WO2016062278A1 - 内分泌疾病用药在制备抑制癌症的医药组合物中的应用 - Google Patents

内分泌疾病用药在制备抑制癌症的医药组合物中的应用 Download PDF

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WO2016062278A1
WO2016062278A1 PCT/CN2015/092753 CN2015092753W WO2016062278A1 WO 2016062278 A1 WO2016062278 A1 WO 2016062278A1 CN 2015092753 W CN2015092753 W CN 2015092753W WO 2016062278 A1 WO2016062278 A1 WO 2016062278A1
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cancer
drugs
hormone
insulin
drug
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French (fr)
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陈丘泓
庄秀美
萧乃文
梁瑞岳
陈筱彤
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朗齐生物医学股份有限公司
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Definitions

  • the present invention relates to the use of new indications for a variety of drugs for endocrine diseases, in particular, the use of the plurality of drugs for clinical trials and for inhibiting various cancers.
  • Cancer has long been the leading cause of death worldwide, and the number of cancer patients has increased year by year. Therefore, treating cancer has become an important issue.
  • the treatment of cancer can be divided into surgical treatment, radiation therapy, chemotherapy and target treatment.
  • cancer drug treatment is intended to prevent cancer cells from replicating and dividing to block the spread and spread of tumors.
  • chemotherapy chemotherapy or target treatment
  • cancer drug treatment is intended to prevent cancer cells from replicating and dividing to block the spread and spread of tumors.
  • chemotherapeutic drugs and target treatment hoping to kill cancer cells by different mechanisms to improve the therapeutic effect, but in fact, patients often react to the treatment of drugs Not good.
  • many cancer cells successively develop drug resistance, which greatly reduces the effectiveness of drug use, and ultimately leads to failure of cancer treatment.
  • endocrine diseases There are three reasons for the endocrine diseases: the destruction of endocrine glands, defects in endocrine gland hormone synthesis and other factors; endocrine gland tumors such as various pituitary tumors and other causes of hyperactivity; hormone sensitivity defects, receptors and (or The post-receptor defect prevents the hormone from functioning properly.
  • Endocrine commonly known as Hormones, is an active substance secreted by an organ system in the body, or released from the natural product of a gland through its internal secretion, into the blood circulation, and acts on On the distant target organ (Target Organ). It has a regulating person The function of the body function, together with the nervous system, is responsible for the complex physiological and chemical reactions of the entire human body, so that the organisms can produce synergistic effects to cope with changes in the external environment. Endocrine hormones are different from vitamins (Vitamine), which is secreted by an organ or gland in the body, but vitamins must be taken from outside food. The secretion of endocrine hormones must be appropriate.
  • endocrine hormones in the body, no one can use synthetic substances like endocrine hormones to inhibit or supplement.
  • Such substances are clinically used endocrine drugs such as Cortisone, Insulin, Thyroxine, Testesterone, Pro-gesterones and the like.
  • the present invention aims at the development of new indications for various endocrine drugs through clinical experiments, and achieves the goal of new use of old drugs.
  • the experimental design results show that endocrine disease medication has no or only minimal toxicity to normal cells, but whether endocrine disease drugs have selective effects between normal cells and tumor cells, more research is needed, and not all The endocrine disease medication can effectively inhibit tumor cells under the same conditions, and many problems need to be overcome.
  • Endocrine disease medication can be divided into six categories according to the structure of the drug, including adrenal cortical hormone drugs, androgen and anabolic hormone drugs, estrogen and progesterone drugs, pancreatic hormone and other drugs that affect blood sugar, thyroid hormone and anti-thyroid Medicine, parathyroid and calcium metabolism regulating drugs.
  • glucocorticoids include the C3 carbonyl, ⁇ 4 and 17 ⁇ ketol side chains of the adrenocortical hormone, and 17 ⁇ -OH and 11 ⁇ -OH, which are unique to glucocorticoids.
  • the concept of glucocorticoids not only includes endogenous substances with the above characteristics and activities, but also includes many structurally optimized synthetic drugs with similar structures and activities.
  • glucocorticoid drugs are a clinically useful class. drug. [Physiological effects] Promote gluconeogenesis, reduce the uptake and utilization of glucose by peripheral tissues, and increase blood sugar, which also increases the synthesis of glycogen glycogen.
  • [Pharmacological action] includes: anti-inflammatory effect: increase vasoconstriction, reduce vascular permeability, antagonize vasodilating effects of histamine and other inflammatory mediators, reduce local congestion, reduce leukocyte and body fluid exudation; stabilize lysosomes Membrane, which reduces the release of cathepsins and hydrolases due to lysosomal rupture, reduces tissue breakdown and inflammatory mediator release; inhibits the recruitment of neutrophils, monocytes and macrophages to inflammatory sites; inhibits phospholipase A2 Activity, reducing the conversion of membrane phospholipids to arachidonic acid, which is the biosynthesis precursor of many inflammatory mediators such as prostaglandins, leukotrienes, and platelet activating factors.
  • glucocorticoids in addition to anti-inflammatory effects
  • glucocorticoids can also inhibit the conversion of B cells to plasma cells, reduce antibody production, inhibit humoral immunity, and reduce the release of aggressive substances caused by antigen-antibody reactions
  • Role Although glucocorticoid has no effect on bacterial exotoxin, it has strong antibacterial endotoxin effect, reduces the release of endogenous heat source substances, has good antipyretic effect and greatly improves the symptoms of poisoning; Shock: This is the result of a combination of anti-inflammatory immunosuppressive and anti-endotoxin effects, glucocorticoids can inhibit the vasoconstriction of epinephrine, norepinephrine, vas
  • the endocrine diseases according to the present invention include Budesonide, Trilostane, Aminoglutethimide (Cytadren), Medrysone, Melatonin, Deoxycorticosterone acetate, Verteporfin (Visudyne), and Naftopidil (Flivas).
  • Testosterone testosteron0 some new derivatives, commonly used in the clinical test for methyltestosterone (android; methyltestosterone, methyltestosterone), testosterone propionate (andronate; testosterone propionate, testosterone propionate) and testosterone testosterone (testosterone phenylacetate).
  • the chemical structure of androgen testosterone is easily absorbed orally, but is rapidly destroyed in the liver, so it is orally ineffective. Protein binding. Metabolites are inactivated by binding to glucuronic acid or sulfuric acid, excreted by the urine.
  • testosterone ester compounds are less polar and soluble. After intramuscular injection in oil, absorption is slow and lasts for a long time. For example, intramuscular injection of testosterone propionate can be maintained for 2 to 4 days. Methyltestosterone is not easily destroyed by the liver, and is effective orally. It can also be administered sublingually. Physiological and pharmacological effects] 1. The reproductive system promotes male sexual and reproductive organs development and maintains its mature state. Testosterone can also inhibit the secretion of anterior pituitary Glandular hormone (negative feedback) can reduce estrogen secretion in women. There is anti-estrogen effect. 2.
  • the endocrine disease drug of the present invention includes Abiraterone (CB-7598), Bicalutamide (Casodex), Finasteride, Dutasteride, Letrozole, and Alprostadil (Caverject) in this category.
  • estrogen is a type of female hormones, including estrone, estradiol and so on.
  • Estradiol is the most important estrogen.
  • Estrogen is mainly secreted by the ovaries, and a small amount is secreted by the liver, adrenal cortex, and breast. The placenta can also be secreted in large amounts during pregnancy. Male testes also secrete small amounts.
  • the main secretion of ovaries is ⁇ -estradiol, and other estrogens are less important.
  • Steroids There are female natural estrogens such as estrone (E1), estradiol (estradiol, E2), and estriol (E3), which account for 10-20% in the circulatory system.
  • estriol is the most abundant, it is the weakest estrogen, and estradiol is about 80 times more potent than estriol.
  • Estradiol is the most important estrogen for unpregnant women between menarche and menopause. However, for pregnant women, the important role is switched to estriol; estrone is the main form of estrogen in menopausal women. There is another estrogen, estetrol (E4), which only appears during pregnancy. All different forms of estrogen are aromatase-converted androgens, especially testosterone and androstenedione.
  • Premarin a commonly used estrogen drug, is obtained from a pregnant mare. It contains steroids of estrogen, equilin and equilenin. 2.
  • Non-steroids Many natural and synthetic substances have been identified to possess estrogenic activity. [Biosynthesis] Estrogen is mainly produced from the ovary, corpus luteum and placenta. Follicle stimulating hormone (FSH) stimulates ovarian granulosa cells to synthesize estrogen. A small amount of estrogen is also synthesized by other tissues, such as liver, adrenal gland, and breast. These small amounts of estrogen are especially important for menopausal women. In addition, fat cells also produce estrogen [source request]. Synthetic estrogen is the synthesis of androstenediol from cholesterol in the ovarian endometrial cells. Androstene glycol has moderate estrogenic activity and will penetrate or the basement membrane to reach granulocyte and then be converted to estrone or estradiol.
  • FSH Follicle stimulating hormone
  • estradiol has a high and low fluctuation with the menstrual cycle, and only a high concentration is present before ovulation.
  • Metabolism The liver can metabolize estrogens, especially estrogen ketones. In patients with liver disease, due to the decline of liver function, the concentration of estrogen in the blood rises, showing symptoms such as liver palm and spider mites.
  • Estrogen has only a small amount of secretion during childhood; it will increase a lot after puberty, and promote the development of female first and second sexual characteristics: female reproductive system: estrogen promotes fallopian tube, uterus, vagina and female genital enlargement, vaginal increase Thick, and most importantly, endometrial thickening.
  • Breast Estrogen can accumulate fat in the breast.
  • Estrogen causes women to grow taller and faster during puberty and stop growing taller in the early years.
  • Fat Estrogen increases the amount of subcutaneous fat and causes fat to build up on the breasts and buttocks.
  • Blood vessels Estrogen causes the small arteries to dilate, and the super-expanded superficial small arteries present symptoms such as liver palm and spider mites.
  • the endocrine diseases according to the present invention include Anastrozole, Exemestane, Evista (Raloxifene Hydrochloride), Dienogest, Gestodene, Drospirenone, Ethinyl Estradiol, Estrone, Progesterone (Prometrium), Estradiol, Misoprostol, Levonorgestrel (Levonelle), Toremifene Citrate. (Fareston, Acapodene), Tamoxifen Citrate (Nolvadex), Mestranol, Estradiol valerate, Ethynodiol diacetate, Benfotiamine.
  • pancreatic hormone and other drugs that affect blood sugar insulin is a protein hormone, from the pancreas Secretion of islet beta cells within. Insulin is involved in regulating carbohydrate and fat metabolism, controlling blood sugar balance, and promoting liver and skeletal muscle to convert glucose in the blood into glycogen. Lack of insulin can lead to high blood sugar and diabetes. Therefore insulin can be used to treat diabetes. Its molecular weight is 5,808 Daltons. Insulin has been used in clinical practice for decades, from the antigenic first-generation animal insulin to genetic recombination, but it takes 30 minutes before the meal to wait for 30 minutes of second-generation human insulin, and then it can be used to simulate the physiological human insulin secretion pattern. Pancreatic third-generation insulin analogs.
