genomic DNA or mRNA of molecules included in the HH signaling pathway, RXR ⁇ inhibitor, and Wnt signaling pathway, so that the expression level/activity of the corresponding molecules is reduced.
  • the siRNA, shRNA and/or CRISPR/Cas9 system may include targeting gamma secretase (Gamma Secretase), ADAM-17, Notch ligand, Notch receptor, CSL-DNA binding protein, Hedgehog, Gli, Smo , Tankyrases, Porcupine, Dvl-2, DKK, CK1a and/or Frizzled receptor siRNA, shRNA and/or CRISPR/Cas9 system.
  • the CRISPR/Cas9 system includes guide RNA and /Cas9 protein.
  • the ascorbic acid and its derivatives include members selected from the group consisting of ascorbic acid (vitamin C), ascorbic acid derivatives and combinations thereof.
  • the ascorbic acid derivative may also include dehydroascorbic acid, ascorbic acid salt, or a salt of an ascorbic acid derivative.
  • Ascorbic acid is sensitive to the influence of environmental parameters (such as light, heat, oxygen) due to its ⁇ -ketolactone structure. It may be unstable in water or other aqueous solutions. Chemically stabilize the ascorbic acid molecule to prepare ascorbic acid derivatives with higher stability than the parent compound (for example, see US Patent Nos. 5,137,723 and US 5,078,989), the contents of which are incorporated into this application by way of introduction.
  • the ascorbic acid derivative may be an ascorbic acid analog.
  • Typical ascorbic acid derivatives include the following compounds: at least one of the hydroxyl groups of the ascorbic acid molecule (e.g. 2-OH, 3-OH, 5-OH, 6-OH) is derivatized with a modified group (see, for example, Ando et al., U.S. Patent 5,078,989).
  • one or more of the hydroxyl groups may be substituted by another moiety.
  • the ascorbic acid and its derivatives include ascorbic acid and at least one ascorbic acid derivative.
  • the ascorbic acid derivative may include free 2-OH and free 3-OH.
  • the ascorbic acid derivatives include esters of ascorbic acid, which are derived from at least one of 5-OH and 6-OH.
  • the ascorbic acid derivatives include esters, such as 6-O-octanoyl-ascorbic acid, 6-O-dodecanoyl-ascorbic acid, 6-O-tetradecanoyl-ascorbic acid, 6-O-octadecanoyl-ascorbic acid, Ascorbic acid, 6-O-dodecanedioyl-ascorbic acid, 6-O-docosanedioyl-ascorbic acid, 6-O-thapsoyl-ascorbic acid, 6-O-sebacedioyl-ascorbic acid, 6-O-Adipyl-Ascorbic Acid.
  • the ascorbic acid derivatives may also include esters in which the lipophilic part of the molecule is a mono- or polyunsaturated fatty acid.
  • unsaturated fatty acids may include essential fatty acids related to health, such as omega-3 ( ⁇ -linolenic acid), omega-6 or omega-9 fatty acids.
  • esters containing amino acid residues may also be included.
  • the ascorbic acid derivative may also include a 2-O-alkyl or 3-O-alkyl derivative of ascorbic acid.
  • 3-O-alkyl-ascorbic acid was reported by Nihro et al. in Chem. Pharm. Bull. 1991, 39: 1731-1735, which is incorporated into this application by reference.
  • the ascorbic acid derivative may include ascorbic acid glycosides; for example, ascorbic acid 1-glycoside, ascorbic acid 2-glycoside, ascorbic acid 3-glycoside, ascorbic acid 5-glycoside, and ascorbic acid 6-glycoside.
  • the ascorbic acid derivative may include 2-O-( ⁇ -D-glucopyranosyl)-ascorbic acid (see, for example, U.S. Patent No. 5,137,723) and 2-O-( ⁇ -D-glucopyranosyl) -Ascorbic acid (see, for example, US Patent Application No. US 2005/0113312).
  • 2-O-( ⁇ -D-glucopyranosyl)-ascorbic acid see, for example, U.S. Patent No. 5,137,723
  • 2-O-( ⁇ -D-glucopyranosyl) -Ascorbic acid see, for example, US Patent Application No. US 2005/0113312.
  • the ascorbic acid derivative may include a bifunctionalized derivative of ascorbic acid, such as, for example, 6-O-acyl-2-O-( ⁇ -D-glucopyranosyl) ascorbic acid (see, for example, Yamamoto et al., J Med. Chem. 2002, 45(2): 462-468. This document is incorporated into this application by reference.
  • the ascorbic acid derivative may include the phosphate of ascorbic acid.
  • ascorbic acid phosphate is an alkali metal salt, alkaline earth metal salt or transition metal salt.
  • it may include magnesium ascorbyl phosphate, sodium ascorbyl phosphate (such as sodium ascorbyl-2-monophosphate), calcium ascorbyl phosphate, potassium ascorbyl phosphate and mixed salts, for example, sodium magnesium ascorbyl phosphate, sodium calcium ascorbyl phosphate, aminopropyl Ascorbyl phosphate.
  • ascorbyl phosphate can exist as hydrates, with dihydrates being common.
  • a typical dihydrate can be purchased from DSM, for example, under the product name STAY-C50.
  • the ascorbic acid derivative comprises a pharmaceutically acceptable ascorbate salt.
  • the pharmaceutically acceptable ascorbate alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, basic amino acid salts such as arginine, and organic amine salts such as triethanolamine.
  • the salt of ascorbate or ascorbic acid derivative may be an edible (e.g., pharmaceutically acceptable) salt, such as calcium, sodium, magnesium, potassium, and zinc salt, and a mixed salt of ascorbic acid or ascorbic acid derivative.
  • edible salt such as calcium, sodium, magnesium, potassium, and zinc salt
  • the pharmaceutically acceptable ascorbate salt includes sodium ascorbate.
  • the dosage form of the first formulation, the second formulation or the pharmaceutical composition may include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams Preparations, gels, patches, inhalants, injections, etc. These preparations can be prepared according to conventional methods.
  • liquid preparation in the case of a liquid preparation, it may be in the form of being dissolved or suspended in water or other suitable solvents during use
  • tablets and granules can be coated by a known method.
  • the active ingredient (including the ascorbic acid or its derivatives described in this application, and the second therapeutic agent described in this application) can be prepared by dissolving it in water, or it can be dissolved in physiologically if necessary.
  • a buffer or a preservative may be added in the saline or glucose solution.
  • any preparation form for oral administration or parenteral administration can also be provided in any preparation form for oral administration or parenteral administration.
  • it can be prepared into a preparation for oral administration in the form of granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids;
  • it may be in the form of injections, drips, transdermal absorbers, transmucosal absorbers, nasal drops, inhalants, suppositories, etc. for intravenous administration, intramuscular administration, or subcutaneous administration.
  • Formulations for parenteral administration for parenteral administration.
  • injections, drips, etc. can be prepared into powdered dosage forms such as freeze-dried form, and dissolved in a suitable aqueous medium such as physiological saline for use.
  • a suitable aqueous medium such as physiological saline for use.
  • a sustained-release preparation covered with a polymer or the like may be directly administered into organs such as the brain.
  • formulation additives used in the manufacture of pharmaceutical formulations
  • the ratio of formulation additives (carriers) to active ingredients, or the manufacturing method of formulations those skilled in the art can use the form of the formulation And suitable choice.
  • an additive (carrier) for a formulation an inorganic or organic substance, or a solid or liquid substance can be used.
  • it can be blended in the range of 1% to 90% by weight relative to the weight of the active ingredient.
  • the carrier may include lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminum metasilicate, synthetic aluminum silicate, sodium carboxymethyl cellulose, hydroxypropyl starch, carboxymethyl Base cellulose calcium, ion exchange resin, methyl cellulose, gelatin, gum arabic, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, stearin Magnesium, talc, tragacanth, bentonite, propolis, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, glyceryl lauric acid, purified lanolin, glycerin gelatin, polysorbate, poly Ethylene glycol, vegetable oil, wax, liquid paraffin, white petrolatum, fluorocarbon, non-ionic surfactant, prop
  • the active ingredients can be combined with carrier ingredients such as lactose, starch, and crystalline fiber.
  • carrier ingredients such as lactose, starch, and crystalline fiber.
  • binders such as sucrose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, and carboxymethyl cellulose can also be added as needed.
  • Disintegrants such as plain calcium, etc., and wet or dry granulation to form granules; for example, when manufacturing tablets, the powders and/or granules can be directly compressed; for example, hard
  • the granules or tablets can be compressed with hydroxypropyl methyl cellulose phthalate, methacrylic acid-methyl methacrylate, etc.
  • Enteric solvent preparations such as polymers are coated to form enteric solvent preparations; for example, it may be coated with ethyl cellulose, carnauba wax, hydrogenated oil, etc. to form long-acting preparations; for example, in the manufacture of capsules,
  • the powder or granule is filled in a hard capsule.
  • the active ingredient may be directly or dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc., and then covered with a gelatin film to form a soft capsule.
  • the active ingredients when manufacturing injections, can be dissolved together with pH regulators such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, glucose and isotonic agents as needed.
  • pH regulators such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, glucose and isotonic agents as needed.
  • distilled water for injection for example, it can be further sterile filtered and filled in an ampoule; for example, mannitol, dextrin, cyclodextrin, gelatin, etc. can be further added and lyophilized in vacuo to prepare a dissolving injection for use.
  • lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc. to the active ingredient and emulsify it in water to prepare an emulsion for injection.
  • the active ingredient in the manufacture of a rectal administration agent, can be humidified and dissolved together with a base material for suppositories such as cocoa butter, fatty acid triglyceride, fatty acid diglyceride, fatty acid monoglyceride, polyethylene glycol, etc., and then poured into it.
  • a base material for suppositories such as cocoa butter, fatty acid triglyceride, fatty acid diglyceride, fatty acid monoglyceride, polyethylene glycol, etc.
  • the active ingredient may be dissolved in polyethylene glycol, soybean oil, etc., and then coated with a gelatin film.
  • the active ingredients can be added to white petrolatum, beeswax, liquid paraffin, polyethylene glycol, etc., humidified and kneaded as needed to make ointments; for example, it can also be combined with rosin,
  • a binder such as an alkyl acrylate polymer is kneaded and spread on a non-woven fabric such as a polyalkyl group to form a tape preparation.
  • a sustained-release preparation such as an implant or a delivery system encapsulated in a microcapsule, which can be prepared using a carrier that can prevent immediate removal from the body.
  • a carrier that can prevent immediate removal from the body.
  • biodegradable and biocompatible polymers such as ethylene-vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester, and polylactic acid can be used.
  • suspensions of liposomes can also be used as pharmaceutically acceptable carriers.
  • the liposome may comprise a lipid composition containing phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE).
  • PEG-PE PEG-derivatized phosphatidylethanolamine
  • the liposome can be prepared in a suitable size for use, and through an appropriate pore size.
  • the filter is prepared and purified by reverse phase evaporation.
  • the dosage and the number of administrations can be appropriately selected according to conditions such as the prevention and/or treatment of the disease progression of the subject (subject), the type of disease, the weight of the patient, and the age.
  • oral administration may be divided into once or several times a day, or may be administered every few days.
  • it can be administered continuously or intermittently.
  • the kit of the present application may include the drug combination described in the present application.
  • the drug combination can be provided in the form of a kit, and the different constituent components of the drug combination can be packaged in different containers, mixed before administration, or administered separately without mixing.
  • separate packaging may be for long-term storage without losing the function of the active constituent.
  • the preparation contained in the kit may be in any kind of container in which the ingredients of the preparation effectively maintain activity for a long time, are not absorbed by the container material, and are not easily deteriorated.
  • a sealed glass ampoule for example, the ampoule may be composed of organic polymers such as glass, polycarbonate, polystyrene, ceramics, metals, or any other suitable materials that can generally be used to hold reagents.
  • suitable containers include simple bottles made of substances similar to ampoules, and packaging materials lined with foils such as aluminum or alloy.
  • Other containers include test tubes, vials, flasks, bottles, syringes, or the like.
  • the container has a sterile access port such as a bottle, and the bottle has a stopper that can be penetrated by a hypodermic injection needle.
  • the kit may also include a buffer solution packaged in the presence of a neutral and non-reactive gas such as nitrogen.
  • a neutral and non-reactive gas such as nitrogen.
  • the kit may also include auxiliary administration devices, such as a measuring cup and a measuring spoon suitable for oral administration, such as a syringe, an infusion tube, an infusion needle, and the like suitable for injection.
  • auxiliary administration devices such as a measuring cup and a measuring spoon suitable for oral administration, such as a syringe, an infusion tube, an infusion needle, and the like suitable for injection.
  • instructions for use are also attached to the kit.
  • the instructions for use of the kit composed of the pharmaceutical composition can be printed on paper or other materials, and/or can be read electronically or electromagnetically with Floppy disks, CD-ROMs, DVD-ROMs, Zip disks, video tapes, audio tapes, etc.
  • the way of taking the medium is supplied.
  • the detailed instructions for use can be actually attached to the kit, or posted on a website designated by the manufacturer or distributor of the kit or notified by e-mail.
  • the drugs used in the examples of this application can be as shown in Table 1, and all can be obtained through conventional commercial channels.
  • the drugs numbered 1-12 use DMSO as the solvent, and sodium ascorbate uses PBS as the solvent.
  • HEK293 cells HOS human osteosarcoma cells, 143B human osteosarcoma cells, MC38 cells and DB cells in the examples of this application were all purchased from ATCC.
  • Example 1 The inhibitory effect of berberine (Berberine) and sodium ascorbate in combination on osteosarcoma cells
  • HEK293 cells, HOS human osteosarcoma cells and 143B human osteosarcoma cells were subcultured using RPMI-1640 medium containing 10% fetal bovine serum FBS at 37°C and 5% carbon dioxide in an incubator.
  • the experimental group is the cell group with different concentrations of drugs
  • the control group is the cell group with only solvent (DMSO)
  • the blank group is the group without cells but only the solvent (DMSO).
  • the result of cell viability is obtained from the above formula ,
  • the cell inhibition rate of the drug 100%-cell activity.
  • the cell viability of the control group obtained according to this formula is 100%.
  • the results of the concentration gradient berberine treatment of the cells are shown in Figure 1.
  • Each experimental group includes the berberine single-drug group (concentration of 20 ⁇ M), the ascorbic acid group (concentration of 0.5mM), and berberine (concentration of 20 ⁇ M). )
  • the control group is the cell group only added solvent DMSO
  • the blank group is the group where no cells are added but only solvent (DMSO) is added.
  • the coefficient of drug in interaction evaluates the nature of the interaction between the two drugs. Divided into the control group, the A drug group, the B drug group and the AB combined drug group, the cell viability of the A, B, and AB groups were detected respectively.
  • the combination of berberine and ascorbic acid can specifically inhibit the activity of 143B cells and HOS cells, and the inhibitory effects on 143B cells and HOS cells are significantly better than the corresponding single-agent group (P ⁇ 0.001) .
  • the results are shown in Figure 2.
  • Example 2 The inhibitory effect of Foxy-5 in combination with sodium ascorbate on osteosarcoma cells
  • the cell viability of HOS cells is 65% under the condition of 0.1 ⁇ M Pyrvinium single agent treatment; the cell viability of HOS cells is 99% under the condition of 0.5mM sodium ascorbate treatment; 0.1 ⁇ M Pyrvinium and 0.5mM ascorbic acid Under the condition of sodium combined use, the cell viability of HOS cells is 49%.
  • the CDI value for HOS cells is 0.76, indicating that the two have a synergistic effect.
  • the inhibitory effect of Pyrvinium and ascorbic acid on HOS cells was significantly better than that of the corresponding single-drug group (P ⁇ 0.05). The results are shown in Figure 5.
  • Example 4 The inhibitory effect of Niclosamide combined with sodium ascorbate on osteosarcoma cells
  • Example 5 The inhibitory effect of ETC-159 combined with sodium ascorbate on osteosarcoma cells
  • Example 1 According to the method of Example 1, the inhibitory effect of ETC-159 on HOS human osteosarcoma cells and 143B human osteosarcoma cells was tested.
  • Example 6 The inhibitory effect of LGK974 in combination with sodium ascorbate on osteosarcoma cells
  • the CDI value is 0.07, and the CDI value for 143B cells is 0.04, indicating that the two have a synergistic effect.
