WO2022007878A1 - β-1肾上腺素受体拮抗剂用于制备减少表皮生长因子受体抑制剂诱导的上皮细胞损伤以及抑制癌细胞的组合物的用途 - Google Patents

β-1肾上腺素受体拮抗剂用于制备减少表皮生长因子受体抑制剂诱导的上皮细胞损伤以及抑制癌细胞的组合物的用途 Download PDF

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WO2022007878A1
WO2022007878A1 PCT/CN2021/105167 CN2021105167W WO2022007878A1 WO 2022007878 A1 WO2022007878 A1 WO 2022007878A1 CN 2021105167 W CN2021105167 W CN 2021105167W WO 2022007878 A1 WO2022007878 A1 WO 2022007878A1
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growth factor
epidermal growth
factor receptor
cells
adrenergic receptor
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PCT/CN2021/105167
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English (en)
French (fr)
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卢俊玮
苏中慧
柯毓贤
钟文宏
陈美均
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长庚医疗财团法人林口长庚纪念医院
长庚大学
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Priority to US18/015,147 priority Critical patent/US20230248671A1/en
Priority to JP2022577113A priority patent/JP2023533911A/ja
Priority to CN202180048775.4A priority patent/CN116056693A/zh
Priority to EP21837895.8A priority patent/EP4180033A4/en
Publication of WO2022007878A1 publication Critical patent/WO2022007878A1/zh

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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • 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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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of a beta-1 adrenergic receptor antagonist for preparing a composition for reducing or preventing epidermal growth factor receptor inhibitor-induced damage to normal epithelial cells and inhibiting cancer cells.
  • Epidermal Growth Factor Receptor (EGFR) is regarded as an effective target for the development of anti-tumor therapy. It has been more than 15 years since its debut, and EGFR-targeted therapy has helped countless cancer patients to prolong their lives.
  • Epidermal Growth Factor Receptor Inhibitor (Epidermal Growth Factor Receptor Inhibitor, EGFRI) includes anti-epidermal growth factor receptor monoclonal antibody (mAb) and epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI).
  • the mechanism of action of the anti-epidermal growth factor receptor monoclonal antibody is changed to specifically bind to the epidermal growth factor receptor, and competitively inhibit the function of the epidermal growth factor, so that the cancer cells cannot proliferate.
  • monoclonal antibody drugs in clinic are Cetuximab, Zalutumumab, Nimotuzumab, Matuzumab and Panitumumab ( Panitumumab).
  • EGFR-TKI is a drug that inhibits the activity of tyrosine kinase. Because tyrosine kinase acts as a switch of many signal transmissions in cells, it plays an important role in cell growth, proliferation and differentiation, and its mutation often causes cancer.
  • tyrosine kinase inhibitors can be used as cancer drugs. In addition to inhibiting the proliferation of cancer cells, they can also prevent new angiogenesis and block the supply of nutrients and oxygen to cancer cells.
  • clinical tyrosine kinase inhibitors include erlotinib, gefitinib, lapatinib, afatinib, dacomitinib ( dacomitinib), osimertinib, etc.
  • epidermal growth factor receptor inhibitors can be used to treat a variety of cancers, the following adverse reactions of epithelial cell damage are still common in clinical practice, including: intestinal epithelial toxicity, pulmonary toxicity, liver toxicity and skin epithelial cells. damage.
  • Skin epithelial cell damage includes papulopustular rash, purpuric drug eruption, skin thinning, dermatitis, rosacea, xerosis, thinning hair, curly hair, or skin barrier damage. Due to the high expression of EGFR in the epidermal base, the use of epidermal growth factor receptor inhibitors is often associated with cutaneous adverse drug reactions that damage normal or uninjured epithelial cells.
  • epidermal growth factor receptor inhibitors can cause inflammatory cell infiltration in the skin, especially in the hair follicle, the stratum corneum of the skin is significantly thinner, the normal basket-weave structure is lost, and the Dermatologic side effects associated with gefitinib therapy: clinical experience and management. Clin Lung Cancer, 2003.4(6):p .366-9).
  • the current treatment for dermal adverse drug reactions caused by EGFR inhibitors is dose reduction or discontinuation of EGFR therapy.
  • the object of the present invention is to provide the use of a beta-1 adrenergic receptor antagonist for preparing a composition for reducing or preventing epidermal growth factor receptor inhibitor-induced damage to normal epithelial cells.
  • EGFRI epidermal growth factor receptor inhibitor
  • the normal epithelial cells are epithelial cells that have not been damaged or toxic by epidermal growth factor receptor inhibitors.
  • the beta-1 adrenergic receptor antagonist may be administered before, after, or concurrently with the epidermal growth factor receptor inhibitor. In one example, the beta-1 adrenergic receptor antagonist may be administered before an epidermal growth factor receptor inhibitor.
  • Some embodiments of the present invention are directed to methods of inhibiting normal (or not yet injured) epithelial cell damage in an individual due to epidermal growth factor receptor inhibitor (EGFRI) treatment of cancer, comprising administering to an individual in need thereof an effective amount of at least one beta-1 adrenergic receptor antagonist, thereby reducing or preventing the symptoms and/or signs of epithelial cell damage in the individual.
  • EGFRI epidermal growth factor receptor inhibitor
  • Some specific examples of the present invention are to provide the use of a beta-1 adrenergic receptor antagonist for preparing a composition for inhibiting cancer cells.
  • the composition comprises at least one beta-1 adrenergic receptor antagonist in combination with at least one dermal growth factor receptor inhibitor. Beta-1 adrenergic receptor antagonists and at least one dermal growth factor receptor inhibitor can produce additive or synergistic effects.
  • Some embodiments of the present invention are directed to methods of inhibiting cancer growth in an individual comprising administering to an individual in need thereof an effective amount of at least one beta-1 adrenergic receptor antagonist and at least one dermal growth factor receptor inhibitor combination, thereby alleviating the symptoms and/or signs of cancer in the individual.
  • compositions and methods of the present invention can be used to treat or inhibit the growth of any type of cancer.
  • the cancer to be treated or the growth of the cancer to be inhibited is a solid tumor or hematological tumor, such as liver cancer, bile duct cancer, breast cancer, lung cancer, stomach cancer, pancreatic cancer, colorectal cancer, uterine cancer, cervical cancer, leukemia and lymphoma.