  • insulin that better mimics the normal human physiological hypoglycemic pattern is the third-generation insulin, an insulin analog.
  • First-generation insulin-animal insulin In 1921, Frederick Banting and John Macleod successfully extracted insulin for the first time, different race mammals (human, cattle, sheep, The amino acid sequence and structure of insulin molecules in pigs, etc., are slightly different, with porcine insulin being the closest to humans. [8].
  • Animal insulin is the earliest insulin injection preparation for the treatment of diabetes. It is usually porcine insulin. Pig insulin and human insulin are different from 1 to 4 amino acids, so it is prone to immune reaction, subcutaneous fat atrophy or hyperplasia at the injection site, and insulin allergic reaction.
  • Insulin is a protein hormone secreted by islet ⁇ cells by excitability of endogenous or exogenous substances such as glucose, lactose, ribose, arginine, glucagon, and the like.
  • the first secreted is a long-chain peptide consisting of 84 amino acids, proinsulin, which is treated with a specific protease, proinsulin converting enzyme (PC1 and PC2) and a carboxypeptide ⁇ E.
  • the C chain) is cleaved, and the carboxy terminal portion (A chain) and the amino terminal portion (B chain) of proinsulin are bonded together by a disulfide bond to form insulin.
  • Mature insulin is stored in secretory vesicles in islet beta cells and exists as a hexamer with zinc ion coordinators. Under external stimulation, insulin is released into the bloodstream with secretory vesicles and exerts its physiological effects.
  • the secretion of insulin is divided into two parts. One part describes insulin that is secreted by normal fasting blood glucose, which is called basal insulin. The other part is insulin that is secreted to reduce postprandial blood glucose and maintain normal postprandial blood glucose. .
  • the early phase secretion of insulin during meals controls the magnitude and duration of postprandial blood glucose elevation, and its main role is to inhibit the production of endogenous glucose in the liver.
  • blood glucose is controlled at a level close to the fasting state at any time; the peak value of postprandial blood glucose is below 7.0 mmol/L, and the blood glucose level is higher than 5.5 mmol/L for no more than 30 minutes.
  • most patients have autoimmune destruction of islet ⁇ cells before diagnosis of diabetes, resulting in a decrease in both mealtime and basal insulin secretion.
  • islet ⁇ -cell dysfunction progresses slowly, often manifested as peripheral insulin resistance, but there is also a decrease in insulin-phase secretion, which can lead to normal fasting blood glucose and elevated postprandial blood glucose.
  • postprandial blood glucose levels can reach 4 times that of non-diabetic physiology, and After the meal, the blood sugar rises for several hours, so that it still rises significantly before the next meal.
  • insulin preparations that make up for insufficient insulin secretion during mealtime are Novo and N, and insulin analog preparations include Novo and Sharp.
  • Basal insulin is a 24-hour continuous pulsed insulin of islet cells, which is mainly used to maintain normal blood glucose levels.
  • ADA American Diabetes Association
  • EASD European Diabetes Association
  • Fibrosis of insulin After extensive clinical medicine and scientific research, amyloid fibrosis of insulin is closely related to type 2 diabetes. [Function] The role of the overall metabolic level: promote the glucose carrier on the cell membrane to transport glucose into the cell, thereby controlling glucose into muscle and adipose tissue. DNA replication and protein synthesis are enhanced by controlling the absorption of amino acids. The activity of various enzymes is regulated by allosteric action.
  • the endocrine disease drug of the present invention includes Repaglinide, Glipizide (Glucotrol), Metformin hydrochloride (Glucophage), Glipizide (Glucotrol), Benfotiamine, and Neostigmine bromide (Prostigmin).
  • thyroid hormones are tyrosine iodides synthesized by thyroid follicular epithelial cells. Mainly tetraiodothyronine (also known as thyroxine, abbreviated as T4) and triiodothyronine (abbreviated as T3), in addition, a small amount of inverse-triiodothyronine (abbreviated as rT3).
  • hormones secreted by the thyroid include calcitonin in addition to thyroid hormones. Because calcitonin is produced by parathyroid cells in the thyroid gland, it is not in the category of thyroid hormones.
  • T4 and T3 have physiological activity, the difference is the time and intensity of action: T4 activity is low, the onset is slow, but the duration is long; T3 activity is high, The effect is fast, but the duration is short [2].
  • T4 activity is low, the onset is slow, but the duration is long; T3 activity is high, The effect is fast, but the duration is short [2].
  • T4 activity is less like a pro-hormone.
  • rT3 has no obvious physiological activity, so in most contexts, "thyroid hormone” refers only to T4 and T3. To date, thyroid hormone is the only class of iodine-containing physiological substances.
  • [Physiological effects] Widely act on a variety of cells; can initiate a variety of transcription factors, thereby initiating the expression of a variety of genes.
  • its physiological role is also related to the developmental stage in which the body is located and the stage of differentiation in which the cells are located. In general, the physiological functions of various systems of the whole body can be enhanced. 1. Metabolism: promotes the maturation of the nerve, improves the body's sensitivity to catecholamine hormones (such as adrenaline), increases the heat production and basal metabolic rate, and stimulates all aspects of glucose metabolism, for example, promoting sugar absorption and sugar. Generation and sugar utilization. It promotes protein synthesis under physiological conditions.
  • Thyroxine plays an important role in normal development and cell differentiation. It controls the metabolism of proteins, fats and carbohydrates and stimulates the metabolism of vitamins. Several physiological and pathological stimuli affect the synthesis of thyroxine. In addition, thyroxine also controls the constant temperature mechanism of humans.
  • thyroxine In the case of sudden drop in body temperature, thyroxine also affects the hibernation of mammals and the moulting of birds. 4. Thyroid hormones maintain the growth and development of mammals, especially the central nervous system and bones. If you suffer from hypothyroidism in your infancy, it can lead to permanent mental retardation and shortness. 5.
  • the nervous system has an allowable effect on catecholamines, stimulating appetite formation. 6
  • circulatory system positively variable, positively variable, positively variable force on the heart. 7. There is a diastolic effect on the peripheral arteries: mainly the indirect effects of heat production and metabolic products. 8. Digestive system: promote the secretion of digestive juice and promote gastrointestinal motility.
  • T4 or T3 artificial synthetic products are widely used. Because the physiological effects of T4 are relatively mild, it is mainly used for long-term replacement therapy of thyroid hormones. Because of its high T3 activity and rapid onset, it is mainly used for the rescue of severe hypothyroidism (myxedema coma). [related diseases] excessive or too little thyroxine secretion can lead to diseases: 1.
  • Hyperthyroidism (such as ocular hyperthyroidism, or Graves Disease), caused by excessive thyroxine release About 2% of women and 0.2% of men suffer from this disease. Thyrotoxicosis Thyrotoxicosis is usually replaced by the term hyperthyroidism, but there is still a slight difference between them. Although thyrotoxicosis is also associated with excessive secretion of thyroxine, the main reason is excessive intake. Thyroid hormone tablets or excessive thyroid secretion, and hyperthyroidism refers to excessive thyroid secretion. 2. Hypothyroidism: (such as Hashimoto's thyroiditis) is caused by insufficient secretion of thyroxine.
  • the endocrine disease medication of the present invention comprises AMG-073HCl (Cinacalcet hydrochloride), Methimazole (Tapazole, Northyx), Potassium iodide, Propylthiouracil, Tiratricol, 2-Thiouracil, Carbenoxolone Sodium. Sodium ascorbate.
  • Parathyroid gland is an endocrine gland of vertebrates that regulates calcium and phosphorus metabolism in the body. Except in humans and some real mammals, it has a certain anatomical positional relationship with the thyroid, and in other animals, there is no close relationship between the two. It is more closely related to the thymus, both of which originate in the pharyngeal sac.
  • Parathyroid gland An endocrine gland, usually 4, divided into upper and lower pairs, is a flat ovoid body, the size of a pea, attached to the back of the thyroid gland. Secreted parathyroid hormone can regulate calcium and phosphorus metabolism in the body.
  • parathyroid hormone is a kind of neck The parathyroid gland secretes a polypeptide hormone with 84 amino acids. It mainly acts on bones and kidneys and increases the concentration of calcium ions in the blood. [Biochemical characteristics] In 1925, a highly active extract was first isolated from the parathyroid gland, and it was confirmed that parathyroid hormone has a blood calcium regulating effect. Parathyroid hormone is synthesized and secreted by the main cells of the parathyroid gland.
  • parathyroid hormone there are at least three forms of parathyroid hormone in the blood circulation: intact parathyroid hormone.
  • Parathyroid hormone fragment biologically active, with a circulating half-life of 2 to 4 minutes, mostly cleared in the liver, and a small part cleared by the kidney.
  • Carboxy-terminal parathyroid hormone fragment no biological activity, the highest concentration of this fragment in normal human blood, circulating half-life of 30 to 40 minutes, mainly cleared by the kidney, so the concentration of this fragment is significantly increased in chronic renal failure.
  • the amino terminal parathyroid hormone fragment is biologically active, has a low blood concentration, and has a short half-life.
  • the complete parathyroid hormone can be secreted into the blood after being cleaved into fragments in the parathyroid main cell, or it can be secreted into the surrounding blood and then lysed into fragments. After the parathyroid hormone multi-strand breaks at the position of the 34th to 37th amino acids, the amino terminus still has the complete biological activity of the complete parathyroid hormone.
  • Serum calcium ion concentration is a major regulator of the synthesis and secretion of parathyroid hormone. Animal experiments have shown that the relationship between blood calcium concentration and parathyroid hormone secretion rate is a curve.
  • the regulation of blood calcium concentration on the secretion of parathyroid hormone by parathyroid cells is achieved by the adenosine membrane cyclization of glandular cells and the intercellular cyclic adenosine monophosphate.
  • the increase of blood phosphorus concentration promotes the secretion of parathyroid hormone.
  • Blood phosphorus can cause hypocalcemia and indirectly promote the secretion of parathyroid hormone.
  • Reduced blood magnesium concentration inhibits parathyroid hormone secretion.
  • a pharmacological dose of calcitonin promotes the secretion of parathyroid hormone.
  • Catecholamines, dopamine and epinephrine all promote the secretion of parathyroid hormone.
  • the concentration of parathyroid hormone in the blood of the elderly is higher than that of the young and middle-aged.
  • the concentration of parathyroid hormone in human blood varies with the season and is higher in summer than in summer, which is related to the seasonal variation of serum 25-hydroxyvitamin D concentration. In winter, there is less sunshine, lower concentration of blood 25-hydroxyvitamin D, decreased intestinal calcium absorption, decreased blood calcium level, and increased physiological compensatory blood parathyroid hormone.