  • the combination of LGK974 and ascorbic acid had significantly better inhibitory effects on 143B cells and HOS cells than the corresponding single-agent group (P ⁇ 0.001). The results are shown in Figure 8.
  • Example 7 The inhibitory effect of Sonidegib and sodium ascorbate on osteosarcoma cells
  • Example 8 The inhibitory effect of Vismodegib in combination with sodium ascorbate on osteosarcoma cells
  • Example 1 According to the method of Example 1, the inhibitory effect of Vismodegib on HOS human osteosarcoma cells and 143B human osteosarcoma cells was tested.
  • Example 9 The inhibitory effect of PF-03084014 in combination with sodium ascorbate on osteosarcoma cells
  • Example 2 According to the method of Example 1, the inhibitory effect of PF-03084014 on HOS human osteosarcoma cells was tested. The concentration gradient of PF-03084014 and the results of cell treatment are shown in Figure 12.
  • Example 11 The inhibitory effect of MK0752 in combination with sodium ascorbate on osteosarcoma cells
  • the CDI value is 0.05, and the CDI value for 143B cells is 0.16, indicating that the two have a synergistic effect.
  • the inhibitory effect of MK0752 combined with ascorbic acid on 143B cells and HOS cells was significantly better than the corresponding single-agent group (P ⁇ 0.001). The results are shown in Figure 15.
  • Example 12 The inhibitory effect of Sulindac in combination with sodium ascorbate on osteosarcoma cells
  • the cell viability of HOS cells was 92% under the condition of 50 ⁇ M Sulindac single agent treatment; the cell viability of HOS cells was 102% under the condition of 0.5mM sodium ascorbate treatment; 50 ⁇ M Sulindac was combined with 0.5mM sodium ascorbate Under the conditions, the cell viability of HOS cells is 39%.
  • the CDI value for HOS cells is 0.42, indicating that the two have a synergistic effect.
  • the inhibitory effect of Sulindac and ascorbic acid on HOS cells was significantly better than that of the corresponding single-drug group (P ⁇ 0.05). See Figure 17 for the results.
  • Example 13 The inhibitory effect of different inhibitors in combination with sodium ascorbate on colon cancer cells
  • the control group only adds solvent DMSO
  • the Nic group adds 1 ⁇ M Niclosamide
  • the Vc group adds 0.5mM ascorbic acid
  • the Nic+Vc group adds 1 ⁇ M Niclosamide and 0.5 mM ascorbic acid.
  • Figure 18 shows that compared with the cell viability of the control group, the cell viability of MC38 cells was 82% when treated with Niclosamide at a concentration of 1 ⁇ M; the cell viability of MC38 cells was 105 when treated with ascorbic acid at a concentration of 0.5mM. %; The cell viability of MC38 cells is 62% under the conditions of Niclosamide at a concentration of 1 ⁇ M and ascorbic acid at a concentration of 0.5 mM. According to the CDI calculation formula in Example 1, the coefficient of drug in interaction (CDI) for MC38 cells was 0.72, indicating that the two have a synergistic effect. At the same time, the combined use of Niclosamide and ascorbic acid has a better inhibitory effect on MC38 cells than the corresponding single-agent group.
  • CDI coefficient of drug in interaction
  • the control group only added solvent DMSO, the Vc group added 2mM ascorbic acid, the low-dose Nic group added 1 ⁇ M Niclosamide, and the low-dose Nic+Vc group added 1 ⁇ M Niclosamide and Ascorbic acid at a concentration of 2mM
  • the high-dose Nic group was added with Niclosamide at a concentration of 2 ⁇ M
  • the high-dose Nic+Vc group was added with Niclosamide at a concentration of 2 ⁇ M and ascorbic acid at a concentration of 2mM.
  • Figure 19 shows that, compared with the cell viability of the control group, the cell viability of DB cells was 76% when treated with ascorbic acid at a concentration of 2mM; the cell viability of DB cells was 57% when treated with Niclosamide at a concentration of 1 ⁇ M ; Niclosamide at a concentration of 1 ⁇ M and ascorbic acid at a concentration of 2mM, the cell viability of DB cells is 17%; Niclosamide at a concentration of 2 ⁇ M, the cell viability of DB cells is 52%; Niclosamide and a concentration of 2 ⁇ M Under the condition of 2mM ascorbic acid treatment, the cell viability of DB cells was 15%. According to the CDI calculation formula in Example 1, the drug interaction coefficient for DB cells was obtained.

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Abstract

本申请涉及一种药物组合，其包含：a)预防和/或治疗有效量的抗坏血酸或其衍生物；以及b)预防和/或治疗有效量的选自下组的第二治疗剂：Notch信号通路抑制剂，HH信号通路抑制剂，Porcupine抑制剂，RXRα抑制剂，Niclosamide，CK1a抑制剂和Frizzled受体抑制剂。

Description

药物组合及其用途 技术领域
本申请涉及生物医药领域，具体的涉及一种药物组合及其用途。
背景技术
恶性肿瘤是当前严重危害人类健康的疾病。例如，骨肉瘤作为一种多见的恶性骨肿瘤，在中国每年新发病率约有3/100万，通常患者在确诊骨肉瘤时有20％已经发生远处转移，如果骨肉瘤发生远处转移，患者五年无病生存率不到20％，目前用于治疗骨肉瘤的药物为大剂量甲氨蝶呤、异环磷酰胺、多柔比星、顺铂等，或者选用两种或两种以上药物联合化疗并保证足够的剂量强度，而这些化疗方式会产生强烈的副作用危害生命健康；结直肠癌占癌症总发病人数的10.2％和死亡人数的9.2％，即每年结直肠癌有约185万的新增病例及88万死亡病例，结直肠癌的临床治疗中以奥沙利铂为主，然而临床中有30％以上的结肠癌患者对奥沙利铂不敏感；卵巢癌发病率约占恶性肿瘤的3.4％，临床化疗方案有铂类药物+环磷酰胺(PC)，以及泰素+卡铂(TP)，然而这些化疗方案也存在严重的副作用，比如对消化系统及血液系统的损害。这些都表明化疗药物在抗肿瘤的同时也表现出不同程度的毒副作用，并且还有部分肿瘤患者对化疗药物不敏感，因此，寻找更为有效的抗肿瘤药物与方法是全世界医学界亟需解决的难题。
发明内容
本申请提供了一种药物组合及其用途或施用方法，主要包括将包含Notch信号通路抑制剂，HH信号通路抑制剂，Porcupine抑制剂，RXRα抑制剂，Niclosamide，CK1a抑制剂和/或Frizzled受体抑制剂的治疗剂与抗坏血酸或其衍生物作为治疗肿瘤的药物组合，或者将包含Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂和/或Wnt信号通路抑制剂的治疗剂与抗坏血酸或其衍生物组合施用以治疗肿瘤，具有至少一种如下技术效果：
1)药物组合可以作为传统化疗药物的替代疗法，以避免传统化疗对人体产生的毒副作用。
2)药物组合用于治疗对传统化疗药物不敏感的肿瘤患者以达到治疗的效果。
3)药物组合可以与传统化疗药物联用以降低化疗药物的剂量，从而降低传统化疗药物的毒副作用。
4)药物的联用组合对肿瘤取得了出乎意料的抑制效果，显著降低了同等效果的单药施用的剂量，提高了用药安全性。
5)药物组合特异性的肿瘤细胞生长，对其他正常细胞(例如293细胞)没有影响，体现了药物安全性。
本申请提供了一种药物组合，其包含：
a)预防和/或治疗有效量的抗坏血酸或其衍生物；以及
b)预防和/或治疗有效量的选自下组的第二治疗剂：Notch信号通路抑制剂，HH信号通路抑制剂，Porcupine抑制剂，RXRα抑制剂，Niclosamide，CK1a抑制剂和Frizzled受体抑制剂。
在某些实施方式中，所述RXRα抑制剂包含小檗碱或其药学上可接受的盐。
在某些实施方式中，所述Notch信号通路抑制剂包含γ-分泌酶抑制剂。
在某些实施方式中，所述γ-分泌酶抑制剂包含MK0752、RO4929097和/或PF-03084014。
在某些实施方式中，所述HH信号通路抑制剂包含SMO抑制剂。
在某些实施方式中，所述SMO抑制剂包含Vismodegib、Sonidegib和/或Glasdegib。
在某些实施方式中，所述Porcupine抑制剂包含LGK974和/或ETC-159。
在某些实施方式中，所述CK1a抑制剂包含Pyrvinium。
在某些实施方式中，所述Frizzled受体抑制剂包含Foxy-5。
在某些实施方式中，所述抑制剂包含Fervenulin、3-Methyltoxoflavin和/或Walrycin B。
在某些实施方式中，所述抗坏血酸衍生物包含药学上可接受的抗坏血酸盐。
在某些实施方式中，所述药学上可接受的抗坏血酸盐包含抗坏血酸钠。
在某些实施方式中，所述第二治疗剂的所述有效量与所述抗坏血酸或其衍生物的所述有效量比率为约1:10至约1:5000。
在某些实施方式中，所述第二治疗剂与所述抗坏血酸或其衍生物的质量比为约1:10至约1:5000。
在某些实施方式中，所述第二治疗剂与所述抗坏血酸或其衍生物各自存在于不同的容器中。
在某些实施方式中，所述药物组合包含第一制剂和第二制剂，所述第一制剂包含所述抗坏血酸或其衍生物和药学上可接受的第一载体，且所述第二制剂包含所述第二治疗剂和药学上可接受的第二载体。
在某些实施方式中，所述药物组合包含药物组合物，且所述药物组合物包含所述第二治 疗剂和所述抗坏血酸或其衍生物。
在某些实施方式中，所述药物组合物中所述第二治疗剂的含量为约5％至约20％(w/w)。
在某些实施方式中，所述药物组合物中所述抗坏血酸或其衍生物的含量为约80％至约95％(w/w)。
另一方面，本申请还提供了试剂盒，其包括本申请所述的药物组合。
另一方面，本申请还提供了抗坏血酸或其衍生物与第二治疗剂的组合在制备药物中的用途，所述药物用于预防和/或治疗肿瘤，其中所述第二治疗剂选自：Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂和Wnt信号通路抑制剂。
在某些实施方式中，所述Wnt信号通路抑制剂包含Porcupine抑制剂，Dvl-2抑制剂、CK1a抑制剂和/或Frizzled受体抑制剂。
在某些实施方式中，所述Porcupine抑制剂包含LGK974和/或ETC-159。
在某些实施方式中，所述Dvl-2抑制剂包含Niclosamide和/或Sulindac。
在某些实施方式中，所述CK1a抑制剂包含Pyrvinium。
在某些实施方式中，所述Frizzled受体抑制剂包含Foxy-5。
在某些实施方式中，所述RXRα抑制剂包含小檗碱或其药学上可接受的盐。
在某些实施方式中，所述Notch信号通路抑制剂包含γ-分泌酶抑制剂。
在某些实施方式中，所述γ-分泌酶抑制剂包含MK0752、RO4929097和/或PF-03084014。
在某些实施方式中，所述HH信号通路抑制剂包含SMO抑制剂。
在某些实施方式中，所述SMO抑制剂包含Vismodegib、Sonidegib和/或Glasdegib。
在某些实施方式中，所述肿瘤包括实体瘤和非实体瘤。
在某些实施方式中，所述实体瘤包括骨肉瘤和/或结肠癌。
在某些实施方式中，所述非实体瘤包括淋巴瘤。
在某些实施方式中，所述抗坏血酸衍生物包含药学上可接受的抗坏血酸盐。
在某些实施方式中，所述药学上可接受的抗坏血酸盐包含抗坏血酸钠。