  • the epidermal growth factor receptor inhibitor is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-Tyrosine Kinase Inhibitor, EGFR-TKI).
  • epidermal growth factor receptor tyrosine kinase inhibitors include gefitinib, erlotinib, afatinib, dacomitinib, osimertinib, lapatinib, or combinations thereof.
  • the epidermal growth factor receptor inhibitor is an anti-epidermal growth factor receptor monoclonal antibody.
  • anti-EGFR monoclonal antibodies include Erlotinib, Gefitinib, Lapatinib, Afatinib, Dacomitinib dacomitinib, osimertinib, or a combination thereof.
  • the epithelial cells refer to skin epithelial cells, intestinal epithelial cells or corneal epithelial cells.
  • non-limiting examples of the beta-1 adrenergic receptor antagonists include atenolol, betaxaolol, bisoprolol, esmolol (esmolol), acebutolol, metoprolol, nebivolol, or a combination thereof.
  • the epidermal growth factor receptor inhibitor (EGFRI)-induced skin epithelial cytotoxicity comprises at least one of the following: papulopustular rash, purpuric drug eruption, skin thinning, dermatitis, rosacea, Dryness, thinning hair, curly hair or skin barrier damage.
  • the epidermal growth factor receptor inhibitor (EGFRI)-induced intestinal epithelial cell toxicity comprises at least one of the following: oral mucositis, genital mucositis, or diarrhea.
  • composition comprising a beta-1 adrenergic receptor antagonist may further comprise the aforementioned epidermal growth factor receptor inhibitor (EGFRI), which is used to inhibit the growth of cancer cells and reduce the effects of EGFRI. epithelial cell damage.
  • EGFRI epidermal growth factor receptor inhibitor
  • Figure 1 is a schematic diagram of the survival rate of normal epithelial cells by administering different concentrations of epidermal growth factor receptor tyrosine kinase inhibitors to normal epithelial cells;
  • Figure 2 is a schematic diagram of the survival rate of epithelial cells after administration of different concentrations of beta-1 adrenergic receptor antagonist betaxolol to normal epithelial cells;
  • Figure 3 shows the survival rate of epithelial cells by first administering beta-1 adrenergic receptor antagonist betaxolol to normal epithelial cells, and then administering epidermal growth factor receptor tyrosine kinase inhibitor after 1 hour schematic diagram;
  • Figure 4 is a schematic diagram of the survival rate of normal epithelial cells when an epidermal growth factor receptor tyrosine kinase inhibitor and a beta-1 adrenergic receptor antagonist are simultaneously administered to normal epithelial cells;
  • FIG. 5 is a schematic diagram showing the survival rate of A549 cancer cells by administering epidermal growth factor receptor tyrosine kinase inhibitor to A549 cancer cells;
  • Figure 6 shows the survival of A549 cancer cells administered with epidermal growth factor receptor tyrosine kinase inhibitor alone and concurrent administration of epidermal growth factor receptor tyrosine kinase inhibitor and beta-1 adrenergic receptor antagonist to A549 cancer cells rate diagram;
  • Figure 7 shows the survival of PC9 cancer cells administered with epidermal growth factor receptor tyrosine kinase inhibitor alone and concurrent administration of epidermal growth factor receptor tyrosine kinase inhibitor and beta-1 adrenergic receptor antagonist to PC9 cancer cells rate diagram;
  • Figure 8 is a schematic diagram of the survival rate of epithelial cells by first administering a non-selective beta-adrenergic receptor antagonist to normal epithelial cells, and then administering an epidermal growth factor receptor tyrosine kinase inhibitor after 1 hour;
  • Figure 9 is a schematic diagram of the survival rate of A549 cancer cells when an epidermal growth factor receptor tyrosine kinase inhibitor and a non-selective beta-adrenergic receptor antagonist are simultaneously administered to A549 cancer cells;
  • Figures 10 to 12 are schematic diagrams showing the effect of ⁇ -1 adrenergic receptor antagonists on epidermal growth factor receptor tyrosine kinase inhibitor-induced rosacea;
  • Figure 13 is a schematic diagram showing the effect of ⁇ -1 adrenergic receptor antagonists against epidermal growth factor receptor monoclonal antibody-induced papulopustular rash;
  • Figure 14 is an eosin-stained image of normal skin cells (A) after treatment with an epidermal growth factor receptor inhibitor (B) (excerpted from Herbst, RS, et al., Dermatologic side effects associated with gefitinib therapy: clinical experience and management. Clin Lung Cancer, 2003.4(6):p.366-9);
  • B epidermal growth factor receptor inhibitor
  • Figure 15 is a schematic diagram of the survival rate of epithelial cells after administration of ⁇ -1 adrenergic receptor antagonist Bisoprolol to normal epithelial cells and then administration of epidermal growth factor receptor tyrosine kinase inhibitor after 1 hour ;
  • Figure 16 shows the survival rate of epithelial cells after administration of ⁇ -1 adrenergic receptor antagonist acebutolol to normal epithelial cells and then administration of epidermal growth factor receptor tyrosine kinase inhibitor after 1 hour Schematic.
  • subject and “patient” are used interchangeably and refer to a diagnosis of EGFRI-induced epithelial cell damage and/or cancer, or a suspected EGFRI-induced epithelial cell damage and/or cancer of mammals.
  • Individuals include primates, preferably humans.
  • an "effective amount" of an antagonist is an amount of an inhibitor that produces the desired effect, eg, a reduction in the rate of epithelial cell damage and/or inhibition of cancer cells by at least about 1%, 5%, as compared to an untreated individual , 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%.
  • treatment includes prophylactic (eg, prophylactic), palliative and curative uses or results.
  • Individuals or patients in need of treatment or prevention are meant to include epithelial cell damage that has or is suspected of having EGFRI; individuals or patients who have or are suspected to have cancer, or patients who have not yet produced EGFRI to cause damage to normal epithelial cells.
  • one skilled in the art can quickly determine the amount of beta-administered for a particular type of epithelial cell damage, depending on, for example, the severity and type of epithelial cell damage, the patient's age, weight, gender, complications, and other drugs administered to the patient. 1 Appropriate doses and dose numbers of adrenergic receptor antagonists; those skilled in the art will appreciate that the preferred dose is one that produces a therapeutic effect in a patient in need, such as a dose that accelerates epithelial cell repair.