  • Bone is the largest calcium reservoir in the body. More than 99% of the body's calcium is stored in bones and teeth.
  • Parathyroid hormone has enhanced osteoclast activity, forms new osteoclasts and temporarily inhibits osteoblasts. of Function, which promotes bone absorption and dissolution, releases bone calcium into the blood, and increases blood calcium levels.
  • parathyroid hormone inhibits the reabsorption of phosphate by the proximal tubules and increases the release of phosphate in the urine. Therefore, there are hypophosphatemia and hyperuricemia when there are too many parathyroid hormones. In contrast, parathyroid hormone increases the reabsorption of calcium by remote renal tubules. In addition, parathyroid hormone also inhibits the absorption of sodium and bicarbonate by the renal tubules, so that the bicarbonate is excreted from the urine, and when the parathyroid hormone is excessive, the urine is often alkaline. The effect of parathyroid hormone on renal tubular resorption is very rapid, can occur in a few minutes, and can continue to function for a long time.
  • parathyroid hormone Another important role of parathyroid hormone is to promote the conversion of 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D in the kidney by 1-hydroxylation, which is the most active vitamin D metabolite known to date. It can increase the absorption of calcium and phosphorus in the intestine, so parathyroid hormone indirectly promotes the absorption of intestinal calcium. Under normal circumstances, the body regulates and maintains the balance of calcium and phosphorus metabolism mainly depends on the three hormones of parathyroid hormone, 1,25-dihydroxyvitamin D and calcitonin. Through the synergy and antagonism of the three, the blood calcium concentration is maintained. normal range. The synthesis and secretion of these three hormones are closely related to the concentration of calcium ions in the serum.
  • the parathyroid hormone secretory thyroxine increases rapidly, promotes bone resorption, and bone calcium mobilization is released into the blood: renal tubular absorption of calcium increases: 25-hydroxyvitamin D is converted to 1,25 - Dihydroxyvitamin D increases, and the full effect of the latter effect takes about 20 to 24 hours, thereby increasing intestinal calcium absorption. In this way, the blood calcium concentration is increased again by the above three routes.
  • the function of the parathyroid gland is inhibited, and the synthesis and secretion of parathyroid hormone are rapidly reduced, thereby reducing bone absorption and bone calcium mobilization, and reducing renal tubular absorption of calcium and 1 , the production of 25-dihydroxyvitamin D, the absorption of calcium in the intestine is correspondingly reduced; on the other hand, it stimulates the secretion of calcitonin due to high blood calcium, which inhibits bone absorption and bone calcium mobilization, inhibits renal tubular to calcium And the absorption back of phosphorus.
  • the endocrine disease medication of the present invention comprises Calcitriol (Rocaltrol), Doxercalciferol (Hectorol), Alfacalcidol, Calcifediol, Etidronate in this category. (Didronel) Deflazacort (Calcort), Vitamin D2.
  • the present invention provides a pharmaceutical composition for endocrine diseases, which comprises a drug selected from the group consisting of endocrine diseases.
  • the adrenocortical hormone drug is one or more selected from the group consisting of Budesonide, Trilostane, Aminoglutethimide (Cytadren), Medrysone, Melatonin, Deoxycorticosterone acetate, Verteporfin (Visudyne), and Naftopidil (Flivas).
  • Budesonide Trilostane
  • Aminoglutethimide Cytadren
  • Medrysone Aminoglutethimide
  • Melatonin Deoxycorticosterone acetate
  • Verteporfin Verteporfin
  • Naftopidil Frazier as
  • the androgen and anabolic hormone drugs are selected from one or more selected from the group consisting of Abiraterone (CB-7598), Bicalutamide (Casodex), Finasteride, Dutasteride, Letrozole, and Alprostadil (Caverject).
  • CBD-798 Abiraterone
  • Bicalutamide Casodex
  • Finasteride Finasteride
  • Dutasteride Dutasteride
  • Letrozole and Alprostadil (Caverject).
  • Alprostadil Alprostadil
  • the estrogen and progestin agent are selected from the group consisting of Anastrozole, Exemestane, Evista (Raloxifene Hydrochloride), Dienogest, Gestodene, Drospirenone, Ethinyl Estradiol, Estrone, Progesterone (Prometrium), Estradiol, Misoprostol, A drug consisting of one or more of Levonorgestrel (Levonelle), Toremifene Citrate (Fareston, Acapodene), Tamoxifen Citrate (Nolvadex), Mestranol, Estradiol valerate, Ethynodiol diacetate, Benfotiamine.
  • pancreatic hormone and other blood glucose inducing agents are one selected from the group consisting of Repaglinide, Glipizide (Glucotrol), Metformin hydrochloride (Glucophage), Glipizide (Glucotrol), Benfotiamine, Neostigmine bromide (Prostigmin) or A variety of drugs.
  • the thyroid hormone and the antithyroid drug are selected from the group consisting of AMG-073HCl (Cinacalcet hydrochloride), Methimazole (Tapazole, Northyx), Potassium iodide, Propylthiouracil, Tiratricol, 2-Thiouracil, Carbenoxolone Sodium.
  • a drug consisting of one or more of Sodium ascorbate.
  • the parathyroid and calcium metabolism regulating agent is one selected from the group consisting of Calcitriol (Rocaltrol), Doxercalciferol (Hectorol), Alfacalcidol, Calcifediol, Etidronate (Didronel) Deflazacort (Calcort), and Vitamin D2. Or a variety of drugs.
  • the cancer obtained is one or more selected from the group consisting of lung cancer, gastric cancer, liver cancer, rectal cancer, skin cancer, cervical cancer, prostate cancer, bladder cancer, breast cancer, and blood cancer.
  • the effective dose concentration of the drug is from 20 mg/kg/day to 500 mg/kg/day.
  • Fig. 1 shows the application of the endocrine disease of the present invention to the inhibition of cancer cell analysis results.
  • the cell lines of different cancer types were subcultured, and after counting the number of cells, 2 ⁇ 10 6 cells were placed in a culture dish, and then the culture medium in which the cell strain was cultured was added to a volume of 10 ml, and the culture was continued. 2-3 days. The cells were then counted and dispensed into 96-well plates where the number of cells per well was fixed at 3000 cells and the volume was 100 ul.
  • the original culture solution in the 96-well plate was aspirated, and a commercially available drug having a concentration of 10 ⁇ M and a volume of 100 ul was added to each well. After 72 hours, 100 ul of diluted WST-1 reagent was added to each well, and the dilution ratio was the culture solution and The volume ratio of the WST-1 stock solution is 9:1. Finally, the total volume of each well plate is 200 ul. Then, the 96-well plate is placed at 37 ° C for 30-90 minutes, using an elisa reader (ELISA) on the OD450. The absorbance values were detected and the survival rate of each cancer cell line was calculated.
  • ELISA elisa reader
  • Endocrine disease medication is used to inhibit cancer cell analysis results
  • Endocrine diseases are divided into six categories, including adrenal cortical hormone drugs, androgen and anabolic hormone drugs, estrogen and progesterone drugs, pancreatic hormone and other drugs that affect blood sugar, thyroid hormones and antithyroid drugs, parathyroid glands And calcium metabolism regulating drugs inhibit the growth of cancer cells.
  • Endocrine disease drug Inhibition of the number of cancer cell lines Dutasteride 0 Melatonin 0 Calcitriol (Rocaltrol) 0 Aminoglutethimide (Cytadren) 0 Neostigmine bromide (Prostigmin) 0 Phenoxybenzamine HCl 0 Phenytoin (Lepitoin) 0 Pramiracetam 0 Tioxolone 0 Dehydroepiandrosterone (DHEA) 0 Ornidazole 0 Sulfamethazine 0 Milnacipran HCl 0 Valganciclovir hydrochloride 0 Guanabenz acetate 0 Dydrogesterone 0
  • Anastrozole has an inhibitory effect on lung cancer, stomach cancer and liver cancer.
  • Bicalutamide (Casodex) has inhibitory effects on lung cancer, gastric cancer, and liver cancer.
  • Exemestane has inhibitory effects on lung cancer, stomach cancer, liver cancer, rectal cancer and skin cancer.
  • Finasteride has an inhibitory effect on lung cancer, gastric cancer and rectal cancer.
  • Evista (Raloxifene Hydrochloride) has inhibitory effects on lung cancer, gastric cancer, and bladder cancer.
  • Letrozole has an inhibitory effect on lung cancer and gastric cancer.
  • Dienogest has an inhibitory effect on gastric cancer and bladder cancer.
  • AMG-073HCl (Cinacalcet hydrochloride) has an inhibitory effect on lung cancer, gastric cancer and bladder cancer.
  • Budesonide has an inhibitory effect on rectal cancer.
  • Gestodene has an inhibitory effect on lung cancer and skin cancer.
  • Drospirenone has an inhibitory effect on lung cancer.
  • Trilostane has an inhibitory effect on lung cancer, stomach cancer and skin cancer.
  • Repaglinide has inhibitory effects on lung cancer, gastric cancer, rectal cancer, colon cancer, skin cancer and prostate cancer.
  • Doxercalciferol Hectorol has inhibitory effects on lung cancer, gastric cancer, colon cancer, prostate cancer, bladder cancer, breast cancer, and blood cancer.
  • Alfacalcidol has an inhibitory effect on lung cancer, gastric cancer and breast cancer.
  • Calcifediol has an inhibitory effect on lung cancer.
  • Alprostadil (Caverject) has inhibitory effects on gastric cancer, rectal cancer, prostate cancer, and bladder cancer.
  • Methimazole (Tapazole, Northyx) has inhibitory effects on gastric cancer, bladder cancer, and breast cancer.
  • Ethinyl Estradiol has an inhibitory effect on lung cancer, gastric cancer, skin cancer, bladder cancer, and breast cancer.
  • Estrone has an inhibitory effect on gastric cancer.
  • Progesterone (Prometrium) has an inhibitory effect on lung cancer, stomach cancer, and skin cancer.
  • Estradiol has an inhibitory effect on lung cancer, gastric cancer and skin cancer.
  • Deferasirox (Exjade) has an inhibitory effect on lung cancer and gastric cancer.
  • Glipizide (Glucotrol) has an inhibitory effect on lung cancer and gastric cancer.
  • Glyburide (Diabeta) has an inhibitory effect on lung cancer and gastric cancer.
  • Levonorgestrel (Levonelle) has an inhibitory effect on skin cancer and breast cancer.
  • Beta Carotene has an inhibitory effect on lung cancer, skin cancer, and breast cancer.
  • Toremifene Citrate (Fareston, Acapodene) has inhibitory effects on lung cancer, gastric cancer, rectal cancer, skin cancer, and breast cancer.