在某些实施方式中，所述第二治疗剂与所述抗坏血酸或其衍生物被配置为同时向受试者施用。
在某些实施方式中，所述第二治疗剂与所述抗坏血酸或其衍生物被配置为分别向受试者施用。
在某些实施方式中，所述药物被配置为使得所述第二治疗剂以约1mg/kg至约100mg/kg的剂量被施用。
在某些实施方式中，所述药物被配置为使得所述抗坏血酸或其衍生物以约0.05g/kg至约2.5g/kg的剂量被施用。
在某些实施方式中，所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:5000的质量比被施用。
在某些实施方式中，所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:5000的质量比被施用。
另一方面，本申请还提供一种预防和/或治疗肿瘤的方法，其包括向有需要的受试者施用：
a)抗坏血酸或其衍生物；和
b)第二治疗剂，其中所述第二治疗剂选自：Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂和Wnt信号通路抑制剂。
在某些实施方式中，所述Wnt信号通路抑制剂包含Porcupine抑制剂，Dvl-2抑制剂、CK1a抑制剂和/或Frizzled受体抑制剂。
在某些实施方式中，所述Porcupine抑制剂包含LGK974和/或ETC-159。
在某些实施方式中，所述Dvl-2抑制剂包含Niclosamide和/或Sulindac。
在某些实施方式中，所述CK1a抑制剂包含Pyrvinium。
在某些实施方式中，所述Frizzled受体抑制剂包含Foxy-5。
在某些实施方式中，所述RXRα抑制剂包含小檗碱或其药学上可接受的盐。
在某些实施方式中，所述Notch信号通路抑制剂包含γ-分泌酶抑制剂。
在某些实施方式中，所述γ-分泌酶抑制剂包含MK0752、RO4929097和/或PF-03084014。
在某些实施方式中，所述HH信号通路抑制剂包含SMO抑制剂。
在某些实施方式中，所述SMO抑制剂包含Vismodegib、Sonidegib和/或Glasdegib。
在某些实施方式中，所述肿瘤包括实体瘤和非实体瘤。
在某些实施方式中，所述实体瘤包括骨肉瘤和/或结肠癌。
在某些实施方式中，所述非实体瘤包括淋巴瘤。
在某些实施方式中，所述抗坏血酸衍生物包含药学上可接受的抗坏血酸盐。
在某些实施方式中，所述药学上可接受的抗坏血酸盐包含抗坏血酸钠。
在某些实施方式中，所述第二治疗剂与所述抗坏血酸或其衍生物被配置为同时向受试者施用。
在某些实施方式中，所述第二治疗剂与所述抗坏血酸或其衍生物被配置为分别向受试者施用。
在某些实施方式中，所述药物被配置为使得所述第二治疗剂以约1mg/kg至约100mg/kg的剂量被施用。
在某些实施方式中，所述药物被配置为使得所述抗坏血酸或其衍生物以约0.05g/kg至约2.5g/kg的剂量被施用。
在某些实施方式中，所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:5000的质量比被施用。
在某些实施方式中，所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:5000的质量比被施用。
另一方面，本申请还提供监测受试者对药物响应情况的方法，所述方法包括：
a)向所述受试者施用抗坏血酸或其衍生物和第二治疗剂，其中所述第二治疗剂选自：Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂和Wnt信号通路抑制剂；以及
b)检测经a)的所述施用后，所述受试者中下述一种或多种的变化：血液碱性磷酸酶水平和/或活性，乳酸脱氢酶水平和/或活性，CADM1基因的表达水平，CD44基因的表达水平，livin基因的表达水平，HIF-1α基因的表达水平，ET-1基因的表达水平，IGF-1R基因的表达水平，STAT3基因的表达水平，CEA基因的表达水平，CA199基因的表达水平，CA125基因的表达水平，AFP基因的表达水平，CA724基因的表达水平，β-HCG基因的表达水平。
在某些实施方式中，所述Wnt信号通路抑制剂包含Porcupine抑制剂，Dvl-2抑制剂、CK1a抑制剂和/或Frizzled受体抑制剂。
在某些实施方式中，所述Porcupine抑制剂包含LGK974和/或ETC-159。
在某些实施方式中，所述Dvl-2抑制剂包含Niclosamide和/或Sulindac。
在某些实施方式中，所述CK1a抑制剂包含Pyrvinium。
在某些实施方式中，所述Frizzled受体抑制剂包含Foxy-5。
在某些实施方式中，所述RXRα抑制剂包含小檗碱或其药学上可接受的盐。
在某些实施方式中，所述Notch信号通路抑制剂包含γ-分泌酶抑制剂。
在某些实施方式中，所述γ-分泌酶抑制剂包含MK0752、RO4929097和/或PF-03084014。
在某些实施方式中，所述HH信号通路抑制剂包含SMO抑制剂。
在某些实施方式中，所述SMO抑制剂包含Vismodegib、Sonidegib和/或Glasdegib。
在某些实施方式中，所述肿瘤包括实体瘤和非实体瘤。
在某些实施方式中，所述实体瘤包括骨肉瘤和/或结肠癌。
在某些实施方式中，所述非实体瘤包括淋巴瘤。
在某些实施方式中，所述抗坏血酸衍生物包含药学上可接受的抗坏血酸盐。
在某些实施方式中，所述药学上可接受的抗坏血酸盐包含抗坏血酸钠。
在某些实施方式中，所述第二治疗剂与所述抗坏血酸或其衍生物被配置为同时向受试者施用。
在某些实施方式中，所述第二治疗剂与所述抗坏血酸或其衍生物被配置为分别向受试者施用。
在某些实施方式中，所述药物被配置为使得所述第二治疗剂以约1mg/kg至约100mg/kg的剂量被施用。
在某些实施方式中，所述药物被配置为使得所述抗坏血酸或其衍生物以约0.05g/kg至约2.5g/kg的剂量被施用。
在某些实施方式中，所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:5000的质量比被施用。
在某些实施方式中，所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:5000的质量比被施用。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的，本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地，本申请的附图和说明书中的描述仅仅是示例性的，而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明书如下：
图1显示的是本申请所述的不同浓度的小檗碱对143B细胞和HOS细胞的影响。
图2显示的是本申请所述的小檗碱与抗坏血酸钠联用对143B细胞和HOS细胞的抑制作用。
图3显示的是本申请所述的不同浓度的Foxy-5对143B细胞和HOS细胞的影响。
图4显示的是本申请所述的Foxy-5与抗坏血酸钠联用对143B细胞和HOS细胞的抑制作用。
图5显示的是本申请所述的Pyrvinium与抗坏血酸钠联用对143B细胞和HOS细胞的抑制作用。
图6显示的是本申请所述的Niclosamide与抗坏血酸钠联用对143B细胞和HOS细胞的抑制作用。
图7显示的是本申请所述的ETC-159与抗坏血酸钠联用对143B细胞和HOS细胞的抑制作用。
图8显示的是本申请所述的LGK974与抗坏血酸钠联用对143B细胞和HOS细胞的抑制作用。
图9显示的是本申请所述的不同浓度的Sonidegib对143B细胞和HOS细胞的影响。
图10显示的是本申请所述的Sonidegib与抗坏血酸钠联用对143B细胞和HOS细胞的抑制作用。
图11显示的是本申请所述的Vismodegib与抗坏血酸钠联用对143B细胞和HOS细胞的抑制作用。
图12显示的是本申请所述的不同浓度的PF-03084014对143B细胞和HOS细胞的影响。
图13显示的是本申请所述的PF-03084014与抗坏血酸钠联用对143B细胞和HOS细胞的抑制作用。
图14显示的是本申请所述的RO4929097与抗坏血酸钠联用对143B细胞和HOS细胞的抑制作用。
图15显示的是本申请所述的MK0752与抗坏血酸钠联用对143B细胞和HOS细胞的抑制作用。
图16显示的是本申请所述的不同浓度的Sulindac对143B细胞和HOS细胞的影响。
图17显示的是本申请所述的Sulindac与抗坏血酸钠联用对143B细胞和HOS细胞的抑制作用。
图18显示的是本申请所述的Niclosamide与抗坏血酸钠联用对MC38细胞的抑制作用。
图19显示的是本申请所述的不同浓度的Niclosamide与抗坏血酸钠联用对DB细胞的抑制作用。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式，熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
在本申请中，术语“Notch信号通路”通常是指Notch受体介导的细胞信号通路。Notch信号通路是存在于大多数多细胞生物体中高度保守的细胞信号转导系统。Notch信号通路主要由Notch受体、Notch配体(DSL蛋白)、CSL(CBF-1，Su(H)，Lag的合称)DNA结合蛋白、Notch的调节分子和其他的效应物等组成。CBF-1、Su(H)、Lag1是这个蛋白在哺乳动物、果蝇、线虫的不同名称。1917年，Morgan及其同事在突变的果蝇中发现Notch基因，因该基因的部分功能缺失会在果蝇翅膀的边缘造成缺刻(Notch)而得名。哺乳动物有4种Notch受体(Notch1，Notch2，Notch3，Notch4)和5种Notch配体(Delta-like 1，Delta-like 3，Delta-like 4，Jagged1和Jagged2)。研究表明，Notch信号的产生可以通过相邻细胞的Notch配体与受体相互作用，Notch蛋白经过三次剪切(例如由γ-分泌酶介导的剪切)，由胞内段(NICD)释放入胞质，并进入细胞核与转录因子CSL结合，形成NICD/CSL转录激活复合体，从而激活HES、HEY、HERP等碱性-螺旋-环-螺旋(basic helix-loop-helix，bHLH)转录抑制因子家族的靶基因，发挥生物学作用。
在本申请中，术语“功能性变体”通常是指所述功能性变体可以包括在原蛋白序列上进行氨基酸修饰(例如基团取代等)或者进行一个或多个氨基酸的插入、取代、和/或缺失，而保留原序列功能的分子。例如，所述功能性变体可以比原序列具有更好的生物活性(功能)。例如，所述保留不必是完全保留。例如，所述功能性变体可以基本保留原序列功能，例如，保留原序列至少50％、60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％，或99％的功能。
在本申请中，“γ-分泌酶”通常是指一种由四个亚单位组成的膜内蛋白水解酶，可在跨膜结构域内的残基处切割跨膜蛋白。γ分泌酶复合物一般由四个单独的蛋白质亚单位或其功能性变体组成：早老素1(presenilin-1)、尼卡斯特林(nicastrin)，APH-1和早老素增强剂2(presenilin enhancer 2)，Nicastrin的主要作用可以是维持复合物的稳定性并调节细胞内蛋白质的运输；PEN-2通过与早老素的跨膜结构域结合而与复合物缔合，除其他可能的作用外，在早老素蛋白水解产生活化的N端和C端片段后，PEN-2有助于稳定复合物；APH-1是蛋白水解活性所必需的，其通过保守的α螺旋相互作用基序与复合物结合，有助于启动不成熟组分的装配。γ分泌酶参与β－淀粉样蛋白前体(APP)及其他几种I型膜蛋白(例如Notch，ErbB4，E-cadherin，N-cadherin，ephrin-B2和/或CD44)的处理。早老素作为催化亚基是一种天冬氨酰蛋白酶。
在本申请中，术语“HH信号通路”通常是指由Hedgeho(Hh)信号分子介导的细胞信号通路。在脊椎和无脊椎动物的诸多发育过程中，Hedgehog信号通路控制细胞增殖与分化，该信号通路被异常激活时，可能会引起肿瘤的发生与发展。Hedgehog信号分子是一种由信号细胞所分泌的局域性蛋白质配体。哺乳动物中存在三个Hedgehog的同源基因：SonicHedgehog(SHH)、Indian Hedgehog(IHH)和Desert Hedgehog(DHH)，分别编码Shh、Ihh和Dhh蛋白。Hh蛋白家族成员均由两个结构域组成：氨基端结构域(Hh-N)及羧基端结构域(Hh-C)，其中Hh-N有Hh蛋白的信号活性，而Hh-C则具有自身蛋白水解酶活性及胆固醇转移酶功能。Hh信号传递受靶细胞膜上两种受体Patched(Ptc)和Smoothened(Smo)的控制。受体Ptc由肿瘤抑制基因Patched编码，是由12个跨膜区的单一肽链构成，能与配体直接结合，对Hh信号起负调控作用；Smo是Hedgeho(Hh)信号传递所需要的受体。
在本申请中，术语“SMO”通常是指HH信号通路中Hedgeho(Hh)信号传递所需的受体或其功能性变体。受体Smo由原癌基因Smothened编码，与G蛋白偶联受体同源，由7个跨膜区的单一肽链构成，N端位于细胞外，C端位于细胞内，跨膜区氨基酸序列高度保守，C末端的丝氨酸与苏氨酸残基为磷酸化部位，蛋白激酶催化时结合磷酸基团。该蛋白家族成员当维持全长时才有转录启动子的功能，启动下游靶基因的转录；当羧基端被蛋白酶体水解后，形成转录抑制子，抑制下游靶基因的转录。据报道，在无Hh、Ptc的情况下，激活Smo可能导致Hh靶基因的活化；基因Smo突变时，可能出现与Hh基因突变相同的表征。
在本申请中，术语“Wnt信号通路”通常是指由Wnt蛋白介导的细胞信号通路。现在已鉴别出三种Wnt信号通路：经典Wnt通路(canonical Wnt pathway)、非经典Wnt/平面细胞极化通路(noncanonical Wnt/planar cell polarity pathway，PCP)和非经典Wnt/钙离子通路(noncanonical Wnt/calcium pathway)。三种Wnt信号通路都由Wnt蛋白配体与其受体卷曲受体(Frizzled受体)的结合来激活。据报道，经典Wnt信号通路可以参与基因表达的调控，非经典平面细胞极化通路可以调控细胞骨架控制细胞形状，非经典Wnt/钙离子通路可以调控细胞内钙离子的浓度。Wnt信号通路常可用于临近的细胞之间的通信(旁分泌)或同个细胞自身的通信(自分泌)。Wnt信号通路在动物中高度保守。
在本申请中，术语“Dvl-2”通常是指dishevelled(dsh)蛋白家族的成员或其功能性变体。在人类中Dvl-2蛋白由DVL2基因编码。该基因编码一个90kD的蛋白质，该蛋白质经过翻译后磷酸化形成95kD的胞质蛋白，可能在多种Wnt蛋白介导的信号转导途径中起作用。脊椎动物dsh蛋白与果蝇dsh具有约40％的氨基酸序列相似性。
在本申请中，术语“药物组合”通常是指至少包含两种活性成分/治疗剂的组合。在一些实施方式中，各个活性成分/治疗剂可以各自制备成独立的制剂(固体、液体、凝胶体等)，在一些实施方式中，各个活性成分/治疗剂可以存在于不同的容器中，还可以在需要的时候同时或分别与合适的载体配制成期望的制剂；在一些实施方式中，各个活性成分/治疗剂可以是不同来源的(例如不同的商家制备生产或销售的)；在一些实施方式中，各个活性成分/治疗剂可以以混合的形式形成药物组合物。
在本申请中，术语“CK1a”也称作“酪蛋白激酶1α”，通常是指酪蛋白激酶1家族(EC 2.7.11.1)的成员或其功能性变体，属于丝氨酸/苏氨酸激酶(在某种情况下也将酪氨酸残基磷酸化)。作为哺乳类中的其亚型(isoforms)，酪蛋白激酶1已知有α，β1，γ1，γ2，γ3，δ和ε这7种。已知这些亚型通过将各种不同的底物蛋白质磷酸化，使该蛋白质的功能活化或者失活或者稳定化或者不稳定化，从而参与各种不同的生物体功能的调节。酪蛋白激酶1α编码基因可参见HGNC：2451。
在本申请中，术语“Frizzled受体”也称作“卷曲受体”，通常是指G蛋白偶联受体中的一个家族或其功能性变体，可以作为Wnt信号通路和其他信号通路中的受体。一般情况下，当其被激活，能够引起胞内中信号通路下游蛋白(例如，Dishevelled)的激活。卷曲受体蛋白通常包含一个富半胱氨酸结构域，这种结构域常见于受体酪氨酸激酶等蛋白。在人类中，Frizzled受体可以包括Frizzled受体1-8八个成员。
在本申请中，术语“Porcupine”通常是指人类中可参与分泌或内质网转运的蛋白或其功能性变体，其参与Wnt信号通路传导。在秀丽隐杆线虫中，其同源物mom-1在促进Wnt蛋白Mom-2的分泌方面具有相似的功能。Porcupine与o-酰基转移酶家族具有某些同源性，并且可能参与Wnt蛋白的修饰。其编码基因可参见HGNC:17652。