  • the beta-1 adrenergic receptor antagonist can be administered in any effective amount. In some specific examples, it may range from about 0.01% w/w to about 10% w/w, from about 0.05% w/w to about 5% w/w, from about 0.1% w/w to about 1% w/w within the dose administration.
  • Suitable dosages of the compositions provided herein are determined by comparing the in vitro activity of the compositions provided herein with in vivo activity in animal models. Methods for extrapolating effective doses in mice and other animals to human effective doses are known in the art; see, eg, US Pat. No. 4,938,949, which is incorporated herein by reference.
  • the composition is administered in an amount effective to inhibit epithelial cell damage or reduce cancer cell growth.
  • the dosage of the pharmaceutical composition administered will depend on the severity of the condition being treated, the particular formulation, and other clinical factors such as the recipient's weight and general state and route of administration.
  • a single dose is administered once a day for a given number of days (ie, 1 day, 7 days, 14 days, 21 days, 1 month, etc.).
  • multiple doses may be administered in one day (every 2 hours, 4 hours, 6 hours, or 12 hours, etc.), in multiple doses per day for multiple days.
  • compositions are delivered by any of a variety of routes including, but not limited to, injection (eg, subcutaneous, intramuscular, intravenous, intraarterial, intraperitoneal, intradermal); skin; dermis; Transdermal; Oral (e.g., lozenges, pills, liquids, edible tapes); Implanted osmotic pumps; Suppositories; Aerosol sprays; Topical; Intraarticular; in the vagina.
  • injection eg, subcutaneous, intramuscular, intravenous, intraarterial, intraperitoneal, intradermal
  • skin dermis
  • Transdermal e.g., lozenges, pills, liquids, edible tapes
  • Implanted osmotic pumps e.g., lozenges, pills, liquids, edible tapes
  • Implanted osmotic pumps e.g., Suppositories; Aerosol sprays; Topical; Intraarticular; in the vagina.
  • the composition is formulated for topical delivery in one of the following forms: ointment, cream, solution, gel, suspension, spray or lotion; in another embodiment, the composition is formulated as For slow or sustained release.
  • the MTT test (ie, cell viability analysis) was performed on the effect of epidermal growth factor receptor tyrosine kinase inhibitors on epithelial cells.
  • the experimental process is as follows:
  • HaCaT cells human skin keratinocytes
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, bromide (4,5-dimethyl-2-thiazole)-2,5-diphenyltetrazolium
  • Figure 1 is a schematic diagram of the survival rate of epithelial cells by administering different concentrations of epidermal growth factor receptor tyrosine kinase inhibitors to normal epithelial cells; it can be seen from the figure that as the concentration of afatinib increases, The survival rate of HaCaT cells gradually decreased. When the concentration increased to 5 ⁇ M, the cell survival rate was only 34.8%. It can be seen that EGFR tyrosine kinase inhibitor can increase the apoptosis of normal epithelial cells.
  • the MTT test was carried out on the effect of ⁇ -1 adrenergic receptor antagonists on epithelial cells.
  • the experimental process was similar to that in Example 1, except that afatinib was replaced by betaxolol, which will not be repeated here; the experiments were carried out in total 4 times, the data of absorbance and cell viability are shown in Table 2 below.
  • Figure 2 is a schematic diagram of the survival rate of epithelial cells by administering different concentrations of beta-1 adrenergic receptor antagonist betaxolol to normal epithelial cells; it can be seen from the figure that with the concentration of betaxolol Increase, the survival rate of HaCaT cells is at least 90%, and when the concentration is increased to a high concentration of 100 ⁇ M, the cell survival rate drops to 88.1%; it can be seen that basically betaxolol does not affect the survival rate of normal epithelial cells .
  • the MTT test was carried out on the effects of successive administration of ⁇ -1 adrenergic receptor antagonist and epidermal growth factor receptor tyrosine kinase inhibitor on epithelial cells.
  • the experimental procedure was similar to that of Example 1. Lol, administered afatinib after 1 hour and cultured for 24 hours to observe the survival rate of HaCaT cells.
  • FIG. 3 15 and 16 for the first administration of ⁇ -1 adrenergic receptor antagonists to normal epithelial cells, and then administration of epidermal growth factor receptor tyrosine kinase inhibitors after 1 hour, the schematic diagram of the survival rate of epithelial cells ; As can be seen from Figures 3, 15 and 16, the survival rate of HaCaT cells was 100% when only ⁇ -1 adrenergic receptor antagonists were administered, and when only afatinib was administered, as the concentration increased, HaCaT cells increased.
  • the survival rate decreased gradually; however, when the beta-1 adrenergic receptor antagonist was administered first and then afatinib was administered, the survival rate of HaCaT cells was much improved compared with that when only afatinib was administered, and the The higher the concentration of nitric acid, it can be seen that the apoptosis of HaCaT cells is significantly reduced; it can be seen that ⁇ -1 adrenergic receptor antagonists can indeed reduce the epithelial cell damage caused by epidermal growth factor receptor tyrosine kinase inhibitors.
  • a MTT test was conducted on the effects of simultaneous administration of ⁇ -1 adrenergic receptor antagonist and epidermal growth factor receptor tyrosine kinase inhibitor on epithelial cells.
  • the experimental procedure was similar to that in Example 1.
  • Afatinib was added and cultured for 24 hours to observe the survival rate of HaCaT cells.
  • FIG. 4 is a schematic diagram of the survival rate of epithelial cells when an epidermal growth factor receptor tyrosine kinase inhibitor and a beta-1 adrenergic receptor antagonist are simultaneously administered to normal epithelial cells;
  • the survival rate of HaCaT cells was 100% when betaxolol was administered.
  • Fig. 5 is a schematic diagram of the survival rate of A549 cancer cells when an epidermal growth factor receptor tyrosine kinase inhibitor is administered to A549 cancer cells;
  • Fig. 6 is a graph showing the single administration of an epidermal growth factor receptor tyrosine kinase inhibitor
  • Figure 7 is a graph showing the survival rate of A549 cancer cells when EGFR tyrosine kinase inhibitor and ⁇ -1 adrenergic receptor antagonist were administered concurrently; Schematic diagram of the survival rate of PC9 cancer cells with amino acid kinase inhibitor and concurrent administration of epidermal growth factor receptor tyrosine kinase inhibitor and beta-1 adrenergic receptor antagonist to PC9 cancer cells.