  • Verteporfin has an inhibitory effect on lung cancer, skin cancer, and blood cancer.
  • Etidronate (Didronel) has an inhibitory effect on gastric cancer.
  • Deflazacort (Calcort) has an inhibitory effect on lung cancer, prostate cancer, and breast cancer.
  • Potassium iodide has an inhibitory effect on prostate cancer and breast cancer.
  • Menadione has inhibitory effects on lung cancer, stomach cancer, colon cancer, skin cancer, prostate cancer, bladder cancer, and breast cancer.
  • Metformin hydrochloride (Glucophage) has inhibitory effects on lung cancer, gastric cancer, colon cancer, skin cancer, prostate cancer, bladder cancer, and breast cancer.
  • Tamoxifen Citrate (Nolvadex) has inhibitory effects on gastric cancer, colon cancer, and blood cancer.
  • ATP Addenosine-Triphosphate
  • Propylthiouracil has an inhibitory effect on lung cancer and skin cancer.
  • Mestranol has an inhibitory effect on gastric cancer, skin cancer and bladder cancer.
  • Naftopidil (Flivas) has an inhibitory effect on gastric cancer.
  • Oxacillin sodium monohydrate has an inhibitory effect on lung cancer and bladder cancer.
  • Neomycin sulfate has an inhibitory effect on lung cancer and colon cancer.
  • Phenylephrine HCl has an inhibitory effect on lung cancer and bladder cancer.
  • Tetracaine hydrochloride (Pontocaine) has inhibitory effects on lung cancer, colon cancer, prostate cancer, and bladder cancer.
  • Fluocinonide (Vanos) has an inhibitory effect on skin cancer.
  • Arecoline has an inhibitory effect on lung cancer and skin cancer.
  • 2-Thiouracil has an inhibitory effect on lung cancer, gastric cancer, colon cancer, skin cancer, prostate cancer, and bladder cancer.
  • Pyridoxine hydrochloride has inhibitory effects on lung cancer, gastric cancer, colon cancer, skin cancer, bladder cancer, and breast cancer.
  • Estradiol valerate has an inhibitory effect on rectal cancer, skin cancer and blood cancer.
  • Ethynodiol diacetate has an inhibitory effect on rectal cancer and skin cancer.
  • Anagrelide HCl has an inhibitory effect on lung cancer, rectal cancer and skin cancer.
  • Thiamine HCl (Vitamin B1) has an inhibitory effect on skin cancer and prostate cancer.
  • Vitamin D2 has inhibitory effects on lung cancer, gastric cancer, rectal cancer, skin cancer, prostate cancer, and bladder cancer.
  • Dibucaine HCL has inhibitory effects on lung cancer, gastric cancer, rectal cancer, skin cancer, prostate cancer, and bladder cancer.
  • Nafcillin sodium monohydrate has inhibitory effects on lung cancer, gastric cancer, rectal cancer, colon cancer, skin cancer, prostate cancer and bladder cancer.
  • Dequalinium chloride has inhibitory effects on lung cancer, colon cancer, skin cancer and blood cancer.
  • Oxymetholone has an inhibitory effect on skin cancer.
  • Flumethasone has an inhibitory effect on skin cancer.
  • Difluprednate has an inhibitory effect on prostate cancer.
  • Tiratricol has an inhibitory effect on blood cancer.
  • Liothyronine Sodium has an inhibitory effect on lung cancer and colon cancer.
  • Deoxycorticosterone acetate has an inhibitory effect on lung cancer, skin cancer and breast cancer.
  • Sodium ascorbate has inhibitory effects on lung cancer, colon cancer, prostate cancer and breast cancer.
  • Benfotiamine has an inhibitory effect on lung cancer, prostate cancer, and breast cancer.
  • Medrysone has an inhibitory effect on lung cancer and skin cancer.
  • Carbenoxolone Sodium has an inhibitory effect on skin cancer.
  • Misoprostol has inhibitory effects on lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer and breast cancer.

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Abstract

多种内分泌疾病用药的临床新应用。该多种内分泌疾病用药都是经过卫生署通过核准上市的内分泌疾病用药。多种内分泌疾病用药有效的抑制不同类型的癌细胞。

Description

内分泌疾病用药在制备抑制癌症的医药组合物中的应用 技术领域
本发明涉及多种内分泌疾病用药的新适应症的应用，尤其该多种药物为通过临床实验且具有抑制多种癌症的用途。
背景技术
癌症长期高居全球死因之首，且罹患癌症人数更是逐年攀升，因此治疗癌症俨然成为重要的课题。癌症的治疗可区分为手术治疗、放射线治疗、化学治疗及标靶治疗。
一般来说，癌症药物治疗无论是化学治疗或标靶治疗，目的多是让癌细胞无法复制、分裂，来阻断肿瘤的蔓延扩张。在临床治疗选择上，通常会结合一到数种化疗药物以及标靶治疗，希望能藉由不同机制来杀死癌细胞以提高治疗效果，但事实上，还是常遇到患者对于治疗药物的反应不佳。进一步，许多癌细胞相继产生抗药性，使药物的使用成效大幅降低，最终导致癌症治疗失败。
内分泌疾病产生的原因有三方面：内分泌腺破坏、内分泌腺激素合成缺陷等功能减低原因；内分泌腺肿瘤如垂体各种肿瘤等各种功能亢进的原因；激素的敏感性缺陷，有受体和(或)受体后缺陷，使激素不能发挥正常作用。
内分泌激素(Endocrine)，俗称荷尔蒙(Hormones)，是体内某一器官系统所分泌的一种活性物质，或由某一腺体的自然产物经由其内部的分泌作用，释放进入血液循环，而作用于远方的作用器官(Target Organ)上。它有调节人 体机能的作用，与神经系统共同负责整个人体繁杂的生理化学反应，使生物体产生协同作用，以应付外界环境的改变。内分泌激素与维生素(Vitamine)不同，前者是由体内某者器官或腺体所分泌，但维生素则必须由外界食物中摄取。内分泌激素的分泌必须适当，它在体内的浓度过多或过少均会使生理功能失去平衡；严重者，则会引起病变。体内内分泌激素的分泌过多或不足，无人可利用类似内分泌激素的合成物质来抑制或补充。此些物质，即临床所用的内分泌药物，如Cortisone，Insulin，Thyroxine，Testesterone，Pro-gesterones等。
发明人依据长年的研究经验，人类的癌症细胞常常有与正常细胞具有不同的表现性状，型态上的差异或是作用机转的变化或许也有可能被视为一种外来的侵入者，而每一种癌症细胞所在的位置不同，变异的状态又与所处的环境有关，因此，第一个提出使用内分泌疾病用药抑制癌症细胞的发明概念并且进行实验。
相对的，在这些已经使用数十年内分泌疾病用药，是早已被FDA所认可的用药，具有大量药物机转及人体研究成果数据，因此，若应用在癌症方面，这项新发展会更省时、减少成本，也能和其他治疗方式结合来提高效果。目前尚未有任何研究针对本发明所使用的药物，进行癌症治疗研究。
尽管如此，药物开发依然是重要的医学议题，必须经过繁复的临床前试验才能进入临床试验，根据统计，平均每一万个新药约只有五个能够进入第一期临床试验。此外，除了药物本身是否能大量制造的难题外，还需克服药物安全性、病人筛选、试用剂量等问题，即便药物已经通过FDA的核准并上市，亦有可能因上市后于人体发现不良反应而强制下架回收，由此可见药物开发具有一定的困难程度。