在本申请中，术语“RXRα”也称为NR2B1(核受体亚家族2，B组，成员1)通常是指一种核受体或其功能性变体。在人类中是由RXRA基因编码的，编码序列可参见MGI:98214。
在本申请中，术语“药物组合物”通常是指一种混合物，其包含至少两种对受试者施用以治疗影响该个体的具体疾病或病症的活性成分。其允许所述活性成分处于有效的形式并且不含有对该组合物将要给予的受试者具有不可接受的毒性的另外的组分。这种组合物可以是无菌的，也可以包含药学上可接受的载体。
在本申请中，术语“抑制剂”通常指能够完全或部分地阻碍或降低一种或多种特定生物分子(例如，蛋白质、多肽、脂多糖、糖蛋白、核糖核蛋白复合体等)的生理功能的化合物/物质或组合物。所述降低一种或多种特定蛋白质的生理功能可以包含蛋白质本身活性(例如与 其他分子结合的能力等)的降低或者本身存在量的降低。在某些实施方式中，所述抑制剂可以作为不同的晶体、无定形物质、药学上可接受的盐、水合物和溶剂化物而存在。在某些实施方式中，所述抑制剂能够阻碍细胞信号通路的激活。
在本申请中，术语“抗坏血酸衍生物”通常是指在体内或体外释放抗坏血酸(维生素C)的化合物及其溶剂合物，水合物和盐。该术语还包括抗坏血酸类似物，其中抗坏血酸的一个或多个羟基被另一个结构部分取代，并且其中该抗坏血酸类似物在体外或体内基本上保持了抗坏血酸的稳定活性。
在本申请中，术语“有效量”或“有效剂量”通常是指足以实现或至少部分实现所需效果的量。药物或治疗剂的“治疗有效量”或“治疗有效剂量”通常是当单独使用或与另一种治疗剂组合使用时促进疾病消退(这通过疾病症状严重程度的降低、疾病无症状期的频度和持续时间的增加、或者由于罹患疾病而引起的损害或残疾的预防来证明)的任何药物量。药物的“预防有效量”或“预防有效剂量”通常是指当单独或与另一种治疗剂组合给有疾病发展或疾病复发的风险的受试者施用时抑制疾病的发展或复发的药物量。可以使用本领域技术人员已知的多种方法对治疗剂或预防剂促进疾病消退或抑制疾病发展或复发的能力进行评估，比如在处于临床试验期间的人类受试者中、在动物模型系统中预测对人类的功效、或者通过在体外测定中测定药剂的活性。
在本申请中，术语“预防”通常是指对健康受试者预防性地施用组合，以预防某种疾病或病症的发生。其也可以包含对处于待治疗变应性疾病前期的患者预防性地施用组合。“预防”不需要100％消除疾病或病症发生的可能性，换句话说，“预防”通常指在所述施用组合的存在下疾病或病症发生的可能性或发生程度降低了。
在本申请中，术语“治疗”通常指用于改变所处理的个体或细胞在临床病理过程中的自然过程的临床干预。可以包括改善病状态、消除病灶或改善的预后。
在本申请中，术语“施用”通常是指通过任意引入或递送途径将所述药物组合引入受试者的身体中。可以采用本领域技术人员已知的用于使细胞、器官或组织与所述药物组合接触的任何方法。包括而不限于动脉内、鼻内、腹内、静脉内、肌内、皮下透皮或口服。每日剂量可以划分成一个、两个或更多个合适形式的剂量以在某个时间段期间的一个、两个或更多个时间施用。
在本申请中，术语“肿瘤”通常指由异常细胞生长形成的赘生物或实体病变。在本申请中，肿瘤可以是实体瘤或非实体瘤。在某些实施方式中，可通过临床检查如x线摄片、CT扫描， B超、或触诊扪及到的有形肿块可称为实体瘤，X线、CT扫描，B超及触诊无法看到或扪及到的肿瘤例如白血病可称为非实体瘤。
在本申请中，术语“受试者”通常是指人类或非人类动物，包括但不限于猫、狗、马、猪、奶牛、羊、兔、小鼠、大鼠或猴等。
在本申请中，术语“制剂”，也可称作药物制剂，通常是指为适应治疗或预防的需要，按照一定的剂型要求所制成的可以提供给受试者使用的药物。例如，制剂可以包含活性成分、载体。
在本申请中，术语“载体”通常是指活性成分之外的其他任何物质。例如药学上可接受的涉及携带或转运化学试剂的物质、组合物或媒介物。例如缓冲液、表面活性剂、稳定剂、防腐剂、用于增强生物利用度的吸收促进剂、液体或固体填充剂、稀释剂、赋形剂、溶剂、包囊材料和/或其他常规的增溶剂或分散剂等。
在本申请中，术语“容器”通常是指任何适用于盛装药物的器皿或装置。例如，药盒、药瓶、药袋、泡罩、管、注射器等。
在本申请中，术语“包含”或“包括”通常是指包括明确指定的特征，但不排除其他要素。
在本申请中，术语“约”通常是指在指定数值以上或以下0.5％-10％的范围内变动，例如在指定数值以上或以下0.5％、1％、1.5％、2％、2.5％、3％、3.5％、4％、4.5％、5％、5.5％、6％、6.5％、7％、7.5％、8％、8.5％、9％、9.5％、或10％的范围内变动。
发明详述
一方面，本申请提供一种本申请提供了一种药物组合，其包含：
a)预防和/或治疗有效量的抗坏血酸或其衍生物；以及
b)预防和/或治疗有效量的选自下组的第二治疗剂：Notch信号通路抑制剂，Hh信号通路抑制剂，Porcupine抑制剂，RXRα抑制剂，Niclosamide，CK1a抑制剂和Frizzled受体抑制剂。
另一方面，本申请还提供了抗坏血酸或其衍生物与第二治疗剂的组合在制备药物中的用途，所述药物用于预防和/或治疗肿瘤，其中所述第二治疗剂选自：Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂和Wnt信号通路抑制剂。
例如，所述第二治疗剂可以包括Notch信号通路抑制剂。
例如，所述第二治疗剂可以包括SHH信号通路抑制剂。
例如，所述第二治疗剂可以包括RXRα抑制剂。
例如，所述第二治疗剂可以包括Wnt信号通路抑制剂。
另一方面，本申请还提供一种预防和/或治疗肿瘤的方法，其包括向有需要的受试者施用：
a)抗坏血酸或其衍生物；和
b)第二治疗剂，其中所述第二治疗剂选自：Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂和Wnt信号通路抑制剂。
另一方面，本申请还提供监测受试者对药物响应情况的方法，所述方法包括：
a)向所述受试者施用抗坏血酸或其衍生物和第二治疗剂，其中所述第二治疗剂选自：Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂和Wnt信号通路抑制剂；以及
b)检测经a)的所述施用后，所述受试者中下述一种或多种的变化：血液碱性磷酸酶水平和/或活性，乳酸脱氢酶水平和/或活性，CADM1基因的表达水平，CD44基因的表达水平，livin基因的表达水平，HIF-1α基因的表达水平，ET-1基因的表达水平，IGF-1R基因的表达水平，STAT3基因的表达水平，CEA基因的表达水平，CA199基因的表达水平，CA125基因的表达水平，AFP基因的表达水平，CA724基因的表达水平，β-HCG基因的表达水平。
另一方面，本申请还提供了试剂盒，其包括本申请所述的药物组合。
药物组合
本申请的药物组合包含：a)预防和/或治疗有效量的本申请所述的抗坏血酸或其衍生物；和b)预防和/或治疗有效量的选自下组的本申请所述的第二治疗剂：Notch信号通路抑制剂，HH信号通路抑制剂，Porcupine抑制剂，RXRα抑制剂，Niclosamide，CK1a抑制剂和Frizzled受体抑制剂。其中，所述的抗坏血酸或其衍生物可以包括抗坏血酸、抗坏血酸衍生物及其任意组合。所述的第二治疗剂可以包括Notch信号通路抑制剂、HH信号通路抑制剂、Porcupine抑制剂、RXRα抑制剂、Niclosamide、CK1a抑制剂、Frizzled受体抑制剂中的任意一种，或者任意几种的组合。
例如，所述第二治疗剂可以包括Notch信号通路抑制剂。
例如，所述第二治疗剂可以包括HH信号通路抑制剂。
例如，所述第二治疗剂可以包括Porcupine抑制剂。
例如，所述第二治疗剂可以包括RXRα抑制剂。
例如，所述第二治疗剂可以包括Niclosamide。
例如，所述第二治疗剂可以包括CK1a抑制剂。
例如，所述第二治疗剂可以包括Frizzled受体抑制剂。
例如，所述第二治疗剂的所述有效量与所述抗坏血酸或其衍生物的所述有效量比率为约1:1至约1:5000。
例如，所述第二治疗剂的所述有效量与所述抗坏血酸或其衍生物的所述有效量比率为约1:10至约1:5000。
例如，所述第二治疗剂的所述有效量与所述抗坏血酸或其衍生物的所述有效量比率为1:1至约1:20、约1:5至约1:20、约1:10至约1:20、约1:10至约1:25、约1:10至约1:50、约1:10至约1:100、约1:10至约1:150、约1:10至约1:200、约1:10至约1:250、约1:10至约1:300、约1:10至约1:400、约1:10至约1:450、约1:10至约1:500、约1:10至约1:550、约1:10至约1:600、约1:10至约1:650、约1:10至约1:700、约1:10至约1:800、约1:10至约1:900、约1:10至约1:1000、约1:10至约1:1500、约1:10至约1:2000、约1:10至约1:3000、约1:10至约1:4000、约1:10至约1:5000、约1:5至约1:20、约1:5至约1:25、约1:5至约1:35、约1:5至约1:50、约1:5至约1:100、约1:5至约1:150、约1:5至约1:200、约1:25至约1:50、约1:25至约1:100、约1:25至约1:150、约1:25至约1:200、约1:25至约1:1000、约1:25至约1:5000、约1:50至约1:100、约1:50至约1:150、约1:50至约1:200、约1:50至约1:300、约1:50至约1:500、约1:50至约1:1000、约1:50至约1:2000、约1:50至约1:4000或约1:50至约1:5000、约1:4500至约1:5500。
例如，所述第二治疗剂的所述有效量与所述抗坏血酸或其衍生物的所述有效量比率为约1:1、1:5、1:7、1:10、1:12、1:15、1:17、1:20、1:25、1:35、1:40、1:45、1:50、1:55、1:60、1:65、1:70、1:75、1:80、1:85、1:90、1:100、1:120、1:150、1:180、1:200、1:220、1:250、1:280、1:300、1:320、1:350、1:380、1:400、1:420、1:450、1:480、1:500、1:550、1:600、1:650、1:700、1:750、1:800、1:850、1:900、1:950、1:1000、1:1100、1:1200、1:1300、1:1400、1:1500、1:1600、1:1700、1:1800、1:1900、1:2000、1:2100、1:2200、1:2300、1:2400、1:2500、1:2600、1:2700、1:2800、1:2900、1:3000、1:3100、1:3200、1:3300、1:3400、1:3500、1:3600、1:3700、1:3800、1:3900、1:4000、1:4100、1:4200、1:4300、1:4400、1:4500、1:4600、1:4700、1:4800、1:4900或1:5000。
例如，所述有效量比率可以包括有效量摩尔数比率和/或有效量质量比率。
例如，所述第二治疗剂与所述抗坏血酸或其衍生物的质量比为约5000:1至约1:5000。
例如，所述第二治疗剂与所述抗坏血酸或其衍生物的质量比为约20:1至1:1、约20:1至约5:1、约20:1至约10:1、约25:1至约10:1、约50:1至约10:1、约100:1至约10:1、约150:1至约10:1、约200:1至约10:1、约250:1至约10:1、约300:1至约10:1、约400:1至约10:1、约450:1至约10:1、约10:1至约500:1、约10:1至约550:1、约10:1至约600:1、约10:1至约650:1、约700:1至约10:1、约800:1至约10:1、约900:1至约10:1、约1000:1至约10:1、约 1500:1至约10:1、约2000:1至约10:1、约3000:1至约10:1、约4000:1至约10:1、约5000:1至约10:1、约20:1至约5:1约1000:1至约50:1、约2000:1至约50:1、约3000:1至约50:1、约4000:1至约50:1、约5000:1至约1:50、约20:1至1:20、约20:1至约1:20、约20:1至约1:25、约25:1至约50:1、约50:1至约1:100、约100:1至约1:100、约150:1至约1:100、约200:1至约1:200、约250:1至约1:500、约300:1至约1:1000、约400:1至约1:100、约450:1至约1:500、约10:1至约1:500、约10:1至约1:550、约10:1至约1:600、约10:1至约1:650、约700:1至约1:650、约800:1至约1:800、约900:1至约1:900、约1000:1至约1:1000、约1500:1至约1:1000、约2000:1至约1:1500、约3000:1至约1:500、约4000:1至约1:2500、约5000:1至约1:3500、约20:1至约1:1500、约1000:1至约1:2000、约2000:1至约1:5000约1:1至约1:20、约1:5至约1:20、约1:10至约1:20、约1:10至约1:25、约1:10至约1:50、约1:10至约1:100、约1:10至约1:150、约1:10至约1:200、约1:10至约1:250、约1:10至约1:300、约1:10至约1:400、约1:10至约1:450、约1:10至约1:500、约1:10至约1:550、约1:10至约1:600、约1:10至约1:650、约1:10至约1:700、约1:10至约1:800、约1:10至约1:900、约1:10至约1:1000、约1:10至约1:1500、约1:10至约1:2000、约1:10至约1:3000、约1:10至约1:4000、约1:10至约1:5000、约1:5至约1:20、约1:5至约1:25、约1:5至约1:35、约1:5至约1:50、约1:5至约1:100、约1:5至约1:150、约1:5至约1:200、约1:25至约1:50、约1:25至约1:100、约1:25至约1:150、约1:25至约1:200、约1:25至约1:1000、约1:25至约1:5000、约1:50至约1:100、约1:50至约1:150、约1:50至约1:200、约1:50至约1:300、约1:50至约1:500、约1:50至约1:1000、约1:50至约1:2000、约1:50至约1:3000、约1:50至约1:4000或约1:50至约1:5000。
例如，所述第二治疗剂与所述抗坏血酸或其衍生物的质量比为约1:10至约1:5000。
例如，所述第二治疗剂与所述抗坏血酸或其衍生物各自可以是不同来源的，例如不同的商家制备生产或销售的。例如所述制备生产或销售的抗坏血酸或其衍生物不必是单一成分的或者纯的，只要其含有能够在体内或体外释放抗坏血酸(维生素C)的化合物或其溶剂合物、水合物、盐类，和/或含有抗坏血酸的类似物(例如，其中抗坏血酸的一个或多个羟基被另一个结构部分取代，并且其中该抗坏血酸类似物在体外或体内基本上保持了抗坏血酸的稳定活性)均在本申请的范围之内。同理的，所述制备生产或销售的第二治疗剂不必是单一成分的或者纯的，只要其含有能够在体内或体外释放本申请所述的第二治疗剂中的任意一种或多种，或其溶剂合物、水合物、盐类，和/或含有所述的第二治疗剂中的任意一种或多种的类似物(例如，其包含基团修饰或取代，并且该类似物在体外或体内基本上保持了任意第二治疗剂的稳 定活性)均在本申请的范围之内。
例如，所述第二治疗剂与所述抗坏血酸或其衍生物各自存在于不同的容器中。
例如，所述第二治疗剂与所述抗坏血酸或其衍生物各自存在于不同的容器中，且所述第二治疗剂的量与所述抗坏血酸或其衍生物的量可以按照其有效量比率设置，也可以不按照其有效比率设置。
例如，所述第二治疗剂可以存在于1个或以上的容器中，例如2个或以上，3个或以上，4个或以上，5个或以上，6个或以上，7个或以上，8个或以上，9个或以上，10个或以上，11个或以上，12个或以上。
例如，所述抗坏血酸或其衍生物可以存在于1个或以上的容器中，例如2个或以上，3个或以上，4个或以上，5个或以上，6个或以上，7个或以上，8个或以上，9个或以上，10个或以上，11个或以上，12个或以上。
例如，所述容器可以包括药箱、药盒、药瓶、药袋、泡罩、管、注射器等；例如，所述药瓶可以包括密封的玻璃安瓿、试管、小瓶、烧瓶、瓶子等；例如，所述容器可以由玻璃、聚碳酸酯、聚苯乙烯等有机聚合物或陶瓷、金属、复合膜、玻璃纸、部用铝或合金等的箔片内衬的包装材料以及通常可被用于保持试剂的其它任何恰当的材料等构成。
例如，所述第二治疗剂与所述抗坏血酸或其衍生物可以各自存在于不同的容器中，并且可以在需要的时候同时或分别与合适的载体配制成制剂。
例如，所述第二治疗剂与所述抗坏血酸或其衍生物混合配制成合适的制剂。
例如，所述第二治疗剂与所述抗坏血酸或其衍生物各自配制成不同的合适的制剂。