  • Adrenergic receptor antagonists such as, but not limited to, Timolol, co-administered with epidermal growth factor receptor tyrosine kinase inhibitors; to observe their effects on HaCaT cells as well as A549 cancer cells, their experiments The process is similar to that of Embodiment 1, and details are not repeated here.
  • Figure 8 shows the survival of epithelial cells after first administering a non-selective beta-adrenergic receptor antagonist to normal epithelial cells and then administering an epidermal growth factor receptor tyrosine kinase inhibitor after 1 hour.
  • Figure 9 is a schematic diagram of the survival rate of A549 cancer cells when an epidermal growth factor receptor tyrosine kinase inhibitor and a non-selective beta-adrenergic receptor antagonist are simultaneously administered to A549 cancer cells.
  • adrenergic receptor antagonist is formulated as a topical external drug, and is administered to a patient to observe its therapeutic effect.
  • Figure 10 to Figure 12 are schematic diagrams of the effect of ⁇ -1 adrenergic receptor antagonists on epidermal growth factor receptor inhibitor-induced rosacea; wherein, Figure 10 uses 0.25% (w/w) Betaxolol was used to treat afatinib-induced rosacea, and on the 14th day of treatment, the rosacea had a significant improvement compared to the 1st day.
  • Figure 11 shows the treatment of rosacea induced by osimertinib with 0.25% (w/w) betaxolol, and the rosacea was significantly improved on the 4th day of treatment.
  • Figure 12 shows that rosacea was treated with 0.25% (w/w) betaxolol, and the rosacea was significantly improved on the 7th day of treatment.
  • Figure 13 is a schematic diagram of the effect of beta-1 adrenergic receptor antagonists against epidermal growth factor receptor monoclonal antibody-induced papulopustular rash; using 0.25% (w/w) betaxolol on Inceto The papulopustular rash induced by ximab was treated, and the papules and pustules (arrows) were significantly improved on day 30 of treatment.
  • ⁇ -1 adrenergic receptor antagonists can indeed reduce or prevent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and anti-EGFR monoclonal antibody (mAb)-induced Normal epithelial cell damage, reduce epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and anti-epithelial growth factor receptor monoclonal antibody (mAb)-induced epithelial cell damage, and can improve the effect of EGFR-TKI on cancer cells
  • EGFR-TKI epidermal growth factor receptor tyrosine kinase inhibitor
  • mAb anti-epithelial growth factor receptor monoclonal antibody