发明内容
为解决上述的问题，本发明针对通过临床实验的多种内分泌药物进行新适应症的研发，而达到老药新用的目标。
经过实验设计结果显示内分泌疾病用药对正常细胞没有或仅有微小的毒性，但至于内分泌疾病用药在正常细胞与肿瘤细胞之间是否具有选择性的影响，还待更多的研究厘清，而且并非所有的内分泌疾病用药在相同的条件下均能有效的抑制肿瘤细胞，需要有许多的问题进行克服。
名词定义
内分泌疾病用药依据药物的结构可以分为六大类，包含肾上腺皮质激素类药、雄激素及同化激素类药、雌激素及孕激素类药、胰腺素及其他影响血糖药、甲状腺激素及抗甲状腺药、甲状旁腺及钙代谢调节药。
第一大类:肾上腺皮质激素类药糖皮质激素(Glucocorticoid)，又名「肾上腺皮质激素」，是由肾上腺皮质分泌的一类甾体激素，也可由化学方法人工合成。由于可用于一般的抗生素或消炎药所不及的病症，如SARS、败血症等，具有调节糖、脂肪、和蛋白质的生物合成和代谢的作用，还具有抗炎作用，称其为“糖皮质激素”是因为其调节糖类代谢的活性最早为人们所认识。糖皮质激素的基本结构特征包括肾上腺皮质激素所具有的C3的羰基、Δ4和17β酮醇侧链以及糖皮质激素独有的17α-OH和11β-OH。目前糖皮质激素这个概念不仅包括具有上述特征和活性的内源性物质，还包括很多经过结构优化的具有类似结构和活性的人工合成药物，目前糖皮质激素类药物是临床应用较多的一类药物。【生理作用】促进糖异生，减少外周组织对葡萄糖的摄取和利用，升高血糖，也会使肝糖元肌糖元的合成增加。促进肝外组织的蛋白质代谢，减少蛋白质合成，增加血清中的氨基酸含量和尿素氮的排出。促进脂肪分解代谢，减少合成 代谢，使血液中甘油和脂肪酸含量增加，还会因此而增高血液中胆固醇的含量从而启动四肢皮下的脂肪酶活性，分解四肢皮下脂肪，使之重新分布到脸胸腹背及臀部，造成向心性肥胖。有弱的盐皮质激素样作用，可显示排钾保钠作用。【药理作用】包含:抗炎作用：增加血管收缩力，降低血管通透性，拮抗组胺等炎性介质对血管的扩张作用，减轻局部充血，减少白细胞和体液的渗出；稳定溶酶体膜，减少因为溶酶体破裂而造成的组织蛋白酶和水解酶释放，减少组织分解和炎性介质释放；抑制中性白细胞、单核细胞和巨噬细胞向炎性部位募集；抑制磷脂酶A2的活性，减少膜磷脂向花生四烯酸的转化，而花生四烯酸正是很多炎性介质如前列腺素、白三烯，血小板活化因子的生物合成前体。抑制白介素，肿瘤坏死因数，干扰素等与免疫反应相关的细胞因子的合成与释放；抑制成纤维细胞DNA合成和毛细血管增生，阻碍胶原沉积，抑制肉芽组织形成；免疫抑制作用：除抗炎作用中提到的与免疫系统有关的作用之外，糖皮质激素还可以抑制B细胞向浆细胞的转化，减少抗体的生成；抑制体液免疫，减少抗原抗体反应之后引起的攻击性物质的释放；抗毒素作用：糖皮质激素虽然对细菌外毒素没有任何作用，但有强大的抗细菌内毒素作用，减少内源性热源物质的释放，有良好的退热作用和对中毒症状的极大改善作用；抗休克作用：这是抗炎免疫抑制和抗内毒素作用综合的结果，糖皮质激素能够抑制肾上腺素，去甲肾上腺素，加压素，血管紧张素，5-HT，等递质的缩血管作用，改善微循环，其稳定溶酶体的作用可以有效减少心肌抑制因子的释放，从而维持正常的心输出量和维持内脏的血液循环不受血管收缩的影响；影响造血系统：增加红细胞和血红蛋白的生成，使血小板和纤维蛋白原增加，使中性白细胞进入血液循环的量增加，单核细胞淋巴细胞嗜酸性和嗜碱性白细胞减少；中枢兴奋作用：减少脑内抑制性递质GABA的含量，造成中枢兴奋，产生欣快感、激动、失眠等征 状；促进胃酸分泌；抑制松果体褪黑素的分泌；减少甲状腺对碘离子的摄取清除和转化。本发明中的内分泌疾病用药包含在本类别的有Budesonide、Trilostane、Aminoglutethimide(Cytadren)、Medrysone、Melatonin、Deoxycorticosterone acetate、Verteporfin(Visudyne)、Naftopidil(Flivas)。
第二大类:天然雄激素(androgens)主要是睾丸间质细胞分泌的睾酮(睾丸素，testosteron0一些新衍生物，临床常用的为甲睾酮(android；甲基睾丸素，methyltestosterone)、丙酸睾酮(andronate；丙酸睾丸素，testosterone propionate)和苯乙酸睾酮(苯乙酸睾丸素，testosterone phenylacetate)。雄激素类的化学结构睾酮口服易吸收，但在肝被迅速破坏，因此口服无效。大部分与蛋白结合。代谢物与葡萄糖醛酸或硫酸结合失去活性，经尿排泄。也可作成片剂植于皮下，吸收缓慢，作用可长达6周。睾酮的酯类化合物极性较低，溶于油液中肌内注射后，吸收缓慢，持续时间也较长，例如丙酸睾酮一次肌内注射可维持2～4天。甲睾酮不易被肝脏破坏，口服有效。也可舌下给药。【生理及药理作用】1.生殖系统促进男性性征和生殖器官发育，并保持其成熟状态。睾酮还可抑制垂体前叶分泌促性腺激素(负反馈)，对女性可减少雌激素分泌。尚有抗雌激素作用。2.同化作用雄激素能明显地促进蛋白质合成(同化作用)，减少胺基酸分解(异化作用)，使肌肉增长，体重增加，降低氮质血症，同时出现水、钠、钙、磷潴留现象。3.骨髓造血功能在骨髓功能低下时，大剂量雄激素可促进细胞生长。是促进肾脏分泌促红细胞生成素所致，也可能是直接刺激骨髓造血功能。【临床应用】1.睾丸功能不全无睾症或类无睾症(睾丸功能不全)时，作替代疗法。2.功能性子宫出血利用其抗雌激素作用使子宫平滑肌及其血管收缩，内膜萎缩而止血。对严重出血病例，可用已烯雌酚、黄体酮和丙酸睾 酮等三种混合物作注射，以收止血之效，停药后则出现撤退性出血。3.晚期乳腺癌对晚期乳腺癌或乳腺癌转移者，采用雄激素治疗可使部分病例的病情得到缓解。这可能与其抗雌激素作用有关，也可能通过抑制垂体促性腺激素的分泌，减少卵巢分泌雌激素。此外，雄激素尚有抗催乳素刺激乳腺癌的作用。治疗效果与癌细胞中雌激素受体含量有关，受体浓度高者，疗效较好。4.再生障碍性贫血及其他贫血用丙酸睾酮或甲睾酮可使骨髓机能改善。本发明中的内分泌疾病用药包含在本类别的有Abiraterone(CB-7598)、Bicalutamide(Casodex)、Finasteride、Dutasteride、Letrozole、Alprostadil(Caverject)。
第三大类:雌激素及孕激素类药雌激素是一类女性荷尔蒙，包括雌酮、雌二醇等。雌二醇是最重要的雌激素。雌激素主要由卵巢分泌，少量由肝，肾上腺皮质，乳房分泌。怀孕时，胎盘也可大量分泌。男性的睾丸也会分泌少量。卵巢分泌的主要是β-雌二醇，其他雌激素的重要性较小。【类型】1.类固醇:存在女性的天然雌激素有雌酮(estrone,E1)、雌二醇(estradiol,E2)、雌三醇(estriol,E3)，在循环系统分别占有10-20％、10-30％、60-80％。虽然雌三醇是含量最丰富的，但却是作用最弱的雌激素，雌二醇的效力约是雌三醇的80倍。对于处在月经初潮到更年期前这段期间的未怀孕女性，雌二醇是最重要的雌激素。然而，对于怀孕女性，重要角色就转换到雌三醇；而雌酮是更年期女性体内雌激素的主要形式。还有另外一个雌激素，estetrol(E4)，只有在怀孕的时候才会出现。所有不同型态的雌激素都是芳香酶(aromatase)转换雄激素而成，特别是睪酮(testosterone)和雄烯二酮(androstenedione)。普立马(Premarin)，为常用的雌激素药物，是从怀孕的母马取得。它含有类固醇型式的雌激素，equilin和equilenin。2.非类固醇:许多天然和合成的物质已经被确定拥有雌激素活性。【生物合成】雌激素主要是由卵巢、黄体及胎盘制造。 滤泡刺激激素(Follicle stimulating hormone,FSH)刺激卵巢的颗粒性细胞(Granulosa cells)合成雌激素。少量的雌激素也经由其他组织合成，如肝、肾上腺、乳房，这些少量的雌激素对于更年期女性尤其重要。另外，脂肪细胞也生产雌激素[来源请求]。合成雌激素是从卵巢内膜细胞开始，将胆固醇合成雄烯二醇。雄烯二醇有中等的雌激素活性，会穿或基底膜到达颗粒性细胞，接着会被转换成雌酮或雌二醇。雌二酮的浓度随着月经周期而有高低起伏，只有在排卵前才会有高浓度。【代谢】肝脏可以代谢雌激素，尤其是雌激素酮。肝病患者由于肝功能下降，血中雌激素浓度上升，呈现肝掌、蜘蛛痣等症状。【作用】雌激素在儿童期只有少量分泌；青春期后会大量增加，促进女性第一第二性征的发育成熟：女性生殖系统：雌激素促进输卵管、子宫、阴道与女阴增大，阴道增厚，以及最重要的子宫内膜增厚。乳房：雌激素可使脂肪堆积在乳房。但对于制造乳汁的乳房小叶和小泡无太大影响。无法将乳房完全转化为乳汁的制造器官。此外，高剂量的动情素医学上可以做为退乳针，利用负回馈机制进行抑制。骨骼：雌激素会使女性在青春期快速长高，而且早几年停止长高。脂肪：雌激素会使得皮下脂肪积量增加，并且使脂肪堆积在乳房与臀部。血管：雌激素会使小动脉扩张，过度扩张的浅表小动脉呈现肝掌和蜘蛛痣等症状。本发明中的内分泌疾病用药包含在本类别的有Anastrozole、Exemestane、Evista(Raloxifene Hydrochloride)、Dienogest、Gestodene、Drospirenone、Ethinyl Estradiol、Estrone、Progesterone(Prometrium)、Estradiol、Misoprostol、Levonorgestrel(Levonelle)、Toremifene Citrate(Fareston,Acapodene)、Tamoxifen Citrate(Nolvadex)、Mestranol、Estradiol valerate、Ethynodiol diacetate、Benfotiamine。