例如，所述第二治疗剂与所述抗坏血酸或其衍生物可以以制剂的形式各自存在于不同的容器中。
例如，所述药物组合包含第一制剂和第二制剂，所述第一制剂包含所述抗坏血酸或其衍生物和药学上可接受的第一载体，且所述第二制剂包含所述第二治疗剂和药学上可接受的第二载体。
例如，所述第一制剂与所述第二制剂可以是相同的剂型可以是不同的剂型。
例如，所述第一制剂与所述第二制剂可以均为丸剂、散剂、片剂、颗粒剂、凝胶剂、硬胶囊剂、软胶囊剂、糖浆剂、合剂、露剂、注射剂、气雾剂、膏剂、膜剂、栓剂、滴丸等剂型中的任意一种，也可以是其中任意不同的两两组合。
例如，所述第一制剂与所述第二制剂可以以适用于相同的施用方式的制剂形式存在。
例如，所述第一制剂与所述第二制剂可以以适用于不同的施用方式的制剂形式存在。
例如，所述药物组合包含药物组合物，且所述药物组合物包含所述第二治疗剂和所述抗坏血酸或其衍生物。
例如，所述药物组合物中所述第二治疗剂的含量为约1％至约50％(w/w)。
约5％(w/w)至约50％(w/w)，约10％(w/w)至约40％(w/w)，约20％(w/w)至约50％(w/w)，约10％(w/w)至约30％(w/w)，约20％(w/w)至约40％(w/w)，约1％(w/w)至约5％(w/w)。约30％(w/w)至约50％(w/w)，约5％至约20％(w/w)，约20％(w/w)至约30％(w/w)。
例如，所述药物组合物中所述第二治疗剂的含量为约5％至约20％(w/w)。
例如，所述第二治疗剂的含量为约5％(w/w)至约10％(w/w)，约10％(w/w)至约20％(w/w)，约10％(w/w)至约15％(w/w)，约10％(w/w)至约18％(w/w)，约5％(w/w)至约15％(w/w)。
例如，所述药物组合物中所述抗坏血酸或其衍生物的含量为约50％至约95％(w/w)。
例如，所述抗坏血酸或其衍生物的含量为约50％(w/w)至约60％(w/w)，约50％(w/w)至约70％(w/w)，约60％(w/w)至约80％(w/w)，约50％(w/w)至约90％(w/w)，约60％(w/w)至约90％(w/w)，约55％(w/w)至约75％(w/w)。约70％(w/w)至约90％(w/w)，约80至约95％(w/w)。
例如，所述药物组合物中所述抗坏血酸或其衍生物的含量为约80％至约95％(w/w)。
例如，所述第二治疗剂的含量为约80％至约85％(w/w)，约80％至约90％(w/w)，约85％至约95％(w/w)，约85％至约90％(w/w)。
用途和方法
本申请还提供了抗坏血酸或其衍生物与第二治疗剂的组合在制备药物中的用途，所述药物用于预防和/或治疗肿瘤，其中所述第二治疗剂选自：Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂和Wnt信号通路抑制剂。
本申请还提供一种预防和/或治疗肿瘤的方法，其包括向有需要的受试者施用：
a)抗坏血酸或其衍生物；和b)第二治疗剂，其中所述第二治疗剂选自：Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂和Wnt信号通路抑制剂。
本申请还提供监测受试者对药物响应情况的方法，所述方法包括：
a)向所述受试者施用抗坏血酸或其衍生物和第二治疗剂，其中所述第二治疗剂选自：Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂和Wnt信号通路抑制剂；以及
b)检测经a)的所述施用后，所述受试者中下述一种或多种的变化：血液碱性磷酸酶水 平和/或活性，乳酸脱氢酶水平和/或活性，CADM1基因的表达水平，CD44基因的表达水平，livin基因的表达水平，HIF-1α基因的表达水平，ET-1基因的表达水平，IGF-1R基因的表达水平，STAT3基因的表达水平，CEA基因的表达水平，CA199基因的表达水平，CA125基因的表达水平，AFP基因的表达水平，CA724基因的表达水平，β-HCG基因的表达水平。
例如，所述基因的表达水平可以包括基因组DNA的修饰和/或突变、mRNA的表达水平、蛋白质的表达水平，
例如，所述检测可以选自PCR、实时定量PCR、数字PCR、液体芯片、固态芯片、原位杂交、普通测序和高通量测序，以检测基因组DNA的修饰和/或突变、mRNA的表达水平。
例如，所述检测可以选自液体芯片、固态芯片、酶联免疫学、放射免疫、化学发光免疫分析、质谱、高效液相色谱、Western标记和测序，以检测蛋白质的表达水平。
例如，所述的抗坏血酸或其衍生物可以包括抗坏血酸、抗坏血酸衍生物及其任意组合。所述的第二治疗剂可以包括Notch信号通路抑制剂、HH信号通路抑制剂、Wnt信号通路抑制剂RXRα抑制剂中的任意一种，或者其中任意几种的组合。
例如，所述第二治疗剂可以包括Notch信号通路抑制剂。
例如，所述第二治疗剂可以包括HH信号通路抑制剂。
例如，所述第二治疗剂可以包括RXRα抑制剂。
例如，所述第二治疗剂可以包括HH信号通路抑制剂。
例如，所述肿瘤包括实体瘤和非实体瘤。
例如，所述实体瘤可以选自以下组：肝癌、胃癌、肺癌、乳腺癌、结肠癌、直肠癌、肾细胞癌、肝癌、非小细胞肺癌、小肠癌、食道癌、黑素瘤、骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内恶性黑素瘤、子宫癌、卵巢癌、直肠癌、睾丸癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、儿童实体瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊枢椎肿瘤、脑干胶质瘤、垂体腺瘤、Kaposi肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤以及所述癌症的转移病灶。
例如，所述非实体瘤可以选自以下组：慢性淋巴细胞白血病(CLL)、急性白血病、急性淋巴样白血病(ALL)、B细胞急性淋巴样白血病(B-ALL)、T细胞急性淋巴样白血病(T-ALL)、慢性髓性白血病(CML)、急性髓样白血病(AML)、B细胞幼淋巴细胞白血病、母细胞性浆细胞样树状细胞肿瘤、Burkitt淋巴瘤、弥散性大B细胞淋巴瘤、滤泡淋巴瘤、多毛细胞白血病、小细胞或大细胞滤泡淋巴瘤、恶性淋巴细胞增生性疾病、MALT淋巴瘤、套细胞淋巴瘤、边缘区淋巴瘤、多发性骨髓瘤、脊髓发育不良和脊髓发育不良综合征、非霍奇金淋巴瘤、霍奇金 淋巴瘤、浆母细胞淋巴瘤、浆细胞样树状细胞肿瘤和Waldenstrom巨球蛋白血症。
例如，所述实体瘤包括骨肉瘤和/或结肠癌。
例如，所述非实体瘤包括淋巴瘤。
例如，所述第二治疗剂与所述抗坏血酸或其衍生物被配置为同时向受试者施用。
例如，Niclosamide与所述抗坏血酸或其衍生物联用可以用于预防和/或治疗肿瘤。例如，Niclosamide与所述抗坏血酸或其衍生物联用可以用于预防和/或治疗淋巴瘤，骨肉瘤和/或结肠癌。例如，Dvl-2抑制剂与所述抗坏血酸或其衍生物联用可以用于预防和/或治疗淋巴瘤，骨肉瘤和/或结肠癌。例如，Wnt信号通路抑制剂与所述抗坏血酸或其衍生物联用可以用于预防和/或治疗淋巴瘤，骨肉瘤和/或结肠癌。
例如，所述同时向受试者施用可以包括所述第二治疗剂与所述抗坏血酸或其衍生物向受试者施用的时间间隔不超过1小时。例如，所述时间间隔为60分钟、55分钟、50分钟、45分钟、40分钟、35分钟、30分钟、25分钟、20分钟、15分钟、10分钟、8分钟、5分钟、3分钟、2分钟、1分钟，或者以混合的形式一起施用。
例如，所述第二治疗剂与所述抗坏血酸或其衍生物被配置为分别向受试者施用。
例如，所述分别向受试者施用可以包括所述第二治疗剂与所述抗坏血酸或其衍生物向受试者施用的时间间隔大于1小时。例如，所述时间间隔为1.5小时、2小时、2.5小时、3小时、3.5小时、4小时、4.5小时、5小时、5.5小时、6小时、6.5小时、7小时、7.5小时、8小时、9小时、10小时、11小时、12小时、15小时、18小时、21小时、24小时、2天，3天、4天、5天、6天、7天，或更长时间。
例如，所述施用可以包括经口施用、静脉内施用、肌肉内施用、肿瘤位点原位施用、吸入、直肠施用、阴道施用、经皮施用或经皮下储集施用等任意施用方式或其组合。
例如，所述分别向受试者施用可以包括所述第二治疗剂与所述抗坏血酸或其衍生物交替施用，例如施用所述第二治疗剂之后再施用所述抗坏血酸或其衍生物，或者施用所述抗坏血酸或其衍生物之后再施用所述第二治疗剂。
例如，所述施用所述第二治疗剂可以包括施用1次。
例如，所述施用所述第二治疗剂可以包括连续施用2次或以上，，例如3次或以上，4次或以上，5次或以上，6次或以上，7次或以上，8次或以上，9次或以上，10次或以上。
例如，所述施用所述抗坏血酸或其衍生物可以包括施用1次。
例如，所述施用所述抗坏血酸或其衍生物可以包括连续施用2次或以上，，例如3次或以上，4次或以上，5次或以上，6次或以上，7次或以上，8次或以上，9次或以上，10次或以上。
例如，所述药物被配置为使得所述第二治疗剂以约1mg/kg至约100mg/kg的剂量被施用。
例如，所述第二治疗剂以约10mg/kg至约100mg/kg、10mg/kg至约80mg/kg、10mg/kg至约50mg/kg、20mg/kg至约100mg/kg、30mg/kg至约80mg/kg、1mg/kg至约30mg/kg、1mg/kg至约20mg/kg、约1mg/kg至约5mg/kg、5mg/kg至约10mg/kg、3mg/kg至约8mg/kg、5mg/kg至约30mg/kg、30mg/kg至约70mg/kg、40mg/kg至约60mg/kg、20mg/kg至约50mg/kg、30mg/kg至约60mg/kg、20mg/kg至约70mg/kg的剂量被施用。
例如，施用的对象为小鼠。例如，所述药物被配置为使得所述第二治疗剂以约10mg/kg至约100mg/kg的剂量被施用。
例如，施用的对象为人类。例如，所述药物被配置为使得所述第二治疗剂以约1mg/kg至约10mg/kg的剂量被施用。
例如，所述药物被配置为使得所述抗坏血酸或其衍生物以约0.05g/kg至约2.5g/kg的剂量被施用。
例如，所述抗坏血酸或其衍生物以约0.05g/kg至约0.1g/kg、约0.1g/kg至约0.2g/kg、约0.15g/kg至约0.25g/kg、约0.05g/kg至约0.15g/kg、约0.05g/kg至约2.5g/kg、约0.25g/kg至约1g/kg、约0.35g/kg至约0.5g/kg、约0.5g/kg至约1g/kg、约0.5g/kg至约2.5g/kg、约0.5g/kg至约2g/kg、约1g/kg至约2g/kg、约1g/kg至约2.5g/kg、约1.5g/kg至约2.5g/kg、约0.1g/kg至约2.5g/kg、约0.5g/kg至约2g/kg、约0.05g/kg至约0.2g/kg的剂量被施用。
例如，施用的对象为小鼠。例如，所述药物被配置为使得所述抗坏血酸或其衍生物以约0.5g/kg至约2.5g/kg的剂量被施用。
例如，施用的对象为人类。例如，所述药物被配置为使得所述抗坏血酸或其衍生物以约约0.05g/kg至约0.25g/kg的剂量被施用。
例如，所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:5000的质量比被施用。
例如，所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:1至约1:20、约1:5至约1:20、约1:10至约1:20、约1:10至约1:25、约1:10至约1:50、约1:10至约1:100、约1:10至约1:150、约1:10至约1:200、约1:10至约1:250、约1:10至约1:300、约1:10至约1:400、约1:10至约1:450、约1:10至约1:500、约1:10至约1:550、约1:10至约1:600、约1:10至约1:650、约1:10至约1:700、约1:10至约1:800、约1:10至约1:900、约1:10至约1:1000、约1:10至约1:1500、约1:10至约1:2000、约1:10至约1:3000、约1:10至约1:4000、约1:10至约1:5000、约1:5至约1:20、约1:5至约1:25、约1:5至约1:35、约1:5至约1:50、约1:5至约1:100、约1:5至约1:150、约1:5至约1:200、约1:25至约1:50、约 1:25至约1:100、约1:25至约1:150、约1:25至约1:200、约1:25至约1:1000、约1:25至约1:5000、约1:50至约1:100、约1:50至约1:150、约1:50至约1:200、约1:50至约1:300、约1:50至约1:500、约1:50至约1:1000、约1:50至约1:2000、约1:50至约1:4000或约1:50至约1:5000、约1:4500至约1:5000的质量比被施用。
例如，所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:100的质量比被施用。
例如，所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:20、约1:10至约1:20、约1:10至约1:25、约1:10至约1:50、约1:10至约1:100、约1:5至约1:25、约1:5至约1:35、约1:5至约1:50、约1:30至约1:80、约1:40至约1:80、约1:20至约1:100、约1:20至约1:60、约1:20至约1:50、约1:5至约1:100、约1:25至约1:50、约1:25至约1:100、约1:50至约1:100的质量比被施用。
例如，所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:5000的有效量比率被施用。
例如，所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:1至约1:20、约1:5至约1:20、约1:10至约1:20、约1:10至约1:25、约1:10至约1:50、约1:10至约1:100、约1:10至约1:150、约1:10至约1:200、约1:10至约1:250、约1:10至约1:300、约1:10至约1:400、约1:10至约1:450、约1:10至约1:500、约1:10至约1:550、约1:10至约1:600、约1:10至约1:650、约1:10至约1:700、约1:10至约1:800、约1:10至约1:900、约1:10至约1:1000、约1:10至约1:1500、约1:10至约1:2000、约1:10至约1:3000、约1:10至约1:4000、约1:10至约1:5000、约1:5至约1:20、约1:5至约1:25、约1:5至约1:35、约1:5至约1:50、约1:5至约1:100、约1:5至约1:150、约1:5至约1:200、约1:25至约1:50、约1:25至约1:100、约1:25至约1:150、约1:25至约1:200、约1:25至约1:1000、约1:25至约1:5000、约1:50至约1:100、约1:50至约1:150、约1:50至约1:200、约1:50至约1:300、约1:50至约1:500、约1:50至约1:1000、约1:50至约1:2000、约1:50至约1:4000或约1:50至约1:5000、约1:4500至约1:5000的有效量比率被施用。
例如，所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:100的有效量比率被施用。
例如，所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:20、约1:10至约1:20、约1:10至约1:25、约1:10至约1:50、约1:10至约1:100、约1:5至约1:25、约1:5至约1:35、约1:5至约1:50、约1:30至约1:80、约1:40至约1:80、约1:20至 约1:100、约1:20至约1:60、约1:20至约1:50、约1:5至约1:100、约1:25至约1:50、约1:25至约1:100、约1:50至约1:100的有效量比率被施用。
抑制剂
在本申请中，所述Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂、Wnt信号通路抑制剂可以包含小分子化合物。
例如，所述Notch信号通路抑制剂可以包括CB-103、FLI-06、JI051、PsoralidinTangeretin、Carvacrol、Notch抑制剂1、BMS-906024、IMR-1、IMR-1A、Z-Ile-Leu-aldehyde、ZLDI-8、Semagacestat、Bruceine D、RO4929097、LY-411575、YO-01027、Crenigacestat、Avagacestat、Z-Ile-Leu-aldehyde、MK0752和/或PF-03084014。