  • ⁇ -1 adrenergic receptor antagonists can reduce EGFR-TKI-induced epithelial cell damage and also improve the inhibitory effect of EGFR-TKI on cancer cells, which can be obtained by those with ordinary knowledge in the technical field with reference to the prior art. It has an unexpected effect.

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Abstract

一种β-1肾上腺素受体拮抗剂用于制备减少或预防表皮生长因子受体抑制剂诱导的正常上皮细胞损伤以及抑制癌细胞的组合物的用途，通过施用包含β-1肾上腺素受体拮抗剂的组合物以减少表皮生长因子受体抑制剂所诱导的正常上皮细胞损伤，并可与表皮生长因子受体抑制剂一同施用以协同作用抑制癌细胞。

Description

β-1肾上腺素受体拮抗剂用于制备减少表皮生长因子受体抑制剂诱导的上皮细胞损伤以及抑制癌细胞的组合物的用途 技术领域
相关申请案的交互参照
本申请主张2020年7月10日提交的美国临时申请案号63/050,390的优先权的利益。通过引用将上述申请案的全部内容并入本文中。
本发明系关于一种β-1肾上腺素受体拮抗剂用于制备减少或预防表皮生长因子受体抑制剂诱导的正常上皮细胞损伤以及抑制癌细胞的组合物的用途。
背景技术
表皮生长因子受体(Epidermal Growth Factor Receptor,EGFR)被视为发展抗肿瘤治疗的有效目标物，EGFR标靶治疗距离初次登场已经有超过15年的历史，帮助了无数的癌症病患延长生命。表皮生长因子受体抑制剂(Epidermal Growth Factor Receptor Inhibitor,EGFRI)包含有抗表皮生长因子受体单株抗体(mAb)及表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)。
其中，抗表皮生长因子受体单株抗体作用机转为专一性地与表皮生长因子受体结合，竞争性的抑制表皮生长因子功能，使得癌细胞无法增生。目前临床上常用之单株抗体药物为西妥昔单抗(Cetuximab)、扎鲁单抗(Zalutumumab)、尼莫妥单抗(Nimotuzumab)、马妥珠单抗(Matuzumab)以及帕尼单抗(Panitumumab)。
EGFR-TKI是抑制酪氨酸激酶活性的药物，由于酪氨酸激酶在细胞内担任许多信号传递的开关，在细胞生长、增殖及分化中具有重要作用，其突变常常引起癌症。
因此，酪氨酸激酶抑制剂可做为癌症药物使用，其除了可抑制癌细胞增生之外，还可阻止新的血管生成，阻断癌细胞养分及氧气的供给。目前临床上常用之酪氨酸激酶抑制剂包括有厄洛替尼(Erlotinib)、吉非替尼(Gefitinib)、拉帕替尼(Lapatinib)、阿法替尼(Afatinib)、达克替尼(dacomitinib)、奥希替尼(osimertinib)等。
表皮生长因子受体抑制剂虽然可应用于治疗多种癌症，然而在临床上仍常见以下上皮细胞(epithelial cell)损伤的不良反应，包括：肠上皮毒性、肺部毒性、肝毒性及皮肤上皮细胞损伤。皮肤上皮细胞损伤包含丘疹脓疱皮疹、紫癜性药疹、皮肤变薄、皮肤炎、红斑痤疮、干燥症、头发稀疏、卷发或皮肤屏障损害等。由于在表皮基底有高表现量的EGFR，使用表皮生长因子受体抑制剂常会出现皮肤药物不良反应，使正常或是尚未受伤的上皮细胞受损。与正常皮肤相比，表皮生长因子受体抑制剂在皮肤会引起发炎细胞浸润，尤其是在毛囊中，皮肤的角质层明显变薄，失去了正常的篮状编织(basket-weave)结构，并变得更致密、嗜酸性及角化不全(请见图14，摘录于Herbst,R.S.,et al.,Dermatologic side effects associated with gefitinib therapy:clinical experience and management.Clin Lung Cancer,2003.4(6):p.366-9)。目前针对皮生长因子受体抑制剂引起的皮肤药物不良反应的处置为减少剂量或是停止表皮生长因子受体抑制剂治疗。因此对于减少或是预防表皮生长因子受体抑制剂所引起 的上皮细胞损伤的需求仍然存在；本发明解决此需求以及其他需求。
发明内容
有鉴于上述问题，本发明的目的系在于提供一种β-1肾上腺素受体拮抗剂用于制备减少或预防表皮生长因子受体抑制剂诱导的正常上皮细胞损伤的组合物的用途。
为解决表皮生长因子受体抑制剂(EGFRI)治疗癌症时所引起的正常(或尚未受伤)上皮细胞损伤，通过将包含β-1肾上腺素受体拮抗剂的组合物施用于有需要的个体或患者，以减少或预防因施用EGFRI治疗癌症时所造成的正常上皮细胞损伤。
在一实施例中，所述的正常上皮细胞为尚未有表皮生长因子受体抑制剂引起损伤或毒性的上皮细胞。
在一实施例中，所述β-1肾上腺素受体拮抗剂可在表皮生长因子受体抑制剂之前、之后或与其同时施用。在一实施例中，所述β-1肾上腺素受体拮抗剂可在表皮生长因子受体抑制剂之前施用。
本发明的一些具体实例系针对抑制一个体因表皮生长因子受体抑制剂(EGFRI)治疗癌症时所引起的正常(或尚未受伤)上皮细胞损伤的方法，其包含向有需要的个体施用有效量的至少一种β-1肾上腺素受体拮抗剂，藉此减轻或预防该个体上皮细胞损伤的症状及/或征象。
本发明的一些具体实例系在于提供一种β-1肾上腺素受体拮抗剂用于制备抑制癌细胞的组合物的用途。该组合物包含至少一种β-1肾上腺素受体拮抗剂与至少一种皮生长因子受体抑制剂的组合。β-1肾上腺素受体拮抗剂与至少一种皮生长因子受体抑制剂可产生累加或协同作用。
本发明的一些具体实例系针对抑制个体中癌症生长的方法，其包含向有需要的个体施用有效量的至少一种β-1肾上腺素受体拮抗剂与至少一种皮生长因子受体抑制剂的组合，藉此减轻该个体的癌症的症状及/或征象。
本发明组合物及方法可用于治疗或抑制任何类型的癌症生长。在一些具体实例中，待治疗癌症或待抑制的癌症生长为实体肿瘤或血液肿瘤，诸如肝癌、胆管癌、乳癌、肺癌、胃癌、胰脏癌、结肠直肠癌、子宫癌、子宫颈癌、白血病及淋巴瘤。
在一实施例中，所述表皮生长因子受体抑制剂为表皮生长因子受体酪氨酸激酶抑制剂(EGFR-Tyrosine Kinase Inhibitor,EGFR-TKI)。表皮生长因子受体酪氨酸激酶抑制剂的非限制性实例包括吉非替尼、厄洛替尼、阿法替尼、达克替尼、奥希替尼、拉帕替尼或其组合。