第四大类:胰腺素及其他影响血糖药:胰岛素是一种蛋白质激素，由胰脏 内的胰岛β细胞分泌。胰岛素参与调节碳水化合物和脂肪代谢，控制血糖平衡，可促使肝脏、骨骼肌将血液中的葡萄糖转化为糖原。缺乏胰岛素会导致血糖过高、糖尿病。因此胰岛素可用于治疗糖尿病。其分子量为5808道尔顿。胰岛素应用于临床数十年，从抗原性较强的第一代动物胰岛素到基因重组但餐前需要等待30分钟的第二代人胰岛素，再发展到现在可以很好模拟生理性人胰岛素分泌模式的胰第三代胰岛素类似物。目前更好模拟正常人体生理降糖模式的胰岛素是第三代胰岛素——胰岛素类似物。【第一代胰岛素-动物胰岛素】1921年弗雷德里克·班丁(Frederick Banting)与约翰·麦克劳德(John Macleod)合作首次成功提取到了胰岛素，不同种族哺乳动物(人、牛、羊、猪等)的胰岛素分子的氨基酸序列和结构稍有差异，其中猪胰岛素与人的最为接近。[8]。动物胰岛素是最早应用于糖尿病治疗的胰岛素注射制剂，一般是猪胰岛素，猪胰岛素与人胰岛素存在1至4个氨基酸的不同，因此容易发生免疫反应，注射部位皮下脂肪萎缩或增生，胰岛素过敏反应，并且由于其免疫原性高，容易反复发生高血糖和低血糖，容易出现胰岛素耐药。【第二代胰岛素-人胰岛素】20世纪80年代，人们通过基因工程(重组DNA)制造出高纯度的合成人胰岛素，其结构和人体自身分泌的胰岛素一样。对比动物胰岛素，人胰岛素较少发生过敏反应或者胰岛素抵抗，所以皮下脂肪萎缩的现象也随之减少；由于人胰岛素抗体少，所以注射量比动物胰岛素平均减少30％；人胰岛素的稳定性高于动物胰岛素，常温25℃左右常温可保存人胰岛素4周。在起效时间、峰值时间、作用持续时间上不能模拟生理性人胰岛素分泌模式。需在餐前30分钟注射、有较高的夜间低血糖风险。【第三代胰岛素】20世纪90年代末，在对人胰岛素结构和成分的深入研究中发现，对肽链进行修饰：利用基因工程技术，改变胰岛素肽链上某些部位的氨基酸组合；改变等电点；增加六聚体强度；以钴离子替代锌离 子；在分子中增加脂肪酸链，加大与白蛋白的结合，均有可能改变其理化和生物学特征，从而可研制出更适合人体生理需要的胰岛素类似物(insulinsimilitude)。胰岛素类似物可紧临餐使用，也称为餐时胰岛素或速效胰岛素。胰岛素类似物优势包括：更好的模拟生理性人胰岛素分泌模式，更低的夜间低血糖风险，更有效的控制体重，注射无需等待30分钟，每日一次注射长效胰岛素类似物即可。【代谢】胰岛素是由胰岛β细胞受内源性或外源性物质如葡萄糖、乳糖、核糖、精氨酸、胰高血糖素等的激动而分泌的一种蛋白质激素。先分泌的是由84个氨基酸组成的长链多肽—胰岛素原(Proinsulin)，经专一性蛋白酶——胰岛素原转化酶(PC1和PC2)和羧肽脢E的作用，将胰岛素原中间部分(C链)切下，而胰岛素原的羧基端部分(A链)和氨基端部分(B链)通过二硫键结合在一起形成胰岛素。成熟的胰岛素储存在胰岛β细胞内的分泌囊泡中，以与锌离子配位元的六聚体方式存在。在外界刺激下胰岛素随分泌囊泡释放至血液中，并发挥其生理作用。胰岛素的分泌分成两部分，一部分说明维持空腹血糖正常而分泌的胰岛素，称为基础胰岛素，别一部分则是为了降低餐后血糖升高、维持餐后血糖正常而分泌的胰岛素，称为餐时胰岛素。餐时胰岛素的早时相分泌控制了餐后血糖升高的幅度和持续时间，其主要的作用是抑制肝脏内源性葡萄糖的生成。通过该作用机制，血糖在任何时间均被控制在接近空腹状态的水平；餐后血糖的峰值在7.0mmol/L以下，并且血糖水平高于5.5mmol/L的时间不超过30分钟。1型糖尿病患者在确诊糖尿病之前，大部分患者胰岛β细胞发生自身免疫性破坏，导致餐时和基础胰岛素分泌均减少。2型糖尿病患者胰岛β细胞功能异常进展缓慢，常常表现为外周胰岛素抵抗，但是也同时存在胰岛素一相分泌减少，因而可以出现空腹血糖正常而餐后血糖升高的情况。最终，餐后血糖水平可达到非糖尿病的生理状态时的4倍，并且 在进餐后血糖升高持续数小时，以至于在下一餐前仍然显著升高。目前弥补餐时胰岛素分泌不足的胰岛素制剂有诺和灵N，胰岛素类似物制剂有诺和锐等。基础胰岛素是胰岛细胞24小时持续脉冲式分泌的胰岛素，主要用于维持空腹血糖水平的正常。美国糖尿病学会(ADA)与欧洲糖尿病学会(EASD)指南均建议，在生活方式干预和口服糖尿病治疗后，如果血糖控制仍不满意，应尽早开始胰岛素治疗，且首选基础胰岛素与口服降糖药合用。若此疗法仍不能控制血糖，根据该指南的治疗线路图，建议在此基础上在就餐时再加用速效胰岛素[18]。目前用于弥补基础胰岛素不足的制剂主要有基础胰岛素类似物地特胰岛素等。胰岛素由胰岛素降解酶(Insulin Degrading Enzyme,IDE)降解。胰淀素和β淀粉样多肽也是IDE的底物。胰岛素的纤维化：经过大量的临床医学以及科学研究，胰岛素的淀粉样纤维化与II型糖尿病密切相关。【作用】整体代谢水平上的作用:促进细胞膜上的葡萄糖载体将葡萄糖转运入细胞，从而控制葡萄糖进入肌肉和脂肪组织。通过控制氨基酸的吸收来增强DNA复制和蛋白质合成。通过变构作用调控多种酶的活性。本发明中的内分泌疾病用药包含在本类别的有Repaglinide、Glipizide(Glucotrol)、Metformin hydrochloride(Glucophage)、Glipizide(Glucotrol)、Benfotiamine、Neostigmine bromide(Prostigmin)。
第五大类:甲状腺激素(thyroid hormones)是由甲状腺滤泡上皮细胞合成的酪氨酸碘化物。主要是四碘甲腺原氨酸(又名甲状腺素，缩写为T4)和三碘甲腺原氨酸(缩写为T3)，此外，还有少量逆-三碘甲腺原氨酸(缩写为rT3)。注意，甲状腺分泌的激素除了甲状腺激素外，还有降钙素。由于降钙素是甲状腺滤泡旁细胞产生的，所以，不属于甲状腺激素的范畴。T4和T3均有生理活性，区别在于作用时间和强度：T4活性低、起效较慢，但持续时间长；T3活性高、 起效快，但持续时间短[2]。体内研究显示，在细胞水平发挥生理作用的主要是T3；绝大多数T4需转化为T3之后才能发挥生理效应，从这个意义上讲，T4更像是一种前激素。rT3没有明显的生理活性，因此，在多数语境下，“甲状腺激素”只是指T4和T3。到目前为止，甲状腺激素是唯一一类含碘的生理物质。【生理作用】广泛作用于各种细胞；可启动多种转录因子，从而启动多种基因的表达。此外，其生理作用还与机体所处的发育阶段、细胞所处的分化阶段有关。大致而言，可使全身各系统的生理功能增强。1.新陈代谢:促进神经的成熟，提高身体对儿茶酚胺类激素(如肾上腺素)的敏感性，增加产热及基础代谢率，对糖代谢的各个环节均有刺激作用，比如，促进糖吸收、糖生成和糖利用。生理情况下可促进蛋白质合成。甲状腺激素分泌不足时，绝大部分蛋白质合成下降，但粘蛋白合成增加，可造成黏液性水肿。甲状腺激素分泌过多时，会造成蛋白质分解加速。2.促进脂肪利用。所以，甲状腺功能减退症患者常常合并显著的高脂血症，并可有广泛的动脉粥样硬化形成。3.生长发育:甲状腺素在正常发育及细胞分化上扮演了重要的角色，它控制了蛋白质、脂肪以及碳水化合物的代谢，并且刺激维生素的代谢。数种生理上及病理上刺激影响了甲状腺素的合成。此外，甲状腺素还控制人类的恒温机制。在体温骤降的状况下，甲状腺素也影响了哺乳赖的冬眠以及鸟类的换羽。4.甲状腺激素维持哺乳动物的生长发育，尤其是中枢神经系统和骨骼。假如幼年期罹患甲状腺功能减退症，则可导致永久性智障和矮小，称呆小病。5.神经系统:对儿茶酚胺有允许作用，刺激食欲形成。6循环系统:对心脏具有正性变时、正性变传导、正性变力作用。7.对外周动脉有舒张作用：主要是机体产热及代谢产物增多后的间接作用。8.消化系统:促进消化液分泌，促进胃肠道蠕动。因此，甲状腺功能亢进症患者常有大便次数增多，甚至腹泻；而甲状腺功能减退症患者则经常便秘。【药理学】由 于来源于动物的甲状腺片的甲状腺激素含量不稳定，且人工合成的甲状腺激素已能量产，目前广泛使用的是T4或T3的人工合成品。由于T4的生理效应比较缓和，主要用于甲状腺激素的长期替代治疗。由于T3活性高、起效快，主要用于重症甲状腺功能减退症(黏液性水肿昏迷)的抢救。【相关疾病】甲状腺素分泌过多或过少都会导致疾病：1.甲状腺机能亢进(Hyperthyroidism)：(如凸眼性甲状腺肿，或称格雷夫斯症Graves Disease)，甲状腺素释放过多所造成，大约2％的女性及0.2％的男性罹患此病。甲状腺毒症(Thyrotoxicosis)甲状腺毒症通常会被甲状腺机能亢进这个名词替换，但是彼此之间还是有些许的差异性存在，虽然甲状腺毒症也与甲状腺素分泌过多有关，主要原因是摄取过多甲状腺素的药片或者是甲状腺分泌过量，而甲状腺机能亢进则单指甲状腺分泌过量而已。2.甲状腺机能低下(Hypothyroidism)：(如桥本氏甲状腺肿Hashimoto's thyroiditis)是甲状腺素分泌不足所致。本发明中的内分泌疾病用药包含在本类别的有AMG-073HCl(Cinacalcet hydrochloride)、Methimazole(Tapazole,Northyx)、Potassium iodide、Propylthiouracil、Tiratricol、2-Thiouracil、Carbenoxolone Sodium。Sodium ascorbate。
第六大类:副甲状腺(parathyroid gland)是脊椎动物的一种内分泌腺，主要调节体内的钙和磷代谢。除了在人类和一些真兽类，它与甲状腺有一定解剖学位置关系外，在其他动物，两者并无密切关系。它与胸腺的关系更为密切，两者都起源于咽囊。副甲状腺一种内分泌腺，通常有4个，分为上下两对，呈扁卵圆形小体，大小如豌豆，贴在甲状腺的后面。分泌的副甲状激素能调节体内钙、磷代谢。分泌副甲状激素过少会造成血钙降低、血磷升高，产生手足抽搐；分泌副甲状激素过多则会造成血钙升高、骨矿盐减少、发生骨骼病变和泌尿系统结石。副甲状腺素(Parathyroid hormone，简称为PTH)，是一种由颈部 的副甲状腺分泌，具有84个胺基酸的多肽类激素。主要作用在骨骼、肾脏，增加血液中的钙离子浓度。【生物化学特性】1925年首先从副甲状腺分离出高活性的提取物，被确认为副甲状腺素具有调节血钙的作用。副甲状腺素由副甲状腺的主细胞合成和分泌。血循环中的副甲状腺素至少有三种形式﹕完整的副甲状腺素。副甲状腺素片段：具有生物活性，循环半衰期2～4分钟，大部分在肝脏清除，少部分经肾脏滤过清除。羧基端副甲状腺素片段：无生物活性，正常人血中此片段浓度最高，循环半衰期30～40分钟，主要由肾脏清除，因此慢性肾功能衰竭时此片段浓度明显升高。氨基端副甲状腺素片段，有生物活性，血中浓度较低，半衰期亦短。完整的副甲状腺素可在副甲状腺主细胞内裂解成片段后分泌入血，也可先分泌至周围血后再裂解为诸片段。副甲状腺素多链在第34～37个氨基酸的位置断裂后，氨基端依然具有完整的副甲状腺素的全部生物活性。【影响副甲状腺素分泌的因素】血清钙离子浓度是副甲状腺素合成和分泌的主要调节因素。动物实验证明，血钙浓度与副甲状腺素分泌率的关系成一曲线。血钙浓度对副甲状腺细胞分泌副甲状腺素的调节作用是以腺细胞膜上腺酸环化和细胞内环磷酸腺苷的中介环节而实现的，血磷浓度增高促进副甲状腺素的分泌，因为高血磷可导致低血钙而间接促进副甲状腺素的分泌。血镁浓度降低抑制副甲状腺素分泌。药理剂量的降钙素可促进副甲状腺素的分泌。儿茶酚胺、多巴胺和肾上腺素等都可促进副甲状腺素的分泌。老年人血中副甲状腺素浓度较中青年者为高。人体血液中的副甲状腺素浓度随季节而变化，冬季高于夏季，这与血清中25-羟维生素D浓度的季节变化有关。冬天日照少﹐血25-羟维生素D的浓度较低、肠钙吸收减少、血钙水平下降、血副甲状腺素呈生理性代偿增多。【骨的作用】骨是机体最大的钙贮存库，体内99％以上的钙存于骨和牙齿中，副甲状腺素具有加强破骨细胞活性，形成新的破骨细胞和暂时性抑制成骨细胞的 功能，从而促进骨的吸收和溶解，使骨钙释放入血，提高血钙水平。【肾脏的作用】副甲状腺素抑制近端肾小管对磷酸盐的重吸收，增加尿中磷酸盐的排出，故副甲状腺素过多时有低血磷症和高尿磷症。与此相反，副甲状腺素增加远程肾小管对钙的回吸收。此外，副甲状腺素还抑制肾小管对钠和碳酸氢盐吸收，使从尿中排出碳酸氢盐增多，因而副甲状腺素过多时，尿常呈碱性。副甲状腺素影响肾小管回吸收的效应十分快速，几分钟即可出现，且可长期持续作用。副甲状腺素的另一个重要作用是促进25-羟维生素D在肾脏经1-羟化作用易转化为1,25-二羟维生素D，这是至今所知活性最强的维生素D代谢产物，它能增加肠道对钙和磷的吸收，因此副甲状腺素有间接促进肠钙的吸收功能。正常情况下，机体调节和保持钙磷代谢平衡主要依赖于副甲状腺素、1,25-二羟维生素D和降钙素三种激素，通过三者相互协同和拮抗的作用使血钙浓度维持在正常范围。这三种激素的合成和分泌皆与血清中钙离子浓度密切相关。当血清中钙离子浓度降低时，首先副甲状腺分泌副甲状腺素迅速增多，促进骨质吸收，骨钙动员释放入血:肾小管对钙的回吸收增加：25-羟维生素D转化为1﹐25-二羟维生素D增多，后一种作用的充分发挥约需20～24小时，从而使肠钙吸收增加。这样通过上述3个途径，使血钙浓度又复增高。当血清中钙离子浓度增高时、一方面副甲状腺的功能被抑制﹐副甲状腺素的合成和分泌均迅速减少，从而降低骨的吸收和骨钙的动员﹐减少肾小管对钙的回吸收和1,25-二羟维生素D的生成﹐肠对钙的吸收亦相应地降低；另一方面由于高血钙而刺激降钙素的分泌，它抑制骨的吸收和骨钙动员﹐抑制肾小管对钙和磷的回吸收。这样通过机体自身调节﹐副甲状腺素分泌减少和降钙素分泌增多而导致血钙浓度降至正常范围。本发明中的内分泌疾病用药包含在本类别的有Calcitriol(Rocaltrol)、Doxercalciferol(Hectorol)、Alfacalcidol、Calcifediol、Etidronate (Didronel)Deflazacort(Calcort)、Vitamin D2。