例如，所述Notch信号通路抑制剂可以包括γ分泌酶(Gamma Secretase)抑制剂、ADAM-17抑制剂、Notch配体抑制剂、Notch受体抑制剂和/或CSL-DNA结合蛋白抑制剂。
例如，所述Notch信号通路抑制剂可以包括Notch配体抑制剂。
例如，所述Notch配体抑制剂可以包括Delta-like 1抑制剂、Delta-like 3抑制剂、Delta-like 4抑制剂、Jagged 1抑制剂和/或Jagged 2抑制剂。
例如，所述Jagged 1抑制剂可以包括Carvacrol。
例如，所述Notch信号通路抑制剂可以包括Notch受体抑制剂。
例如，所述Notch受体抑制剂可以包括Notch1受体抑制剂、Notch2受体抑制剂、Notch3受体抑制剂和/或Notch4受体抑制剂。
例如，所述Notch受体抑制剂可以包括Tangeretin、Carvacrol、Notch抑制剂1、BMS-906024、IMR-1、IMR-1A、Z-Ile-Leu-aldehyde、Semagacestat和/或Bruceine D。
例如，所述Notch1受体抑制剂可以包括Tangeretin、Carvacrol和/或Notch抑制剂1。
例如，所述Notch3受体抑制剂可以包括Notch抑制剂1。
例如，所述ADAM-17抑制剂可以包括ZLDI-8。
例如，所述Notch信号通路抑制剂包含γ-分泌酶抑制剂。
例如，所述γ分泌酶(Gamma Secretase)抑制剂可以包括RO4929097、LY-411575、YO-01027、Crenigacestat、Semagacestat、Avagacestat、Z-Ile-Leu-aldehyde、MK0752和/或PF-03084014。
例如，所述γ-分泌酶抑制剂包含MK0752、RO4929097和/或PF-03084014。
例如，所述HH信号通路抑制剂可以包括Jervine、Ciliobrevin D、RU-SKI 43 hydrochloride、RU-SKI 43、JK184、Cyclopamine、Mebendazole、Ciliobrevin A、SANT-1、Vismodegib、GANT 61、HhAntag、Saridegib、MRT-83、PF-5274857、20(S)-Hydroxycholesterol、CUR61414、MK- 4101、Vismodegib、Sonidegib和/或Glasdegib。
例如，所述HH信号通路抑制剂可以包括Hedgehog抑制剂、Gli抑制剂和/或smo抑制剂。
例如，所述HH信号通路抑制剂可以包括Hedgehog抑制剂。
例如，所述Hedgehog抑制剂可以包括Jervine、Ciliobrevin D、RU-SKI 43 hydrochloride、RU-SKI 43、JK184、Cyclopamine、Mebendazole、Ciliobrevin A、SANT-1、Vismodegib、CUR61414、MK-4101和/或Dynarrestin。
例如，所述HH信号通路抑制剂可以包括Gli抑制剂。
例如，所述Gli抑制剂可以包括GANT 61和/或HhAntag。
例如，所述Smo抑制剂可以包括Saridegib、MRT-83、Jervine、SANT-1、PF-5274857、20(S)-Hydroxycholesterol、CUR61414、MK-4101、Vismodegib、Sonidegib和/或Glasdegib。
例如，所述HH信号通路抑制剂包含SMO抑制剂。
例如，所述SMO抑制剂可以包含Vismodegib、Sonidegib和/或Glasdegib。
例如，所述Wnt信号通路抑制剂可以包含Tankyrases抑制剂、Porcupine抑制剂、Dvl-2抑制剂、DKK抑制剂、CK1a抑制剂和/或Frizzled受体抑制剂。
例如，所述Wnt信号通路抑制剂可以包含Porcupine抑制剂，Dvl-2抑制剂、CK1a抑制、和/或Frizzled受体抑制剂。
例如，所述Wnt信号通路抑制剂可以包含Tankyrases抑制剂。
例如，所述Tankyrases抑制剂可以包含IWR1、XAV939、NVP-TNKS656和/或JW74。
例如，所述Wnt信号通路抑制剂可以包含Porcupine抑制剂。
例如，所述Porcupine抑制剂可以包含IWP-2、LGK974和/或ETC-159。
例如，所述Porcupine抑制剂可以包含LGK974和/或ETC-159。
例如，所述Wnt信号通路抑制剂可以包含DKK抑制剂。
例如，所述DKK抑制剂可以包含DKN-01。
例如，所述Wnt信号通路抑制剂可以包含CK1a抑制剂。
例如，所述CK1a抑制剂可以包含Pyrvinium。
例如，所述Wnt信号通路抑制剂可以包含Dvl-2抑制剂。
例如，所述Dvl-2抑制剂可以包含NSC668036、J01-017a、Niclosamide和/或Sulindac。
例如，所述Dvl-2抑制剂可以包含Niclosamide和/或Sulindac。
例如，所述Dvl-2抑制剂可以不包含Sulindac。
例如，所述Wnt信号通路抑制剂可以包含Frizzled受体抑制剂。
在某些实施方式中，所述RXRα抑制剂包含小檗碱或其药学上可接受的盐。
例如，所述药学上可接受的盐可以包括小檗碱和R-(+)-α_有机酸、羟基柠檬酸、二十碳五烯酸、二十二碳六烯酸、乌索酸、科罗索酸、肉桂酸、胆酸、奥贝胆酸、熊去氧胆酸、齐墩果酸、水杨酸、桦木酸、绿原酸、咖啡酸、椴树酸、乙酰左旋肉碱、S-烯丙基半胱氨酸亚砜、S-甲基半胱氨酸亚砜、泛酸、抗坏血酸、视黄酸、烟酸和生物素等有机酸中的任意一种或多种形成的盐。
例如，所述抑制剂还可以包含Fervenulin、3-Methyltoxoflavin和/或Walrycin B。
在本申请中，所述Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂、Wnt信号通路抑制剂还可以包含抗体或多肽。所述抗体或多肽与其相应结合靶标的相互作用能够降低或阻碍Notch信号通路、HH信号通路、Wnt信号通路的激活/信号转导，和/或够降低或阻碍RXRα的活性。
例如，所述抗体或多肽可以包括γ分泌酶(Gamma Secretase)的抗体或结合多肽、ADAM-17的抗体或结合多肽、Notch配体的抗体或结合多肽、Notch受体的抗体或结合多肽、CSL-DNA结合蛋白的抗体或结合多肽、Hedgehog的抗体或结合多肽、Gli的抗体或结合多肽、smo的抗体或结合多肽、Tankyrases的抗体或结合多肽、Porcupine的抗体或结合多肽、Dvl-2的抗体或结合多肽、DKK的抗体或结合多肽、CK1a的抗体或结合多肽和/或Frizzled受体的抗体或结合多肽。
例如，所述Frizzled受体的抗体可以包括OMP18RS(Vantictumab)、OMP-54F28(Ipafricept)、OMP131R10和/或OTSA 101。
例如，所述Frizzled的结合多肽可以包括Fz7-21TFA、Fz7-21和/或Foxy-5。
在本申请中，所述Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂、Wnt信号通路抑制剂还可以包含siRNA、shRNA和/或CRISPR/Cas9系统。所述siRNA、shRNA和CRISPR/Cas9系统能够靶向HH信号通路、RXRα抑制剂、Wnt信号通路所包含的分子的编码基因组DNA或mRNA从而使得相应分子的表达水平/活性下降。
例如，所述siRNA、shRNA和/或CRISPR/Cas9系统可以包括靶向γ分泌酶(Gamma Secretase)、ADAM-17、Notch配体、Notch受体、CSL-DNA结合蛋白、Hedgehog的、Gli、Smo、Tankyrases、Porcupine、Dvl-2、DKK、CK1a和/或Frizzled受体的siRNA、shRNA和/或CRISPR/Cas9系统。
例如，所述CRISPR/Cas9系统包括指导RNA和/Cas9蛋白。
抗坏血酸及其衍生物
在本申请中，所述抗坏血酸及其衍生物包括选自抗坏血酸(维生素C)、抗坏血酸衍生物及其组合中的成员。
例如，所述抗坏血酸衍生物可以还可以包括脱氢抗坏血酸、抗坏血酸盐或抗坏血酸衍生物的盐。
抗坏血酸因其α-酮基内酯结构而对环境参数(例如光，热，氧气)的影响敏感。它在水或其它水溶液中可能不稳定。以化学方式稳定抗坏血酸分子的手段制备具有稳定性高于母体化合物的抗坏血酸衍生物(例如，参见美国专利US 5,137,723和US 5,078,989)，该文献内容以引入方式并入本申请。
例如，所述抗坏血酸衍生物可以为抗坏血酸类似物。典型的抗坏血酸衍生物包括如下化合物：抗坏血酸分子的羟基中的至少一个(例如2-OH，3-OH，5-OH，6-OH)被修饰基团衍生(例如，参见Ando等的美国专利US 5,078,989)。例如，羟基中的一个或多个可以被另一个结构部分取代。例如，所述抗坏血酸及其衍生物包括抗坏血酸和至少一种抗坏血酸衍生物。
例如，所述抗坏血酸衍生物可以包括游离2-OH和游离3-OH。
例如，所述抗坏血酸衍生物包括抗坏血酸的酯类，其中衍生自5-OH和6-OH中的至少一种。
例如，所述抗坏血酸衍生物包括酯类，例如6-O-辛酰基-抗坏血酸，6-O-十二烷酰基-抗坏血酸，6-O-十四酰基-抗坏血酸，6-O-十八酰基-抗坏血酸，6-O-十二烷二酰基-抗坏血酸，6-O-二十二烷二酰基-抗坏血酸，6-O-它普酰基(thapsoyl)-抗坏血酸，6-O-癸二酰基-抗坏血酸，6-O-己二酰基-抗坏血酸。
例如，所述抗坏血酸衍生物还可以包括如下酯类：其中分子的亲脂性结构部分为单或多不饱和脂肪酸。例如，不饱和脂肪酸可以包括与健康相关的必需脂肪酸，例如ω-3(α-亚麻酸)，ω-6或ω-9脂肪酸。例如还可以包括含有氨基酸残基的酯类。
例如，所述抗坏血酸衍生物还可以包括抗坏血酸的2-O-烷基或3-O-烷基衍生物。3-O-烷基-抗坏血酸由Nihro等报导在Chem.Pharm.Bull.1991，39：1731-1735中，该文献以引用方式并入本申请。
例如，所述抗坏血酸衍生物可以包括抗坏血酸的糖苷；例如抗坏血酸1-糖苷，抗坏血酸2-糖苷，抗坏血酸3-糖苷，抗坏血酸5-糖苷和抗坏血酸6-糖苷。
例如，所述抗坏血酸衍生物可以包括2-O-(α-D-吡喃葡糖基)-抗坏血酸(参见例如美国专利US 5,137,723)和2-O-(β-D-吡喃葡糖基)-抗坏血酸(参见，例如美国专利申请No.US  2005/0113312)。以上文献以引用方式并入本申请。
例如，所述抗坏血酸衍生物可以包括抗坏血酸的双官能化衍生物，诸如，例如6-O-酰基-2-O-(α-D-吡喃葡糖基)抗坏血酸(参见，例如Yamamoto等，J.Med.Chem.2002，45(2)：462-468。该文献以引用方式并入本申请。
例如，抗坏血酸衍生物可以包括抗坏血酸的磷酸盐。例如，抗坏血酸磷酸盐为碱金属盐，碱土金属盐或过渡金属盐。例如可以包括抗坏血酸磷酸镁，抗坏血酸磷酸钠(例如抗坏血酸基-2-一磷酸钠盐)，抗坏血酸磷酸钙，抗坏血酸磷酸钾和混合的盐，例如，抗坏血酸磷酸镁钠、抗坏血酸磷酸钙钠、氨基丙基抗坏血酸基磷酸盐。
例如，抗坏血酸磷酸盐可以作为水合物存在，其中二水合物常见。典型的二水合物例如可以购自DSM，产品名称为STAY-C50。
在本申请中，所述抗坏血酸衍生物包含药学上可接受的抗坏血酸盐。
例如，所述药学上可接受的抗坏血酸盐其钠盐、钾盐等碱金属盐，钙盐、镁盐等碱土金属盐，精氨酸等碱性氨基酸盐，三乙醇胺等有机胺盐。
例如，抗坏血酸盐或抗坏血酸衍生物的盐可以为可食用的(例如药学上可接受的)盐，诸如钙，钠，镁，钾和锌盐，以及抗坏血酸或抗坏血酸衍生物的混合的盐。
例如，所述药学上可接受的抗坏血酸盐包含抗坏血酸钠。
其它公认的抗坏血酸衍生物也用于本申请的目的。
载体和制剂
在本申请中，所述第一制剂、所述第二制剂或所述的药物组合物的剂型可以包括片剂、胶囊剂、颗粒剂、散剂、糖浆剂、混悬剂、栓剂、软膏、霜剂、凝胶剂、贴剂、吸入剂、注射剂等。这些制剂可按照常规方法制备。
例如，在为液体制剂时，可以是在使用时溶解或混悬于水或其它适当的溶剂中的形式
例如，片剂、颗粒剂可通过公知的方法进行包衣。
例如，在为注射剂的情况下，可以使有效成分(包括本申请所述的抗坏血酸或其衍生物、本申请所述的第二治疗剂)溶解于水而进行制备，也可根据需要溶解于生理盐水或者葡萄糖溶液中，例如，还可以添加缓冲剂、保存剂。
例如，还可以以经口给药用或非经口给药用的任意制剂型态提供。例如，可制备成颗粒剂、细粒剂、散剂、硬胶囊剂、软胶囊剂、糖浆剂、乳剂、混悬剂或液剂等形态的经口给药用制剂；
例如，还可以是静脉内给药用、肌肉内给药用、或者皮下给药用等的注射剂、点滴剂、 经皮吸收剂、经粘膜吸收剂、点鼻剂、吸入剂、栓剂等形态的非经口给药用制剂。
例如，注射剂、点滴剂等可制备成冻干形态等粉末状剂型，在使用时溶解于生理盐水等适宜的水性介质中来使用。
例如，还可以将用高分子等覆盖的缓释制剂直接给予至脑等器官内。
就药物制剂的制造中所使用的制剂用添加物(载体)的种类、制剂用添加物(载体)相对于有效成分的比例、或制剂的制造方法而言，本领域技术人员可根据制剂的形态而适宜选择。例如，作为制剂用添加物(载体)，可使用无机或有机物质、或固体或液体的物质，例如，可以在相对于有效成分重量为1重量％～90重量％之间进行配合。例如，所述载体可以包含乳糖、葡萄糖、甘露醇、糊精、环糊精、淀粉、蔗糖、偏硅酸铝镁、合成硅酸铝、羧甲基纤维素钠、羟丙基淀粉、羧甲基纤维素钙、离子交换树脂、甲基纤维素、明胶、阿拉伯胶、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、轻质无水硅酸、硬脂酸镁、滑石、西黄耆胶、膨润土、蜂胶、氧化钛、脱水山梨醇脂肪酸酯、月桂基硫酸钠、甘油、月旨肪酸甘油醋、纯化羊毛脂、甘油明胶、聚山梨醋、聚乙二醇、植物油、蜡、液体石蜡、白色矿脂、碳氟化合物、非离子性表面活性剂、丙二醇、水等。
例如，在制造经口给药用固体制剂时，可以将有效成分(包括本申请所述的抗坏血酸或其衍生物、本申请所述的第二治疗剂)与载体成分例如乳糖、淀粉、结晶纤维素、乳酸钙、无水硅酸等混合而制成散剂；例如，还可以进而根据需要添加蔗糖、羟丙基纤维素、聚乙烯吡咯烷酮等粘结剂、羧甲基纤维素、羧甲基纤维素钙等崩解剂等并进行湿式或干式造粒而制成颗粒剂；例如，在制造片剂时，可以将所述的散剂和/或颗粒剂直接压片；例如，还可以添加硬脂酸镁、滑石粉等润滑剂而进行压片；例如，还可以将所述的颗粒或片剂用羟丙基甲基纤维素邻苯二甲酸酯、甲基丙烯酸-甲基丙烯酸甲酯聚合物等肠溶剂基质包被而制成肠溶剂制剂；例如，还可以用乙基纤维素、巴西棕榈蜡、氢化油等包被而制成长效制剂；例如，在制造胶囊剂时，可以将散剂或颗粒剂填充于硬胶囊中，例如，还可以将所述有效成分直接或者溶解于甘油、聚乙二醇、芝麻油、橄榄油等后用明胶膜覆盖而制成软胶囊。
例如，在制造注射剂时，可以根据需要将有效成分与盐酸、氢氧化钠、乳糖、乳酸、钠、磷酸氢钠、磷酸二氢钠等pH调整剂、氯化钠、葡萄糖等等渗剂一起溶解于注射用蒸馏水；例如，还可以进一步进行无菌过滤而填充于安瓿中；例如，还可以进一步添加甘露醇、糊精、环糊精、明胶等并真空冻干而制成用时溶解型注射剂。例如，还可以在有效成分中添加卵磷脂、聚山梨酯80、聚氧乙烯氢化蓖麻油等并在水中乳化而制成注射剂用乳剂。
例如，在制造直肠给药剂时，可以将所述有效成分与可可脂、脂肪酸三甘油酯、脂肪酸 双甘油酯及脂肪酸单甘油酯、聚乙二醇等栓剂用基材一起进行加湿并溶解而后流入模具中进行冷却，例如，还可以将有效成分溶解于聚乙二醇、大豆油等后用明胶膜包被。
例如，在制造皮肤用外用剂时，可以将有效成分添加到白色矿脂、蜜蜡、液体石蜡、聚乙二醇等中根据需要加湿并捏合，制成软膏剂；例如，还可以与松香、丙烯酸烷基酯聚合物等粘合剂捏合后延展于聚烷基类等无纺布而制成带状制剂。
例如，还可以作为植入片或被封入微囊而成的传递系统等缓释性制剂，其能够使用可防止从体内即刻除去的载体来制备。例如，可使用乙烯-乙酸乙烯酯、聚酸酐、聚乙醇酸、胶原、聚原酸酯、及聚乳酸等生物降解性、生物相容性聚合物。本领域技术人员能够容易地制备这些材料。例如，脂质体的混悬液也可用作药学上可接受的载体。所述脂质体可以包含制成含有磷脂酰胆碱、胆固醇及PEG衍生化磷脂酰乙醇胺(PEG-PE)的脂质组合物，可以通过制备适于使用的尺寸的方式，通过适当孔径大小的过滤器来制备，通过反相蒸发法来纯化。
在本申请中，给药量及给药次数可以根据治疗对象(受试者)疾病的进展的预防和/或治疗的目的、疾病种类、患者体重、年龄等条件来适当选择。例如，经口给药时可分成一天1次或数次，或者可每隔数日施用。在用作注射剂的情况下可连续施用或间歇施用。
试剂盒