在一实施例中，所述表皮生长因子受体抑制剂为，抗表皮生长因子受体单株抗体。抗表皮生长因子受体单株抗体的非限制性实例包括厄洛替尼(Erlotinib)、吉非替尼(Gefitinib)、拉帕替尼(Lapatinib)、阿法替尼(Afatinib)、达克替尼(dacomitinib)、奥希替尼(osimertinib)或其组合。
在一实施例中，所述上皮细胞系指皮肤上皮细胞，肠上皮细胞或角膜上皮细胞。
在一实施例中，所述β-1肾上腺素受体拮抗剂的非限制性实例包括阿替洛尔(atenolol)、倍他洛尔(betxaolol)、比索洛尔(bisoprolol)、艾司洛尔(esmolol)、醋丁洛尔(acebutolol)、美托洛尔(metoprolol)、奈比洛尔(nebivolol)或其组合。
在一实施例中，所述表皮生长因子受体抑制剂(EGFRI)引起的皮肤上皮细胞毒性包括下述至少一 种：丘疹脓疱皮疹、紫癜性药疹、皮肤变薄、皮肤炎、红斑痤疮、干燥症、头发稀疏、卷发或皮肤屏障损害。
在一实施例中，所述表皮生长因子受体抑制剂(EGFRI)引起的肠上皮细胞毒性包括下述至少一种：口腔粘膜炎、生殖器粘膜炎或腹泻。
在一实施例中，所述包含β-1肾上腺素受体拮抗剂的组合物可进一步包含前文所述的表皮生长因子受体抑制剂(EGFRI)，用于抑制癌细胞生长时减少EGFRI所引起的上皮细胞损伤。
本案中使用的术语“发明”、“该发明”、“此发明”及“本发明”旨在广泛指称本案的发明标的和下述申请专利范围的全部。包含这些术语的陈述应理解为不限制本文所述之发明标的或下述申请专利范围的含义或其涵盖范围。本案涵盖之发明实施例由下述申请专利范围所定义，而非由本发明内容所定义。本发明内容是本发明各方面之高层次概述，并介绍了在以下实施方式中进一步描述的部分概念。本发明内容非旨在识别出所要求保护之发明标的的关键或必要特征，也非旨在单独用以判定所要求保护之发明标的。发明标的应通过参考整份说明书、任何或所有图式以及每项申请专利范围之适当部分来理解。
搭配所附图式以及以下之详细描述阅读，将使本发明变得更加明显易懂。
附图说明
图1为施用不同浓度的表皮生长因子受体酪氨酸激酶抑制剂至正常上皮细胞，其上皮细胞的存活率示意图；
图2为施用不同浓度的β-1肾上腺素受体拮抗剂倍他洛尔(betaxolol)至正常上皮细胞，其上皮细胞的存活率示意图；
图3为先施用β-1肾上腺素受体拮抗剂倍他洛尔(betaxolol)至正常上皮细胞，经1小时后再施用表皮生长因子受体酪氨酸激酶抑制剂，其上皮细胞的存活率示意图；
图4为同时施用表皮生长因子受体酪氨酸激酶抑制剂与β-1肾上腺素受体拮抗剂至正常上皮细胞，其上皮细胞的存活率示意图；
图5为施用表皮生长因子受体酪氨酸激酶抑制剂至A549癌细胞，其癌细胞的存活率示意图；
图6为单独施用表皮生长因子受体酪氨酸激酶抑制剂以及同时施用表皮生长因子受体酪氨酸激酶抑制剂与β-1肾上腺素受体拮抗剂至A549癌细胞，其癌细胞的存活率示意图；
图7为单独施用表皮生长因子受体酪氨酸激酶抑制剂以及同时施用表皮生长因子受体酪氨酸激酶抑制剂与β-1肾上腺素受体拮抗剂至PC9癌细胞，其癌细胞的存活率示意图；
图8为先施用非选择性β肾上腺素受体拮抗剂至正常上皮细胞，经1小时后再施用表皮生长因子受体酪氨酸激酶抑制剂，其上皮细胞的存活率示意图；
图9为同时施用表皮生长因子受体酪氨酸激酶抑制剂与非选择性β肾上腺素受体拮抗剂至A549癌细胞，其癌细胞的存活率示意图；
图10至图12为β-1肾上腺素受体拮抗剂对表皮生长因子受体酪氨酸激酶抑制剂诱导的红斑痤疮影响示意图；
图13为β-1肾上腺素受体拮抗剂对抗表皮生长因子受体单株抗体诱导的丘疹脓疱皮疹影响示意图；
图14为正常皮肤细胞(A)与表皮生长因子受体抑制剂治疗后(B)的皮肤细胞伊红染色影像图(摘录于Herbst,R.S.,et al.,Dermatologic side effects associated with gefitinib therapy:clinical experience and management.Clin Lung Cancer,2003.4(6):p.366-9)；
图15为先施用β-1肾上腺素受体拮抗剂比索洛尔(Bisoprolol)至正常上皮细胞，经1小时后再施用表皮生长因子受体酪氨酸激酶抑制剂，其上皮细胞的存活率示意图；
图16为先施用β-1肾上腺素受体拮抗剂醋丁洛尔(acebutolol)至正常上皮细胞，经1小时后再施用表皮生长因子受体酪氨酸激酶抑制剂，其上皮细胞的存活率示意图。
实施方式
以下内容将搭配图式，通过特定的具体实施例说明本发明的技术内容，熟悉此技术之人士可由本说明书所揭示的内容轻易地了解本发明的其他优点与功效。本发明亦可通过其他不同的具体实施例加以施行或应用。本说明书中的各项细节亦可基于不同观点与应用，在不背离本发明的精神下，进行各种修饰与变更。
用语“个体(subject)”和“患者(patient)”可交互使用，且是指被诊断出有EGFRI所造成的上皮细胞损伤及/或癌症，或疑似有EGFRI造成的上皮细胞损伤及/或癌症的哺乳动物。个体包括灵长类动物，较佳为人类。
“有效量”的拮抗剂是指能产生所需效果的一定量的抑制剂，例如与未受治疗的个体相比，减少上皮细胞损伤率及/或癌细胞抑制率至少约1％、5％、10％、20％、30％、40％、50％、60％、70％、80％、90％、95％。
本文所用之专有术语“治疗”包括预防性(例如防治性)、缓解性及治愈性用途或结果。需要治疗或预防的个体或患者意指包含已经有或疑似有EGFRI造成的上皮细胞损伤；已经有或疑似有癌症的个体或患者，或尚未产生EGFRI造成正常上皮细胞损伤的患者。
本文中所有数字可被理解为以“约”修饰。如用于本文中，术语“约”意指包含正负10％的变化。
另外，本领域技术人员可依据例如上皮细胞损伤的严重程度和类型、患者年龄、体重、性别、并发症以及施予患者的其它药物，快速地判定针对特定类型的上皮细胞损伤施予的β-1肾上腺素受体拮抗剂的合适剂量和剂量数；本领域技术人员将了解到，较佳的剂量为对有需求的患者产生治疗效果，例如加速上皮细胞修复的剂量。
β-1肾上腺素受体拮抗剂可以任何有效量施用。在一些具体实例中，其可以约0.01％w/w至约10％w/w、约0.05％w/w至约5％w/w、约0.1％w/w至约1％w/w范围内的剂量施用。
