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WO1993006853A1 - Facteur de reparation de lesions cellulaires - Google Patents

Facteur de reparation de lesions cellulaires

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Publication number
WO1993006853A1
WO1993006853A1 PCT/JP1992/001286 JP9201286W WO9306853A1 WO 1993006853 A1 WO1993006853 A1 WO 1993006853A1 JP 9201286 W JP9201286 W JP 9201286W WO 9306853 A1 WO9306853 A1 WO 9306853A1
Authority
WO
WIPO (PCT)
Prior art keywords
hgf
indulin
activity
tissue
tissue injury
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1992/001286
Other languages
English (en)
Japanese (ja)
Inventor
Toshikazu Nakamura
Kunio Matsumoto
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Individual
Original Assignee
Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of WO1993006853A1 publication Critical patent/WO1993006853A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a tissue injury healing factor, and more specifically, to promote the production of HGF by Hepatocyto Growth Fact or (HGF) -producing cells derived from arbor or animal tissue or blood components. Regarding substances. Background art
  • HGF is a protein found by the present inventors as a factor that allows mature liver parenchymal cells to proliferate in vitro from regenerated liver rat serum (Biochem Biophys Res Commun, 122, 1450, 1984).
  • the present inventors have further succeeded in isolating HGF from rat platelets (Proc. Natl. Acad. Sci, 83, 6489, 1986, FFBS Letter, 22, 311, 1987), and Partially decided.
  • the present inventors cloned human and rat-derived HGF cDNA based on the elucidated HGF amino acid sequence, and recombined the cDNA into animal tissues to obtain hepatocyte growth factor as a protein.
  • Human HGF Nature, 342, 440, 1989
  • Rat HGF Proc. Natl. Acad. Sci, 87, 3200, 1990).
  • HGF The molecular weight of HGF is 82-85 kD by SDS-polyacrylamide gel electrophoresis.
  • Rat HGF molecules have a heterodimer structure in which an ⁇ chain consisting of 463 amino acid residues and a / 9 chain consisting of 233 amino acid residues are bridged by a single disulfide bond. Each chain has two glucosamine-type sugar chain binding sites.
  • Human HGF also has almost the same physiological activity, and is composed of an ⁇ chain composed of 463 amino acid residues and a ⁇ chain composed of 234 amino acid residues.
  • the ⁇ -chain has four kringle structures similar to the fibrinolytic enzyme plasmin, and the / 9-chain amino acid sequence has about 37% homology with the plasmin ⁇ chain having serine protease activity.
  • Rat HGF The homology between the amino acid sequences of human and human HGF has a very high homology of 91.6% in the ⁇ chain and 88.9% in the ⁇ chain, and their activities are completely compatible.
  • HGF which was discovered as a factor that specifically proliferates hepatocytes, has been shown to show various activities in vivo based on recent research results by the present inventors and other researchers. Expectations are rising not only for application to humans and animals but also to therapeutic drugs.
  • HGF acts not only on hepatocytes but also on epithelial cells widely as a growth factor.
  • HGF promotes the proliferation of proximal tubule cells of the kidney.
  • HGF promotes the proliferation of normal epithelial cells such as melanocytes and keratinocytes, and is used as a therapeutic agent for epidermal cells to treat wounds, skin ulcers, and hair roots. He achieved the development of application to cell growth agents and disclosed the details.
  • HGF- is suitable for practical use because it does not have the canceration activity and cancer cell proliferation activity found in many other growth factors such as EGF.
  • the present inventors have disclosed in Japanese Patent Application No. 140812/1991 that cancers such as HepG2 cell line derived from human liver cancer of HGF, and I ⁇ 9 cell line derived from lymphoblastoid cancer. It disclosed that it can be used as an anticancer agent by utilizing its cell growth inhibitory activity.
  • HGF histoneum growth factor
  • HGF promotes the proliferation of epithelial cells as well as hepatocytes, and has the activity of inhibiting the growth of cancer cells. It is expected that healing works on tissue injury.
  • HGF-producing cells are not epithelial cells themselves, but are mesenchymal in the liver, such as Kuffff cells and sinusoidal vascular endothelial cells in the liver, capillary endothelial cells in the kidney, and alveolar macrophages in the lung It has been elucidated that it is produced by cells, and it has been revealed that the so-called paracrine mechanism, in which HGF is supplied from neighboring cells as needed, has been established.
  • HGF production is also increased in non-injured organs such as the lungs, so it is considered that HGF is supplied by the so-called endocrine mechanism. This fact means that there is a substance that transmits production promotion from the injured tissue to HGF-producing cells.
  • substances that promote HGF production are secreted from injured tissues, reach HGF-producing cells via blood, etc., and release HGF stored in the cells or start new production. It is thought to have a function.