本申请的试剂盒可以包括本申请所述的药物组合。所述药物组合可以以试剂盒的方式提供，该药物组合中的不同构成成分可包装在不同的容器中，在施用前混合，或者不混合而分别施用。
例如，分别包装可以是为了可在不失去活性构成成分的功能的情况下长期贮存。
例如，试剂盒中含有的制剂可存在于制剂成分长期有效地保持活性、不被容器材质所吸附、不容易变质的任何种类的容器中。例如，密封的玻璃安瓿，例如，安瓿可以由玻璃、聚碳酸酯、聚苯乙烯等有机聚合物、陶瓷、金属、或通常可被用于保持试剂的其它任何恰当的材料等构成。在其它恰当的容器的例子中，包括由与安瓿等类似的物质制成的简单的瓶子，及内部用铝或合金等的箔片内衬的包装材料。其它容器包括试管、小瓶、烧瓶、瓶子、注射器、或其类似物。容器具有瓶子等的无菌接入端口，该瓶子具有用皮下用注射针可贯通的塞子。
例如，试剂盒还可以包含在氮气之类的中性且非反应性气体存在下包装的缓冲液。
例如，试剂盒中还可以包括辅助施用装置，例如适用于口服的量杯、量勺，例如适用于注射的注射器、输液管、输液针等。
例如，试剂盒中还附加使用说明书。由该医药组合物构成的试剂盒的使用说明可被印刷 于纸或其它材质上，和/或以Floppy盘、CD-ROM、DVD-ROM、Zip盘、录像带、录音带等可电或电磁地读取的介质的方式供给。详细的使用说明可实际附加在试剂盒内，或者登载于由试剂盒的制造者或分销商指定或用电子邮件等通知的网址。
不欲被任何理论所限，下文中的实施例仅仅是为了阐释本申请的药物组合、治疗/预防癌症的方法和用途等，而不用于限制本申请发明的范围。
实施例
本申请实施例中所用药物可以如表1所示，均可以通过常规商业渠道获得。
表1 药物列表
编号 药物名称 货号 厂家
1 小檗碱 S9046 Selleck
2 MK0752 T2625 Targetmol
3 RO4929097 S1575 Selleck
4 PF-03084014 S8018 Selleck
5 Vismodegib T2590 Targetmol
6 Sonidegib S2151 Selleck
7 Glasdegib S7160 Selleck
8 LGK974 BD295733-毕得医药 NBW
9 ETC-159 24104 Cayman
11 Foxy-5 HY-P1416A MedChemExpress
12 抗坏血酸钠 S105024 Aladdin
其中，编号为1-12的药物使用时以DMSO为溶剂，抗坏血酸钠使用时以PBS为溶剂。
本申请实施例中的HEK293细胞、HOS人骨肉瘤细胞、143B人骨肉瘤细胞、MC38细胞和DB细胞均购自于ATCC。
实施例1 小檗碱(Berberine)与抗坏血酸钠联用对骨肉瘤细胞的抑制作用
1.1细胞系与细胞培养
HEK293细胞、HOS人骨肉瘤细胞和143B人骨肉瘤细胞、使用含10％胎牛血清FBS的RPMI-1640培养基于37℃、5％二氧化碳条件下培养箱传代培养。
1.2单药施用细胞活性(cell viability)检测
(1)铺被在10cm培养板的细胞长至90％左右的密度后，去除培养基，用PBS缓冲液将贴壁的细胞清洗一遍，加入1mL胰酶混匀后立即弃去，放置培养箱中消化约5min，之后加入 约10ml的新鲜培养基，吸取10uL计数。
(2)计数后，将细胞稀释至每mL有1*10 5个细胞，按照每孔100uL将稀释后的细胞铺被到96孔板中，即每孔约1万个细胞。
(3)铺被在96孔板中的细胞培养24h后，向其中加入不同浓度梯度的小檗碱，梯度设置成1μM、2μM、4μM、8μM、16μM、32μM这六个浓度梯度。
(4)加药24h后，加入10μL的CCK-8溶液，在培养箱中孵育1-2小时后，使用酶标仪在490nm处测定各孔吸光值(OD值)记录结果。计算细胞相对活性：
细胞活性＝(实验组吸光值-空白组吸光值)/(对照组吸光值-空白组吸光值)×100％
其中，实验组为加入不同浓度药物的细胞组，对照组为只加入溶剂(DMSO)的细胞组，空白组为不加入细胞而只加入溶剂(DMSO)的组，由以上公式得到细胞活性的结果，药物的细胞抑制率＝100％-细胞活性。根据该公式所得的对照组细胞活性为100％。浓度梯度的小檗碱处理细胞的结果如图1所示。
1.3药物联用细胞计数
(1)铺被在10cm培养板的细胞长至90％左右的密度后，去除培养基，用PBS缓冲液将贴壁的细胞清洗一遍，加入1mL胰酶混匀后立即弃去，放置培养箱中消化约5min，之后加入约10ml的新鲜培养基，吸取10uL计数。
(2)吸取混匀的细胞10uL混入10uL的台盼蓝溶液中，计数。
(3)计数后，将细胞稀释至每mL有1*10 5个细胞，稀释后的细胞混匀后吸取500uL/孔到24孔板中，即每孔约5万个细胞。
(4)培养铺被在24孔板的细胞约24h后加药，各实验组包括小檗碱单药组(浓度为20μM)，抗坏血酸组(浓度为0.5mM)，小檗碱(浓度为20μM)与抗坏血酸(浓度为0.5mM)联用组，对照组为只加了溶剂DMSO的细胞组，空白组为不加入细胞而只加入溶剂(DMSO)的组。
(5)加药24h后，弃掉培养基，加入约150uL的胰酶后弃掉消化5分钟；
(6)消化后，每孔加入同样量的PBS混匀，再加入10uL/孔的台盼蓝溶液混匀，吸取10uL混匀后的溶液计数。按照“细胞活性＝实验组细胞个数/对照组细胞个数x100％”计算各组的细胞活性。
1.4数据处理
数据均表示为平均值±标准差(Mean±SD)，使用GraphPad Prism 7.0软件用单因素方差分析(One-way ANOVA)。当P<0.05时，表示差异具有统计学意义。*表示P<0.05，**表示 P<0.01，***表示P<0.001，****表示P<0.0001。
药物相互作用系数(coefficient of drug in interaction,CDI)评价两药相互作用性质。分为对照组、A药组、B药组和AB联合用药组，分别检测出A、B、AB三组的细胞活性。
CDI＝AB组细胞活性/A组细胞活性*B组细胞活性，如CDI<1，证明两药作用性质为协同，CDI<0.7时为两药协同作用非常显著；如CDI＝1，则两药作用性质为相加；如CDI>1，则两药作用性质为拮抗。
联用结果：20μM的小檗碱单药处理条件下，HOS细胞的细胞活性为82％，143B细胞的细胞活性为94％；0.5mM的抗坏血酸钠处理条件下，HOS细胞的细胞活性为106％，143B细胞的细胞活性为106％；20μM的小檗碱与0.5mM的抗坏血酸钠联用条件下，HOS细胞的细胞活性为29％，143B细胞的细胞活性为26％，按照上述CDI计算公式得到针对HOS细胞的CDI值为0.33，针对143B细胞的CDI值为0.26，表明两者具有协同作用。同时，相对于HEK293细胞，小檗碱与抗坏血酸联用能够特异性抑制143B细胞和HOS细胞的活性，并且对于143B细胞和HOS细胞的抑制效果均显著好于相应的单药组(P<0.001)。结果参见图2所示。
实施例2 Foxy-5与抗坏血酸钠联用对骨肉瘤细胞的抑制作用
按照实施例1的方法检测Foxy-5对HOS人骨肉瘤细胞和143B人骨肉瘤细胞的抑制作用。Foxy-5的浓度梯度及其处理细胞的结果如图3所示。
联用结果：10μM的Foxy-5单药处理条件下，HOS细胞的细胞活性为92％，143B细胞的细胞活性为71％；0.5mM的抗坏血酸钠处理条件下，HOS细胞的细胞活性为103％，143B细胞的细胞活性为90％；10μM的Foxy-5与0.5mM的抗坏血酸钠联用条件下，HOS细胞的细胞活性为39％，143B细胞的细胞活性为47％，按照上述CDI计算公式得到针对HOS细胞的CDI值为0.41，针对143B细胞的CDI值为0.74，表明两者具有协同作用。同时，Foxy-5与抗坏血酸联用对于143B细胞和HOS细胞的抑制效果均显著好于相应的单药组(P<0.01)。结果参见图4所示。
实施例3 Pyrvinium与抗坏血酸钠联用对骨肉瘤细胞的抑制作用
按照实施例1的方法检测Pyrvinium对HOS人骨肉瘤细胞的抑制作用。
联用结果：0.1μM的Pyrvinium单药处理条件下，HOS细胞的细胞活性为65％；0.5mM的抗坏血酸钠处理条件下，HOS细胞的细胞活性为99％；0.1μM的Pyrvinium与0.5mM的抗坏血酸钠联用条件下，HOS细胞的细胞活性为49％，按照上述CDI计算公式得到针对HOS细胞的CDI值为0.76，表明两者具有协同作用。同时，Pyrvinium与抗坏血酸联用对于HOS 细胞的抑制效果显著好于相应的单药组(P<0.05)。结果参见图5所示。
实施例4 Niclosamide与抗坏血酸钠联用对骨肉瘤细胞的抑制作用
按照实施例1的方法检测Niclosamide对HOS人骨肉瘤细胞和143B人骨肉瘤细胞的抑制作用。
联用结果：50μM的Niclosamide单药处理条件下，HOS细胞的细胞活性为56％，143B细胞的细胞活性为59％；0.5mM的抗坏血酸钠处理条件下，HOS细胞的细胞活性为86％，143B细胞的细胞活性为83％；50μM的Niclosamide与0.5mM的抗坏血酸钠联用条件下，HOS细胞的细胞活性为15％，143B细胞的细胞活性为8％，按照上述CDI计算公式得到针对HOS细胞的CDI值为0.31，针对143B细胞的CDI值为0.16，表明两者具有协同作用。同时，Niclosamide与抗坏血酸联用对于143B细胞和HOS细胞的抑制效果均显著好于相应的单药组(P<0.001)。结果参见图6所示。
实施例5 ETC-159与抗坏血酸钠联用对骨肉瘤细胞的抑制作用
按照实施例1的方法检测ETC-159对HOS人骨肉瘤细胞和143B人骨肉瘤细胞的抑制作用。
联用结果：20μM的ETC-159单药处理条件下，HOS细胞的细胞活性为67％，143B细胞的细胞活性为60％；0.5mM的抗坏血酸钠处理条件下，HOS细胞的细胞活性为80％，143B细胞的细胞活性为77％；20μM的ETC-159与0.5mM的抗坏血酸钠联用条件下，HOS细胞的细胞活性为3％，143B细胞的细胞活性为7％，按照上述CDI计算公式得到针对HOS细胞的CDI值为0.06，针对143B细胞的CDI值为0.15，表明两者具有协同作用。同时，相对于HEK293细胞，ETC-159与抗坏血酸联用能够特异性抑制143B细胞HOS细胞的活性，并且对于143B细胞和HOS细胞的抑制效果均显著好于相应的单药组(P<0.001)。结果参见图7所示。
实施例6 LGK974与抗坏血酸钠联用对骨肉瘤细胞的抑制作用
按照实施例1的方法检测LGK974对HOS人骨肉瘤细胞和143B人骨肉瘤细胞的抑制作用。
联用结果：20μM的LGK974单药处理条件下，HOS细胞的细胞活性为67％，143B细胞的细胞活性为64％；0.5mM的抗坏血酸钠处理条件下，HOS细胞的细胞活性为87％，143B细胞的细胞活性为80％；20μM的LGK974与0.5mM的抗坏血酸钠联用条件下，HOS细胞的细胞活性为4％，143B细胞的细胞活性为2％，按照上述CDI计算公式得到针对HOS细胞的 CDI值为0.07，针对143B细胞的CDI值为0.04，表明两者具有协同作用。同时，LGK974与抗坏血酸联用对于143B细胞和HOS细胞的抑制效果均显著好于相应的单药组(P<0.001)。结果参见图8所示。
实施例7 Sonidegib与抗坏血酸钠联用对骨肉瘤细胞的抑制作用
按照实施例1的方法检测Sonidegib对HOS人骨肉瘤细胞和143B人骨肉瘤细胞的抑制作用。Sonidegib的浓度梯度及其处理细胞的结果如图9所示。
联用结果：10μM的Sonidegib单药处理条件下，HOS细胞的细胞活性为89％，143B细胞的细胞活性为74％；0.5mM的抗坏血酸钠处理条件下，HOS细胞的细胞活性为106％，143B细胞的细胞活性为81％；10μM的Sonidegib与0.5mM的抗坏血酸钠联用条件下，HOS细胞的细胞活性为62％，143B细胞的细胞活性为52％，按照上述CDI计算公式得到针对HOS细胞的CDI值为0.66，针对143B细胞的CDI值为0.87，表明两者具有协同作用。同时，Sonidegib与抗坏血酸联用对于143B细胞和HOS细胞的抑制效果均显著好于相应的单药组(P<0.05)。结果参见图10所示。
实施例8 Vismodegib与抗坏血酸钠联用对骨肉瘤细胞的抑制作用
按照实施例1的方法检测Vismodegib对HOS人骨肉瘤细胞和143B人骨肉瘤细胞的抑制作用。
联用结果：50μM的Vismodegib单药处理条件下，HOS细胞的细胞活性为53％，143B细胞的细胞活性为60％；0.5mM的抗坏血酸钠处理条件下，HOS细胞的细胞活性为106％，143B细胞的细胞活性为82％；50μM的Vismodegib与0.5mM的抗坏血酸钠联用条件下，HOS细胞的细胞活性为84％，143B细胞的细胞活性为13％，按照上述CDI计算公式得到针对HOS细胞的CDI值为0.09，针对143B细胞的CDI值为0.26，表明两者具有协同作用。同时，Vismodegib与抗坏血酸联用对于143B细胞和HOS细胞的抑制效果均显著好于相应的单药组(P<0.001)。结果参见图11所示。
实施例9 PF-03084014与抗坏血酸钠联用对骨肉瘤细胞的抑制作用
按照实施例1的方法检测PF-03084014对HOS人骨肉瘤细胞的抑制作用。PF-03084014的浓度梯度及其处理细胞的结果如图12所示。
联用结果：10μM的PF-03084014单药处理条件下，HOS细胞的细胞活性为113％；0.5mM的抗坏血酸钠处理条件下，HOS细胞的细胞活性为75％；10μM的PF-03084014与0.5mM的抗坏血酸钠联用条件下，HOS细胞的细胞活性为52％，按照上述CDI计算公式得到针对HOS 细胞的CDI值为0.61，表明两者具有协同作用。同时，PF-03084014与抗坏血酸联用对于HOS细胞的抑制效果显著好于相应的单药组(P<0.001)。结果参见图13所示。
实施例10 RO4929097与抗坏血酸钠联用对骨肉瘤细胞的抑制作用
按照实施例1的方法检测RO4929097对HOS人骨肉瘤细胞和143B人骨肉瘤细胞的抑制作用。
联用结果：10μM的RO4929097单药处理条件下，HOS细胞的细胞活性为56％，143B细胞的细胞活性为58％；0.5mM的抗坏血酸钠处理条件下，HOS细胞的细胞活性为84％，143B细胞的细胞活性为82％；10μM的RO4929097与0.5mM的抗坏血酸钠联用条件下，HOS细胞的细胞活性为5％，143B细胞的细胞活性为3％，按照上述CDI计算公式得到针对HOS细胞的CDI值为0.11，针对143B细胞的CDI值为0.06，表明两者具有协同作用。同时，RO4929097与抗坏血酸联用对于143B细胞和HOS细胞的抑制效果均显著好于相应的单药组(P<0.001)。结果参见图14所示。
实施例11 MK0752与抗坏血酸钠联用对骨肉瘤细胞的抑制作用
按照实施例1的方法检测MK0752对HOS人骨肉瘤细胞和143B人骨肉瘤细胞的抑制作用。
联用结果：20μM的MK0752单药处理条件下，HOS细胞的细胞活性为67％，143B细胞的细胞活性为62％；0.5mM的抗坏血酸钠处理条件下，HOS细胞的细胞活性为85％，143B细胞的细胞活性为80％；20μM的MK0752与0.5mM的抗坏血酸钠联用条件下，HOS细胞的细胞活性为3％，143B细胞的细胞活性为8％，按照上述CDI计算公式得到针对HOS细胞的CDI值为0.05，针对143B细胞的CDI值为0.16，表明两者具有协同作用。同时，MK0752与抗坏血酸联用对于143B细胞和HOS细胞的抑制效果均显著好于相应的单药组(P<0.001)。结果参见图15所示。
实施例12 Sulindac与抗坏血酸钠联用对骨肉瘤细胞的抑制作用
按照实施例1的方法检测Sulindac对HOS人骨肉瘤细胞的抑制作用。Sulindac的浓度梯度及其处理细胞的结果如图16所示。
联用结果：50μM的Sulindac单药处理条件下，HOS细胞的细胞活性为92％；0.5mM的抗坏血酸钠处理条件下，HOS细胞的细胞活性为102％；50μM的Sulindac与0.5mM的抗坏血酸钠联用条件下，HOS细胞的细胞活性为39％，按照上述CDI计算公式得到针对HOS细 胞的CDI值为0.42，表明两者具有协同作用。同时，Sulindac与抗坏血酸联用对于HOS细胞的抑制效果显著好于相应的单药组(P<0.05)。结果参见图17所示。
实施例13 不同抑制剂分别与抗坏血酸钠联用对结肠癌细胞的抑制作用
按照实施例1的方法检测小檗碱、Foxy-5、Pyrvinium、Niclosamide、ETC-159、LGK974、Sonidigib、Vismodegib、PF-03084014、RO4929097、MK0752、对结肠癌细胞的抑制作用。
例如，对于MC38结肠癌细胞，对照组只加溶剂DMSO，Nic组加入浓度为1μM的Niclosamide，Vc组为加入浓度为0.5mM的抗坏血酸，Nic+Vc组为加入浓度为1μM的Niclosamide以及浓度为0.5mM的抗坏血酸。