本发明提供一种内分泌疾病用药物在制备抑制癌症的医药组合物中的应用，其中，所述医药组合物是选自由内分泌疾病用药所组的药物。
本发明一实施例中，其中所述肾上腺皮质激素类药是选自由Budesonide、Trilostane、Aminoglutethimide(Cytadren)、Medrysone、Melatonin、Deoxycorticosterone acetate、Verteporfin(Visudyne)、Naftopidil(Flivas)中的一种或多种所组成的药物。
本发明一实施例中，其中所述雄激素及同化激素类药是选自由Abiraterone(CB-7598)、Bicalutamide(Casodex)、Finasteride、Dutasteride、Letrozole、Alprostadil(Caverject)中的一种或多种所组成的药物。
本发明一实施例中，其中所述雌激素及孕激素类药是选自由Anastrozole、Exemestane、Evista(Raloxifene Hydrochloride)、Dienogest、Gestodene、Drospirenone、Ethinyl Estradiol、Estrone、Progesterone(Prometrium)、Estradiol、Misoprostol、Levonorgestrel(Levonelle)、Toremifene Citrate(Fareston,Acapodene)、Tamoxifen Citrate(Nolvadex)、Mestranol、Estradiol valerate、Ethynodiol diacetate、Benfotiamine中的一种或多种所组成的药物。
本发明一实施例中，其中所述胰腺素及其他影响血糖药是选自由Repaglinide、Glipizide(Glucotrol)、Metformin hydrochloride(Glucophage)、Glipizide(Glucotrol)、Benfotiamine、Neostigmine bromide(Prostigmin)中的一种或多种所组成的药物。
本发明一实施例中，其中所述甲状腺激素及抗甲状腺药是选自由AMG-073HCl(Cinacalcet hydrochloride)、Methimazole(Tapazole,Northyx)、 Potassium iodide、Propylthiouracil、Tiratricol、2-Thiouracil、Carbenoxolone Sodium。Sodium ascorbate中的一种或多种所组成的药物。
本发明一实施例中，其中所述甲状旁腺及钙代谢调节药是选自由Calcitriol(Rocaltrol)、Doxercalciferol(Hectorol)、Alfacalcidol、Calcifediol、Etidronate(Didronel)Deflazacort(Calcort)、Vitamin D2中的一种或多种所组成的药物。
本发明一实施例中，其中得到癌症是选自肺癌、胃癌、肝癌、直肠癌、皮肤癌、子宫颈癌、前列腺癌、膀胱癌、乳癌、血癌中的一种或多种。
本发明一实施例中，其中所述药物的有效剂量浓度为20mg/kg/天～500mg/kg/天。
现今癌症药物费用动辄上万至数百万元，若未来更进一步证实内分泌疾病用药对肿瘤的疗效，对于无法负担昂贵治疗的患者们，这些便宜而历史悠久的药物，会是带来健康的新希望。
附图说明
图1显示本发明内分泌疾病用药应用于抑制癌细胞分析结果。
具体实施方式
建立细胞株
参照表一，将不同癌症类型的细胞株进行继代培养，计算细胞数目后，将2×106细胞数置入培养皿，然后加入培养该细胞株的培养液补至体积为10ml，继续培养2-3天。之后将细胞计数，并分装至96孔盘，其中每孔的细胞数目固定为3000个细胞，且体积为100ul。
表一、细胞株及其培养所用的培养液
Figure PCTCN2015092753-appb-000001
细胞存活分析方法
将96孔盘中原有的培养液吸掉，每孔加入浓度10μM、体积100ul的市售药物，放置72小时后，每孔再加入100ul已稀释的WST-1试剂，该稀释比例为培养液与WST-1原液的体积比为9：1，最后每个孔盘的总体积为200ul，然后将96孔盘放置于37℃，30～90分钟，利用elisa reader(酶联免疫检测仪)于OD450侦测吸光值，并计算各癌症细胞株的存活率。
内分泌疾病用药应用于抑制癌细胞分析结果
内分泌疾病用药分为六大类，包含肾上腺皮质激素类药、雄激素及同化激素类药、雌激素及孕激素类药、胰腺素及其他影响血糖药、甲状腺激素及抗甲状腺药、甲状旁腺及钙代谢调节药抑制癌细胞生长的效果。
实验结果明显的显示有许多的内分泌疾病用药并无法有效的抑制癌症的细胞的生长(表二)。
表二、对抑制癌症细胞无效的内分泌疾病药物
内分泌疾病药物 抑制癌症细胞株数量
Dutasteride 0
Melatonin 0
Calcitriol(Rocaltrol) 0
Aminoglutethimide(Cytadren) 0
Neostigmine bromide(Prostigmin) 0
Phenoxybenzamine HCl 0
Phenytoin(Lepitoin) 0
Pramiracetam 0
Tioxolone 0
Dehydroepiandrosterone(DHEA) 0
Ornidazole 0
Sulfamethazine 0
Milnacipran HCl 0
valganciclovir hydrochloride 0
Guanabenz acetate 0
Dydrogesterone 0
而相对的各种的内分泌疾病用药分子对于各种癌症细胞的抑制效果也不尽相同(图一)，经过发明人实验结果，证实内分泌疾病用药药物Abiraterone(CB-7598),Anastrozole,Bicalutamide(Casodex),Exemestane,Finasteride,Dutasteride,Melatonin,Evista(Raloxifene Hydrochloride),Letrozole,Dienogest,AMG-073 HCl(Cinacalcet hydrochloride),Budesonide, Gestodene,Drospirenone,Trilostane,Repaglinide,Calcitriol(Rocaltrol),Doxercalciferol(Hectorol),Alfacalcidol,Calcifediol,Alprostadil(Caverject),Methimazole(Tapazole,orthyx),Ethinyl Estradiol Estrone,Aminoglutethimide(Cytadren),Progesterone(Prometrium),Estradiol,Deferasirox(Exjade),Glipizide(Glucotrol),Glyburide(Diabeta),Levonorgestrel(Levonelle),Beta Carotene,Toremifene Citrate(Fareston,Acapodene),Verteporfin(Visudyne),Etidronate(Didronel),Deflazacort(Calcort),Potassium iodide,Menadione,Metformin hydrochloride(Glucophage),Tamoxifen,Citrate(Nolvadex),ATP(Adenosine-Triphosphate),Propylthiouracil,Mestranol,Naftopidil(Flivas),Neostigmine bromide(Prostigmin),Phenoxybenzamine HCl,Phenytoin(Lepitoin),Oxacillin sodium monohydrate,Neomycin sulfate,Phenylephrine HCl,Tetracaine hydrochloride(Pontocaine),Pramiracetam,Tioxolone,Dehydroepiandrosterone(DHEA),Fluocinonide(Vanos),Arecoline,2-Thiouracil,Pyridoxine hydrochloride,Ornidazole,Sulfamethazine,Milnacipran HCl Estradiol valerate,Ethynodiol diacetate,Anagrelide HCl,Thiamine HCl(Vitamin B1),Vitamin D2,Dibucaine HCL,nafcillin sodium monohydrate,valganciclovir hydrochloride,Guanabenz acetate,Dequalinium chloride,Oxymetholone,Flumethasone,Difluprednate,Dydrogesterone,Tiratricol,Liothyronine Sodium,Deoxycorticosterone acetate,Sodium ascorbate,Benfotiamine,Medrysone,Carbenoxolone Sodium,Misoprostol等药物对于不同的癌症细胞有明显的抑制效果。(表三)
Figure PCTCN2015092753-appb-000002
Figure PCTCN2015092753-appb-000003
Figure PCTCN2015092753-appb-000004
Figure PCTCN2015092753-appb-000005
如表三所示，Abiraterone(CB-7598)对肺癌有抑制效果。
Anastrozole对肺癌,胃癌,肝癌有抑制效果。
Bicalutamide(Casodex)对肺癌,胃癌,肝癌有抑制效果。
Exemestane对肺癌,胃癌,肝癌,直肠癌,皮肤癌有抑制效果。
Finasteride对肺癌,胃癌,直肠癌有抑制效果。
Evista(Raloxifene Hydrochloride)对肺癌,胃癌,膀胱癌有抑制效果。
Letrozole对肺癌,胃癌有抑制效果。
Dienogest对胃癌,膀胱癌有抑制效果。
AMG-073HCl(Cinacalcet hydrochloride)对肺癌,胃癌,膀胱癌有抑制效果。
Budesonide对直肠癌有抑制效果。
Gestodene对肺癌,皮肤癌有抑制效果。
Drospirenone对肺癌有抑制效果。
Trilostane对肺癌,胃癌,皮肤癌有抑制效果。
Repaglinide对肺癌,胃癌,直肠癌,结肠癌,皮肤癌,前列腺癌有抑制效果。
Doxercalciferol(Hectorol)对肺癌,胃癌,结肠癌,前列腺癌,膀胱癌,乳癌,血癌有抑制效果。