通过比较本文提供的组合物的试管内活性与动物模型中的活体内活性来测定本文提供的组合物的适用剂量。此项技术中已知将小鼠及其他动物中的有效剂量外推成人类有效剂量的方法；例如参看美国专利第4,938,949号，其以引用的方式并入本文中。
组合物以有效抑制上皮细胞损伤或减少癌细胞生长的量施用。所施用医药组合物的剂量将视所治 疗病状的严重程度、特定调配物及其他临床因素(诸如接受者的体重及一般状态及投药途径)而定。在一实施例中，单一剂量在给定数量的天数(即1天、7天、14天、21天、1个月等)中一天施予一次。
在又一实施例中，可在一天内(每2小时、4小时、6小时或12小时等)施予多剂量，以每天多次剂量地施予多天。
根据本文提供的方法，通过多种途径中的任一者递送组合物，包括(但不限于)注射(例如皮下、肌肉内、静脉内、动脉内、腹膜内、皮内)；皮肤；真皮；经皮；经口(例如锭剂、药丸、药液、可食用膜带)；植入渗透泵；栓剂；气溶胶喷雾；局部；关节内；经眼；鼻吸入；肺吸入；压入皮肤及阴道中。
在一实施例中，组合物被配制成下列形式之一以进行局部递送：软膏、乳霜、溶液、凝胶、悬浮液、喷雾或洗剂；在另一实施例中，组合物被配制成用于缓慢或持续释放。
实施例1
针对表皮生长因子受体酪氨酸激酶抑制剂对上皮细胞的影响进行MTT试验(即细胞存活率分析)，其实验流程如下：
在多孔盘(24孔)中每孔种入固定数量(7×10 4cell/dish)的HaCaT细胞(人类皮肤角质细胞)，于培养24小时后，将不同浓度的阿法替尼(0、1、2.5、5、10、20、50μM)与0.1％的DMSO加入细胞中并培养24小时；加入MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide，溴化-3-(4,5-二甲基-2-噻唑)-2,5-二苯基四氮唑)300λ，经1小时后抽掉上清液再加入DMSO并震荡，抽取200λ/孔液体加入另一多孔盘(96孔)中，并用ELISA测量吸光值(OD 570，optical density 570nm)，计算出细胞存活率，实验共进行3次，其吸光值与细胞存活率的数据如下表1所示。
表1
Figure PCTCN2021105167-appb-000001
参照图1，图1为施用不同浓度的表皮生长因子受体酪氨酸激酶抑制剂至正常上皮细胞，其上皮细胞的存活率示意图；由图中可知，随着阿法替尼的浓度提高，HaCaT细胞的存活率逐渐下降，当浓度提高至5μM时，细胞存活率仅剩34.8％；由此可知，表皮生长因子受体酪氨酸激酶抑制剂会增加正常上皮细胞的凋亡。
实施例2
针对β-1肾上腺素受体拮抗剂对上皮细胞的影响进行MTT试验，其实验流程与实施例1相似，仅将阿法替尼置换为倍他洛尔，于此不再赘述；实验共进行4次，其吸光值与细胞存活率的数据如下表2所示。
表2
Figure PCTCN2021105167-appb-000002
Figure PCTCN2021105167-appb-000003
参照图2，图2为施用不同浓度的β-1肾上腺素受体拮抗剂倍他洛尔至正常上皮细胞，其上皮细胞的存活率示意图；由图中可知，随着倍他洛尔的浓度提高，HaCaT细胞的存活率至少为90％以上，当浓度提高至100μM的高浓度时，细胞存活率才下降至88.1％；由此可知，基本上倍他洛尔不影响正常上皮细胞的存活率。
实施例3
针对先后施用β-1肾上腺素受体拮抗剂与表皮生长因子受体酪氨酸激酶抑制剂对上皮细胞的影响进行MTT试验，其实验流程与实施例1相似，将HaCaT细胞先施用的倍他洛尔，经1小时后再施用阿法替尼并培养24小时，观察HaCaT细胞的存活率。
参照图3、15及16，为先施用β-1肾上腺素受体拮抗剂至正常上皮细胞，经1小时后再施用表皮生长因子受体酪氨酸激酶抑制剂，其上皮细胞的存活率示意图；由图3、15及16中可知，仅施用β-1肾上腺素受体拮抗剂时，HaCaT细胞的存活率为100％，仅施用阿法替尼时，随着浓度提高时，HaCaT细胞的存活率逐渐下降；但先施用β-1肾上腺素受体拮抗剂后再施用阿法替尼时，HaCaT细胞的存活率相较于仅施用阿法替尼时提高不少，且于阿法替尼浓度越高时，可看出HaCaT细胞凋亡明显减少；由此可知，β-1肾上腺素受体拮抗剂确实可降低表皮生长因子受体酪氨酸激酶抑制剂所造成的上皮细胞损伤。
实施例4
针对同时施用β-1肾上腺素受体拮抗剂与表皮生长因子受体酪氨酸激酶抑制剂对上皮细胞的影响进行MTT试验，其实验流程与实施例1相似，将HaCaT细胞同时施用倍他洛尔及阿法替尼并培养24小时，观察HaCaT细胞的存活率。
参照图4，图4为同时施用表皮生长因子受体酪氨酸激酶抑制剂与β-1肾上腺素受体拮抗剂至正常上皮细胞，其上皮细胞的存活率示意图；由图中可知，仅施用倍他洛尔时，HaCaT细胞的存活率为100％，仅施用阿法替尼时，随着浓度提高时，HaCaT细胞的存活率逐渐下降；但同时施用倍他洛尔及阿法替尼时，HaCaT细胞的存活率相较于仅施用阿法替尼时提高不少；由此可知，β-1肾上腺素受体拮抗剂确实可降低表皮生长因子受体酪氨酸激酶抑制剂所造成的上皮细胞损伤。
实施例5
由前述实施例中，可发现同时施用β-1肾上腺素受体拮抗剂及表皮生长因子受体酪氨酸激酶抑制剂于正常上皮细胞时，可提高正常上皮细胞的存活率；接着，针对癌细胞，分别测试仅施用表皮生长因子受体酪氨酸激酶抑制剂以及同时施用β-1肾上腺素受体拮抗剂及表皮生长因子受体酪氨酸激酶抑制剂对癌细胞的抑制效果，其实验流程与实施例1相似，于此不再赘述。
参照图5至图7，图5为施用表皮生长因子受体酪氨酸激酶抑制剂至A549癌细胞，其癌细胞的存活率示意图；图6为单独施用表皮生长因子受体酪氨酸激酶抑制剂以及同时施用表皮生长因子受体酪氨酸激酶抑制剂与β-1肾上腺素受体拮抗剂至A549癌细胞，其癌细胞的存活率示意图；以及图7为单独施 用表皮生长因子受体酪氨酸激酶抑制剂以及同时施用表皮生长因子受体酪氨酸激酶抑制剂与β-1肾上腺素受体拮抗剂至PC9癌细胞，其癌细胞的存活率示意图。
由图5可知，阿法替尼施用于A549癌细胞(EGFR突变的肺癌细胞)时，随着浓度越高，A549癌细胞的存活率逐渐下降，于浓度为50μM时，A549癌细胞的存活率下降至26.4％；由此可知，表皮生长因子受体酪氨酸激酶抑制剂可显著增加癌细胞的凋亡；其实验共进行3次，其吸光值与细胞存活率的数据如下表3所示。