图18显示的是，相比于对照组的细胞活性，浓度为1μM的Niclosamide处理条件下，MC38细胞的细胞活性为82％；浓度为0.5mM的抗坏血酸处理条件下，MC38细胞的细胞活性为105％；浓度为1μM的Niclosamide以及浓度为0.5mM的抗坏血酸处理条件下，MC38细胞的细胞活性为62％。按照实施例1中的CDI计算公式得到针对MC38细胞的药物相互作用系数(coefficient of drug in interaction,CDI)为0.72，表明两者具有协同作用。同时，Niclosamide与抗坏血酸联用对于MC38细胞的抑制效果好于相应的单药组。
结果显示，上述各药物，例如Wnt信号通路抑制剂，分别与抗坏血酸钠联用对于结肠癌细胞的抑制效果显著好于相应的单药组，并且两者具有协同作用。
实施例14 不同抑制剂分别与抗坏血酸钠联用对淋巴瘤细胞的抑制作用
按照实施例1的方法检测小檗碱、Foxy-5、Pyrvinium、Niclosamide、ETC-159、LGK974、Sonidigib、Vismodegib、PF-03084014、RO4929097、MK0752、Sulindac对淋巴瘤细胞的抑制作用。
例如，对于DB淋巴瘤细胞，对照组只加溶剂DMSO，Vc组为加入浓度为2mM的抗坏血酸，低剂量Nic组加入浓度为1μM的Niclosamide，低剂量Nic+Vc组为加入浓度为1μM的Niclosamide以及浓度为2mM的抗坏血酸，高剂量Nic组加入浓度为2μM的Niclosamide，高剂量Nic+Vc组为加入浓度为2μM的Niclosamide以及浓度为2mM的抗坏血酸。
图19显示的是，相比于对照组的细胞活性，浓度为2mM的抗坏血酸处理条件下，DB细胞的细胞活性为76％；浓度为1μM的Niclosamide处理条件下，DB细胞的细胞活性为57％；浓度为1μM的Niclosamide以及浓度为2mM的抗坏血酸处理条件下，DB细胞的细胞活性为17％；浓度为2μM的Niclosamide处理条件下，DB细胞的细胞活性为52％；浓度为2μM的Niclosamide以及浓度为2mM的抗坏血酸处理条件下，DB细胞的细胞活性为15％。按照实 施例1中的CDI计算公式得到针对DB细胞的药物相互作用系数，低剂量Niclosamide与抗坏血酸联合CDI值为0.39，高剂量Niclosamide与抗坏血酸联合CDI值为0.38，表明两者具有显著的协同作用。同时，低剂量和高剂量Niclosamide与抗坏血酸联用对于DB细胞的抑制效果均显著好于相应的单药组(P<0.0001)。
结果显示，上述各药物，例如Wnt信号通路抑制剂，分别与抗坏血酸钠联用对于淋巴瘤细胞的抑制效果显著好于相应的单药组，并且两者具有协同作用。
前述详细说明是以解释和举例的方式提供的，并非要限制所附权利要求的范围。目前本申请所列举的实施方式的多种变化对本领域普通技术人员来说是显而易见的，且保留在所附的权利要求和其等同方案的范围内。

Claims (85)

  1. 药物组合，其包含：
    a)预防和/或治疗有效量的抗坏血酸或其衍生物；以及
    b)预防和/或治疗有效量的选自下组的第二治疗剂：Notch信号通路抑制剂，HH信号通路抑制剂，Porcupine抑制剂，RXRα抑制剂，Niclosamide，CK1a抑制剂和Frizzled受体抑制剂。
  2. 根据权利要求1所述的药物组合，其中所述RXRα抑制剂包含小檗碱或其药学上可接受的盐。
  3. 根据权利要求1-2中任一项所述的药物组合，其中所述Notch信号通路抑制剂包含γ-分泌酶抑制剂。
  4. 根据权利要求3所述的药物组合，其中所述γ-分泌酶抑制剂包含MK0752、RO4929097和/或PF-03084014。
  5. 根据权利要求1-4中任一项所述的药物组合，其中所述HH信号通路抑制剂包含SMO抑制剂。
  6. 根据权利要求5所述的药物组合，其中所述SMO抑制剂包含Vismodegib、Sonidegib和/或Glasdegib。
  7. 根据权利要求1-6中任一项所述的药物组合，其中所述Porcupine抑制剂包含LGK974和/或ETC-159。
  8. 根据权利要求1-7中任一项所述的药物组合，其中所述CK1a抑制剂包含Pyrvinium。
  9. 根据权利要求1-8中任一项所述的药物组合，其中所述Frizzled受体抑制剂包含Foxy-5。
  10. 根据权利要求1-9中任一项所述的药物组合，其中所述抗坏血酸衍生物包含药学上可接受的抗坏血酸盐。
  11. 根据权利要求10所述的药物组合，其中所述药学上可接受的抗坏血酸盐包含抗坏血酸钠。
  12. 根据权利要求1-11中任一项所述的药物组合，其中所述第二治疗剂的所述有效量与所述抗坏血酸或其衍生物的所述有效量比率为约1:10至约1:5000。
  13. 根据权利要求1-12中任一项所述的药物组合，其中所述第二治疗剂与所述抗坏血酸或其衍生物的质量比为约1:10至约1:5000。
  14. 根据权利要求1-13中任一项所述的药物组合，其中所述第二治疗剂与所述抗坏血酸或其衍生物各自存在于不同的容器中。
  15. 根据权利要求1-14中任一项所述的药物组合，其中所述药物组合包含第一制剂和第二制 剂，所述第一制剂包含所述抗坏血酸或其衍生物和药学上可接受的第一载体，且所述第二制剂包含所述第二治疗剂和药学上可接受的第二载体。
  16. 根据权利要求1-13中任一项所述的药物组合，其包含药物组合物，且所述药物组合物包含所述第二治疗剂和所述抗坏血酸或其衍生物。
  17. 根据权利要求16所述的药物组合，其中所述药物组合物中所述第二治疗剂的含量为约5％至约20％(w/w)。
  18. 根据权利要求16-17中任一项所述的药物组合，其中所述药物组合物中所述抗坏血酸或其衍生物的含量为约80％至约95％(w/w)。
  19. 试剂盒，其包括权利要求1-18中任一项所述的药物组合。
  20. 抗坏血酸或其衍生物与第二治疗剂的组合在制备药物中的用途，所述药物用于预防和/或治疗肿瘤，其中所述第二治疗剂选自：Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂和Wnt信号通路抑制剂。
  21. 根据权利要求20所述的用途，其中所述Wnt信号通路抑制剂包含Porcupine抑制剂，Dvl-2抑制剂、CK1a抑制剂和/或Frizzled受体抑制剂。
  22. 根据权利要求21所述的用途，其中所述Porcupine抑制剂包含LGK974和/或ETC-159。
  23. 根据权利要求21-22中任一项所述的用途，其中所述Dvl-2抑制剂包含Niclosamide和/或Sulindac。
  24. 根据权利要求21-23中任一项所述的用途，其中所述CK1a抑制剂包含Pyrvinium。
  25. 根据权利要求21-24中任一项所述的用途，其中所述Frizzled受体抑制剂包含Foxy-5。
  26. 根据权利要求20-25中任一项所述的用途，其中所述RXRα抑制剂包含小檗碱或其药学上可接受的盐。
  27. 根据权利要求20-26中任一项所述的用途，其中所述Notch信号通路抑制剂包含γ-分泌酶抑制剂。
  28. 根据权利要求27所述的用途，其中所述γ-分泌酶抑制剂包含MK0752、RO4929097和/或PF-03084014。
  29. 根据权利要求20-28中任一项所述的用途，其中所述HH信号通路抑制剂包含SMO抑制剂。
  30. 根据权利要求29所述的用途，其中所述SMO抑制剂包含Vismodegib、Sonidegib和/或Glasdegib。
  31. 根据权利要求20-30中任一项所述的用途，其中所述肿瘤包括实体瘤和非实体瘤。
  32. 根据权利要求31所述的用途，其中所述实体瘤包括骨肉瘤和/或结肠癌。
  33. 根据权利要求31-32中任一项所述的用途，其中所述非实体瘤包括淋巴瘤。
  34. 根据权利要求20-33中任一项所述的用途，其中所述抗坏血酸衍生物包含药学上可接受的抗坏血酸盐。
  35. 根据权利要求34所述的用途，其中所述药学上可接受的抗坏血酸盐包含抗坏血酸钠。
  36. 根据权利要求20-35中任一项所述的用途，其中所述第二治疗剂与所述抗坏血酸或其衍生物被配置为同时向受试者施用。
  37. 根据权利要求20-35中任一项所述的用途，其中所述第二治疗剂与所述抗坏血酸或其衍生物被配置为分别向受试者施用。
  38. 根据权利要求20-37中任一项所述的用途，其中所述药物被配置为使得所述第二治疗剂以约1mg/kg至约100mg/kg的剂量被施用。
  39. 根据权利要求20-38中任一项所述的用途，其中所述药物被配置为使得所述抗坏血酸或其衍生物以约0.05g/kg至约2.5g/kg的剂量被施用。
  40. 根据权利要求20-39中任一项所述的用途，其中所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:5000的质量比被施用。
  41. 根据权利要求20-40中任一项所述的用途，其中所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:5000的有效量比率被施用。
  42. 一种预防和/或治疗肿瘤的方法，其包括向有需要的受试者施用：
    a)抗坏血酸或其衍生物；和
    b)第二治疗剂，其中所述第二治疗剂选自：Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂和Wnt信号通路抑制剂。
  43. 根据权利要求42所述的方法，其中所述Wnt信号通路抑制剂包含Porcupine抑制剂，Dvl-2抑制剂、CK1a抑制剂和/或Frizzled受体抑制剂。
  44. 根据权利要求43所述的方法，其中所述Porcupine抑制剂包含LGK974和/或ETC-159。
  45. 根据权利要求43-44中任一项所述的方法，其中所述Dvl-2抑制剂包含Niclosamide和/或Sulindac。
  46. 根据权利要求43-45中任一项所述的方法，其中所述CK1a抑制剂包含Pyrvinium。
  47. 根据权利要求43-46中任一项所述的方法，其中所述Frizzled受体抑制剂包含Foxy-5。
  48. 根据权利要求43-47中任一项所述的方法，其中所述RXRα抑制剂包含小檗碱或其药学上可接受的盐。
  49. 根据权利要求42-48中任一项所述的方法，其中所述Notch信号通路抑制剂包含γ-分泌 酶抑制剂。
  50. 根据权利要求49所述的方法，其中所述γ-分泌酶抑制剂包含MK0752、RO4929097和/或PF-03084014。
  51. 根据权利要求42-50中任一项所述的方法，其中所述HH信号通路抑制剂包含SMO抑制剂。
  52. 根据权利要求51所述的方法，其中所述SMO抑制剂包含Vismodegib、Sonidegib和/或Glasdegib。
  53. 根据权利要求42-52中任一项所述的方法，其中所述肿瘤包括实体瘤和非实体瘤。
  54. 根据权利要求53所述的方法，其中所述实体瘤包括骨肉瘤和/或结肠癌。
  55. 根据权利要求53-54中任一项所述的方法，其中所述非实体瘤包括淋巴瘤。
  56. 根据权利要求42-55中任一项所述的方法，其中所述抗坏血酸衍生物包含药学上可接受的抗坏血酸盐。
  57. 根据权利要求56所述的方法，其中所述药学上可接受的抗坏血酸盐包含抗坏血酸钠。
  58. 根据权利要求42-57中任一项所述的方法，其中所述第二治疗剂与所述抗坏血酸或其衍生物被配置为同时向受试者施用。
  59. 根据权利要求42-57中任一项所述的方法，其中所述第二治疗剂与所述抗坏血酸或其衍生物被配置为分别向受试者施用。
  60. 根据权利要求42-59中任一项所述的方法，其中所述药物被配置为使得所述第二治疗剂以约1mg/kg至约100mg/kg的剂量被施用。
  61. 根据权利要求42-60中任一项所述的方法，其中所述药物被配置为使得所述抗坏血酸或其衍生物以约0.05g/kg至约2.5g/kg的剂量被施用。
  62. 根据权利要求42-61中任一项所述的方法，其中所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:5000的质量比被施用。
  63. 根据权利要求42-62中任一项所述的方法，其中所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以约1:5至约1:5000的有效量比率被施用。
  64. 监测受试者对药物响应情况的方法，所述方法包括：
    a)向所述受试者施用抗坏血酸或其衍生物和第二治疗剂，其中所述第二治疗剂选自：Notch信号通路抑制剂、HH信号通路抑制剂、RXRα抑制剂和Wnt信号通路抑制剂；以及
    b)检测经a)的所述施用后，所述受试者中下述一种或多种的变化：血液碱性磷酸酶水平和/或活性，乳酸脱氢酶水平和/或活性，CADM1基因的表达水平，CD44基因的表达 水平，livin基因的表达水平，HIF-1α基因的表达水平，ET-1基因的表达水平，IGF-1R基因的表达水平，STAT3基因的表达水平，CEA基因的表达水平，CA199基因的表达水平，CA125基因的表达水平，AFP基因的表达水平，CA724基因的表达水平，β-HCG基因的表达水平。
  65. 根据权利要求64所述的方法，其中所述Wnt信号通路抑制剂包含Porcupine抑制剂，Dvl-2抑制剂、CK1a抑制剂和/或Frizzled受体抑制剂。
  66. 根据权利要求65所述的方法，其中所述Porcupine抑制剂包含LGK974和/或ETC-159。
  67. 根据权利要求65-66中任一项所述的方法，其中所述Dvl-2抑制剂包含Niclosamide和/或Sulindac。
  68. 根据权利要求65-67中任一项所述的方法，其中所述CK1a抑制剂包含Pyrvinium。
  69. 根据权利要求65-68中任一项所述的方法，其中所述Frizzled受体抑制剂包含Foxy-5。
  70. 根据权利要求64-69中任一项所述的方法，其中所述RXRα抑制剂包含小檗碱或其药学上可接受的盐。
  71. 根据权利要求64-70中任一项所述的方法，其中所述Notch信号通路抑制剂包含γ-分泌酶抑制剂。
  72. 根据权利要求71所述的方法，其中所述γ-分泌酶抑制剂包含MK0752、RO4929097和/或PF-03084014。
  73. 根据权利要求64-72中任一项所述的方法，其中所述HH信号通路抑制剂包含SMO抑制剂。
  74. 根据权利要求73所述的方法，其中所述SMO抑制剂包含Vismodegib、Sonidegib和/或Glasdegib。
  75. 根据权利要求64-74中任一项所述的方法，其中所述肿瘤包括实体瘤和非实体瘤。
  76. 根据权利要求75所述的方法，其中所述实体瘤包括骨肉瘤和/或结肠癌。
  77. 根据权利要求75-76中任一项所述的方法，其中所述非实体瘤包括淋巴瘤。
  78. 根据权利要求64-77中任一项所述的方法，其中所述抗坏血酸衍生物包含药学上可接受的抗坏血酸盐。
  79. 根据权利要求78所述的方法，其中所述药学上可接受的抗坏血酸盐包含抗坏血酸钠。
  80. 根据权利要求64-79中任一项所述的方法，其中所述第二治疗剂与所述抗坏血酸或其衍生物被配置为同时向受试者施用。
  81. 根据权利要求64-79中任一项所述的方法，其中所述第二治疗剂与所述抗坏血酸或其衍 生物被配置为分别向受试者施用。
  82. 根据权利要求64-81中任一项所述的方法，其中所述药物被配置为使得所述第二治疗剂以约1mg/kg至约100mg/kg的剂量被施用。
  83. 根据权利要求64-82中任一项所述的方法，其中所述药物被配置为使得所述抗坏血酸或其衍生物以约0.05g/kg至约2.5g/kg的剂量被施用。
  84. 根据权利要求64-83中任一项所述的方法，其中所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以1:5至约1:5000的质量比被施用。
  85. 根据权利要求64-84中任一项所述的方法，其中所述药物被配置为使得所述第二治疗剂与所述抗坏血酸或其衍生物以1:5至约1:5000的有效量比率被施用。
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4129282A4 (en) * 2020-03-31 2024-05-01 Natural Medicine Institute Of Zhejiang Yangshengtang Co., Ltd. PHARMACEUTICAL COMBINATION AND USE THEREOF

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