Alfacalcidol对肺癌,胃癌,乳癌有抑制效果。
Calcifediol对肺癌有抑制效果。
Alprostadil(Caverject)对胃癌,直肠癌,前列腺癌,膀胱癌有抑制效果。
Methimazole(Tapazole,Northyx)对胃癌,膀胱癌,乳癌有抑制效果。
Ethinyl Estradiol对肺癌,胃癌,皮肤癌,膀胱癌,乳癌有抑制效果。
Estrone对胃癌有抑制效果。
Progesterone(Prometrium)对肺癌,胃癌,皮肤癌有抑制效果。
Estradiol对肺癌,胃癌,皮肤癌有抑制效果。
Deferasirox(Exjade)对肺癌,胃癌有抑制效果。
Glipizide(Glucotrol)对肺癌,胃癌有抑制效果。
Glyburide(Diabeta)对肺癌,胃癌有抑制效果。
Levonorgestrel(Levonelle)对皮肤癌,乳癌有抑制效果。
Beta Carotene对肺癌,皮肤癌,乳癌有抑制效果。
Toremifene Citrate(Fareston,Acapodene)对肺癌,胃癌,直肠癌,皮肤癌,乳癌有抑制效果。
Verteporfin(Visudyne)对肺癌,皮肤癌,血癌有抑制效果。
Etidronate(Didronel)对胃癌有抑制效果。
Deflazacort(Calcort)对肺癌,前列腺癌,乳癌有抑制效果。
Potassium iodide对前列腺癌,乳癌有抑制效果。
Menadione对肺癌,胃癌,结肠癌,皮肤癌,前列腺癌,膀胱癌,乳癌有抑制效果。
Metformin hydrochloride(Glucophage)对肺癌,胃癌,结肠癌,皮肤癌,前列腺癌,膀胱癌,乳癌有抑制效果。
Tamoxifen Citrate(Nolvadex)对胃癌,结肠癌,血癌有抑制效果。
ATP(Adenosine-Triphosphate)对肺癌有抑制效果。
Propylthiouracil对肺癌,皮肤癌有抑制效果。
Mestranol对胃癌,皮肤癌,膀胱癌有抑制效果。
Naftopidil(Flivas)对胃癌有抑制效果。
Oxacillin sodium monohydrate对肺癌,膀胱癌有抑制效果。
Neomycin sulfate对肺癌,结肠癌有抑制效果。
Phenylephrine HCl对肺癌,膀胱癌有抑制效果。
Tetracaine hydrochloride(Pontocaine)对肺癌,结肠癌,前列腺癌,膀胱癌有抑制效果。
Fluocinonide(Vanos)对皮肤癌有抑制效果。
Arecoline对肺癌,皮肤癌有抑制效果。
2-Thiouracil对肺癌,胃癌,结肠癌,皮肤癌,前列腺癌,膀胱癌有抑制效果。
Pyridoxine hydrochloride对肺癌,胃癌,结肠癌,皮肤癌,膀胱癌,乳癌有抑制效果。
Estradiol valerate对直肠癌,皮肤癌,血癌有抑制效果。
Ethynodiol diacetate对直肠癌,皮肤癌有抑制效果。
Anagrelide HCl对肺癌,直肠癌,皮肤癌有抑制效果。
Thiamine HCl(Vitamin B1)对皮肤癌,前列腺癌有抑制效果。
Vitamin D2对肺癌,胃癌,直肠癌,皮肤癌,前列腺癌,膀胱癌有抑制效果。
Dibucaine HCL对肺癌,胃癌,直肠癌,皮肤癌,前列腺癌,膀胱癌有抑制效果。
nafcillin sodium monohydrate对肺癌,胃癌,直肠癌,结肠癌,皮肤癌,前列腺癌,膀胱癌有抑制效果。
Dequalinium chloride对肺癌,结肠癌,皮肤癌,血癌有抑制效果。
Oxymetholone对皮肤癌有抑制效果。
Flumethasone对皮肤癌有抑制效果。
Difluprednate对前列腺癌有抑制效果。
Tiratricol对血癌有抑制效果。
Liothyronine Sodium对肺癌,结肠癌有抑制效果。
Deoxycorticosterone acetate对肺癌,皮肤癌,乳癌有抑制效果。
Sodium ascorbate对肺癌,结肠癌,前列腺癌,乳癌有抑制效果。
Benfotiamine对肺癌,前列腺癌,乳癌有抑制效果。
Medrysone对肺癌,皮肤癌有抑制效果。
Carbenoxolone Sodium对皮肤癌有抑制效果。
Misoprostol对肺癌,肝癌,结肠癌,皮肤癌,膀胱癌,乳癌,有抑制效果。
重复性实验
依据表三所示结果，针对对癌症细胞株有效的药物进行重复性实验，其结果如表四所示。
Figure PCTCN2015092753-appb-000006
Figure PCTCN2015092753-appb-000007

Claims (9)

  1. 一种内分泌疾病用药物在制备抑制癌症的医药组合物中的应用，其特征是，所述医药组合物是选自内分泌疾病用药物所组成的药物。
  2. 如权利要求1所述的应用，其特征是，所述内分泌疾病用药为肾上腺皮质激素类药、雄激素及同化激素类药、雌激素及孕激素类药、胰腺素及其他影响血糖药、甲状腺激素及抗甲状腺药、甲状旁腺及钙代谢调节药中的一种或多种。
  3. 如权利要求2所述的应用，其特征是，所述肾上腺皮质激素类药是选自由Budesonide、Trilostane、Aminoglutethimide(Cytadren)、Medrysone、Melatonin、Deoxycorticosterone acetate、Verteporfin(Visudyne)、Naftopidil(Flivas)中的一种或多种所组成的药物。
  4. 如权利要求2所述的应用，其特征是，所述雄激素及同化激素类药是选自由Abiraterone(CB-7598)、Bicalutamide(Casodex)、Finasteride、Dutasteride、Letrozole、Alprostadil(Caverject)中的一种或多种所组成的药物。
  5. 如权利要求2所述的应用，其特征是，所述雌激素及孕激素类药是选自由Anastrozole、Exemestane、Evista(Raloxifene Hydrochloride)、Dienogest、Gestodene、Drospirenone、Ethinyl Estradiol、Estrone、Progesterone(Prometrium)、Estradiol、Misoprostol、Levonorgestrel(Levonelle)、Toremifene Citrate(Fareston,Acapodene)、Tamoxifen Citrate(Nolvadex)、Mestranol、Estradiol valerate、Ethynodiol diacetate、Benfotiamine中的一种或多种所组成的药物。
  6. 如权利要求2所述的应用，其特征是，所述胰腺素及其他影响血糖药是选自由Repaglinide、Glipizide(Glucotrol)、Metformin hydrochloride (Glucophage)、Glipizide(Glucotrol)、Benfotiamine、Neostigmine bromide(Prostigmin)中的一种或多种所组成的药物。
  7. 如权利要求2所述的应用，其特征是，所述甲状腺激素及抗甲状腺药是选自由AMG-073HCl(Cinacalcet hydrochloride)、Methimazole(Tapazole,Northyx)、Potassium iodide、Propylthiouracil、Tiratricol、2-Thiouracil、Carbenoxolone Sodium。Sodium ascorbate中的一种或多种所组成的药物
  8. 如权利要求2所述的应用，其特征是，所述甲状旁腺及钙代谢调节药是选自由Calcitriol(Rocaltrol)、Doxercalciferol(Hectorol)、Alfacalcidol、Calcifediol、Etidronate(Didronel)Deflazacort(Calcort)、Vitamin D2中的一种或多种所组成的药物
  9. 如权利要求1所述的应用，其特征是，所述癌症是选自肺癌、胃癌、肝癌、直肠癌、皮肤癌、子宫颈癌、前列腺癌、膀胱癌、乳癌、血癌中的一种或多种。
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PCT/CN2015/092761 WO2016062279A1 (zh) 2014-10-24 2015-10-23 苹果酸丙氯陪拉辛锭用于制备治疗癌症药物的用途
PCT/CN2015/092702 WO2016062274A1 (zh) 2014-10-24 2015-10-23 消化系统疾病用药物在制备抑制癌症的医药组合物中的应用
PCT/CN2015/092677 WO2016062270A1 (zh) 2014-10-24 2015-10-23 呼吸系统疾病用药用于制备抗癌医药组合物的用途
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PCT/CN2015/092771 WO2016062283A1 (zh) 2014-10-24 2015-10-23 抗发炎用药物在制备抑制癌症的医药组合物中的应用
PCT/CN2015/092782 WO2016062291A1 (zh) 2014-10-24 2015-10-23 千忧解药物在用于制备治疗癌症的医药组合物中的用途
PCT/CN2015/092781 WO2016062290A1 (zh) 2014-10-24 2015-10-23 氨苯蝶啶药物在用于制备治疗癌症的医药组合物中的用途
PCT/CN2015/092777 WO2016062287A1 (zh) 2014-10-24 2015-10-23 山喜多药物在用于制备抑制癌症的医药组合物中的用途
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PCT/CN2015/092697 WO2016062272A1 (zh) 2014-10-24 2015-10-23 免疫疾病用药物在制备抑制癌症的医药组合物中的应用
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PCT/CN2015/092653 WO2016062267A1 (zh) 2014-10-24 2015-10-23 奈必洛尔在制备抑制癌症的医药组合物中的用途
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PCT/CN2015/092617 WO2016062265A1 (zh) 2014-10-24 2015-10-23 莫诺苯宗药物在用于制备治疗癌症的医药组合物中的用途
PCT/CN2015/092768 WO2016062281A1 (zh) 2014-10-24 2015-10-23 心血管疾病用药物在制备抑制癌症的医药组合物中的应用
PCT/CN2015/092780 WO2016062289A1 (zh) 2014-10-24 2015-10-23 帕罗西汀药物用于制备治疗癌症的医药组合物中的用途
PCT/CN2015/092686 WO2016062271A1 (zh) 2014-10-24 2015-10-23 抗生素药物用于制备治疗癌症的医药组合物的用途
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