表3
Figure PCTCN2021105167-appb-000004
由图6可知，仅施用倍他洛尔时，A549癌细胞的存活率为100％，当阿法替尼与倍他洛尔同时施用时，对于A549癌细胞的抑制效果相较于单独施用阿法替尼，可增加细胞毒性作用；由此可知，β-1肾上腺素受体拮抗剂可提高表皮生长因子受体酪氨酸激酶抑制剂的抗癌效果。
由图7可知，将阿法替尼与倍他洛尔同时施用另一PC9癌细胞(EGFR突变的癌细胞)时，对于PC9癌细胞的抑制效果相较于单独施用阿法替尼，可增加细胞毒性作用；由此可知，EGFR所诱导的相关癌细胞，同时施用β-1肾上腺素受体拮抗剂及表皮生长因子受体酪氨酸激酶抑制剂，可提高抗癌效果。
实施例6
为验证是否仅有β-1肾上腺素受体拮抗剂可减少表皮生长因子受体酪氨酸激酶抑制剂所引起的上皮细胞损伤，且具有增加抑制癌细胞的效果，另找了非选择性β肾上腺素受体拮抗剂，如噻吗洛尔(Timolol)，但不限于此，与表皮生长因子受体酪氨酸激酶抑制剂共同施用；观察其对于HaCaT细胞以及A549癌细胞的作用，其实验流程与实施例1相似，于此不再赘述。
参照图8及图9，图8为先施用非选择性β肾上腺素受体拮抗剂至正常上皮细胞，经1小时后再施用表皮生长因子受体酪氨酸激酶抑制剂，其上皮细胞的存活率示意图；图9为同时施用表皮生长因子受体酪氨酸激酶抑制剂与非选择性β肾上腺素受体拮抗剂至A549癌细胞，其癌细胞的存活率示意图。
由图8可知，固定阿法替尼的浓度，改变施用的噻吗洛尔的浓度时，HaCaT细胞的存活率相较于单独施用阿法替尼显著下降，且于同时施用浓度10μM的噻吗洛尔时，即下降至37％以下；由此可知，非选择性β肾上腺素受体拮抗剂与阿法替尼明显降低了HaCaT细胞的存活率，非选择性β肾上腺素受体拮抗剂无法预防或减少因表皮生长因子受体抑制剂(EGFRI)治疗癌症时所引起的正常(或尚未受伤)上皮细胞损伤。
由图9可知，同时施用噻吗洛尔及阿法替尼于A549癌细胞时，A549癌细胞的存活率并没有显著改变，而当噻吗洛尔的浓度提高至50μM时，A549癌细胞的存活率反而相对提高；由此可知，同时施用非选择性β肾上腺素受体拮抗剂及表皮生长因子受体酪氨酸激酶抑制剂，并无法提高抗癌效果。
实施例7
寻找因表皮生长因子受体酪氨酸激酶抑制剂或抗表皮生长因子受体单株抗体引起的上皮细胞损 伤的患者，例如，患有红斑痤疮或丘疹脓疱皮疹的患者，将包含有β-1肾上腺素受体拮抗剂的组合物配制成局部施用的外用药，施用于患者观察其治疗效果。
参照图10至图12，图10至图12为β-1肾上腺素受体拮抗剂对表皮生长因子受体抑制剂诱导的红斑痤疮影响示意图；其中，图10系使用0.25％(w/w)倍他洛尔对因阿法替尼所诱导引起的红斑痤疮进行治疗，于治疗至第14天时，红斑痤疮相较于第1天具有明显的改善。图11系使用0.25％(w/w)倍他洛尔对因奥希替尼所诱导引起的红斑痤疮进行治疗，于治疗至第4天时，红斑痤疮即具有明显的改善。图12系使用0.25％(w/w)倍他洛尔对红斑痤疮进行治疗，于治疗至第7天时，红斑痤疮即具有明显的改善。
参照图13，图13为β-1肾上腺素受体拮抗剂对抗表皮生长因子受体单株抗体诱导的丘疹脓疱皮疹影响示意图；使用0.25％(w/w)倍他洛尔对因西妥昔单抗所诱导引起的丘疹脓疱皮疹进行治疗，于治疗至第30天时，丘疹脓疱(箭头处)有明显的改善。
综上所述，β-1肾上腺素受体拮抗剂确实可减少或预防表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)以及抗表皮生长因子受体单株抗体(mAb)诱导的正常上皮细胞损伤，减少表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)以及抗表皮生长因子受体单株抗体(mAb)诱导的上皮细胞损伤，并可提高EGFR-TKI对于癌细胞的抑制效果；另使用非选择性β肾上腺素受体拮抗剂作为对比，可知非选择性β肾上腺素受体拮抗剂并无法减少或预防EGFR-TKI诱导的正常上皮细胞损伤，且也无法提高EGFR-TKI对于癌细胞的抑制效果。
因此，使用β-1肾上腺素受体拮抗剂对于减少EGFR-TKI诱导的上皮细胞损伤，也一并提高EGFR-TKI对于癌细胞的抑制效果，非所属技术领域具通常知识者参考先前技术而可得知，故具有无法预期之功效。
上述实施例仅例示性说明本发明的原理及功效，而非用于限制本发明。任何熟习此项技术之人士均可在不违背本发明的精神及范畴下，对上述实施例进行修饰与改变。因此，本发明的权利保护范围，应如本发明权利要求所列。

Claims (9)

  1. 一种β-1肾上腺素受体拮抗剂用于制备减少或预防患者表皮生长因子受体抑制剂(EGFRI)诱导的正常上皮细胞损伤的组合物的用途，其包括向有需要的患者施用包含有效量的β-1肾上腺素受体拮抗剂的组合物的步骤。
  2. 如权利要求1所述的用途，其中该正常上皮细胞为皮肤。
  3. 如权利要求2所述的用途，其中该EGFRI诱导的正常皮肤上皮细胞损伤包括下述至少一种：丘疹脓疱皮疹、紫癜性药疹、皮肤变薄、皮肤炎、红斑痤疮、干燥症、头发稀疏、卷发或皮肤屏障损害。
  4. 如权利要求1所述的用途，其中该正常上皮细胞为肠细胞。
  5. 如权利要求4所述的用途，其中该EGFRI诱导的正常肠上皮损伤包括下述至少一种：口腔粘膜炎、生殖器粘膜炎或腹泻。
  6. 如权利要求1所述的用途，其中该正常上皮细胞为角膜细胞。
  7. 如权利要求1所述的用途，其中该β-1肾上腺素受体拮抗剂选自阿替洛尔、倍他洛尔、比索洛尔、艾司洛尔、醋丁洛尔、美托洛尔、耐比洛及其组合所组成之群。
  8. 如权利要求1所述的用途，其中该EGFRI为表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)。
  9. 一种包含表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)及β-1肾上腺素受体拮抗剂的组合物用于制备抑制个体癌细胞的药物的用途，其包括向该个体施用包含有效量的表皮生长因子受体抑制剂(EGFRI)及β-1肾上腺素受体拮抗剂的组合物的步骤。
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