  • HGF is of course administered for the purpose of wound healing and renal regeneration, but if a substance that promotes HGF production is administered, the same effect is expected to be obtained with a smaller dose and frequency of administration. . More specifically, compared with the case of directly administering HGF as a treatment for tissue injury, administration of an HGF production-promoting substance can maintain the blood concentration of HGF for a longer period of time. It is expected that the amount and frequency of administration can be reduced.
  • living organisms are constantly affected by physical, chemical, or microbial injuries, whether external or internal, in all tissues and organs, including the respiratory system, skin, and digestive system.
  • the tissue injury healing factor is useful not only for studying the compensation function of organ injury such as liver and kidney and for studying the mechanism of HGF expression, but also for any tissue of the living body, It is a factor that cures organ damage and is obviously very useful as a therapeutic agent.
  • organ injury due to hepatectomy or hepatitis
  • administration of HGF can regenerate only hepatic parenchymal cells
  • tissue injury healing factor that controls the overall repair function of organ injury This accelerates regeneration of not only parenchymal cells but also non-parenchymal cells, such as supporting tissues such as peri-sinusoidal connective tissue, and the entire site of injury, thereby promoting true repair.
  • tissue injury healing factor can be used as a therapeutic agent, the injury can be treated much more mildly and promptly compared to the conventional use of various cell growth factors used alone.
  • its usefulness is immense.
  • the most efficient way to track and elucidate the tissue injury healing factor is to make the production promoting activity of cell growth factor Merckmar the most efficient.
  • the HGF production promoting substance is a tissue injury healing factor. It must be thought of as the main body.
  • the present inventors have found that the blood of rats artificially injured to the liver or kidney has the effect of stimulating HGF-producing cells and increasing their production ability.
  • the wound healing factor was named "Indulin” (for convenience, indulin is used as the name of the tissue wound healing factor in this specification).
  • the inventors established a purification method for indulin and elucidated its molecular weight and physicochemical properties, thereby completing the present invention.
  • the present inventors have developed a biogel P-600 and Cefadettas G-150 molecular sieve gel column using the serum of a carbon tetrachloride-administered rat as a raw material, as well as ion-exchange FPLC, reverse-phase HPLC,
  • the active substance was successfully purified using SDS-PAGE or the like (see Examples 2 and 4).
  • the molecular weight of the obtained tissue injury healing factor indulin was measured in more detail by SDS-PAGE and subjected to various physicochemical treatments to examine the stability (see Examples 3 and 4). Disclosure of the invention
  • the present invention is a.
  • HGF hepatocyte growth factor
  • tissue injury healing factor that retains its activity by the following treatments 1) to 3) and is inactivated by the treatment of 4).
  • tissue injury healing factor that exhibits a molecular weight of 10 kD to 30 kD when treated with each of gel columns of Biogel P-600 and Sephadex G'-150.
  • tissue injury healing factor that exhibits a molecular weight of 10-20 kD by SDS polyacrylamide gel electrophoresis under non-reducing conditions. 5. Indulin, a tissue injury healing factor with a molecular weight of 40 kD to 60 kD on SDS polyacrylamide gel electrophoresis under non-reducing conditions.
  • Fig. 1 shows the results of tracing the expression of HGF mRNA in the lungs of serum from rats that had liver injury due to partial hepatectomy and ischemic conditions over time and injected into the peritoneal cavity of normal rats. Show.
  • FIG. 2 shows the results of time-sequential collection of serum from liver injury and kidney injury rats and measurement of indulin activity by induction of HGF expression in MRC-15 cells.
  • FIG. 3 shows the time course of HGF mRNA expression when carbon tetrachloride-administered rat serum was added to the MRC-5 cell culture system. After agarose gel electrophoresis, detection was carried out by Northern hybridization.
  • FIG. 4 shows the results of time-course sampling of human serum subjected to liver surgery and measurement of indulin activity by induction of HGF expression in MRC-5 cells.
  • ⁇ and ⁇ ⁇ indicate two patients, and ⁇ indicates the serum (normal serum) of a healthy person.
  • FIG. 5 shows the results of measurement of indulin activity when physicochemical treatment was performed on serum from rats subjected to partial hepatectomy.
  • A shows the results of HGF mRNA measurement when acid-heat treatment was performed
  • (B) shows the results of HGF mRNA measurement after ultrafiltration.
  • FIG. 6 shows the results of separating indulin from the serum of rats fed with carbon tetrachloride by biogel P-60 column chromatography. ⁇ indicates the measured value of the insulin activity, and ⁇ indicates the absorbance at 280 nm.
  • FIG. 7 shows the results of the separation of indulin from the active fraction after separation on the Biogel P-60 column by Sephadex G-150 gel column chromatography. Hata indicates the measured value of indulin activity, and ⁇ indicates the absorbance at 28 Onm.
  • FIG. 8 shows the results of separation by SDS-PAGE using the active fraction after gel filtration. References indicate the measured values of indulin activity of the gel extract, and the numbers in the figure indicate the elution positions of the molecular weight markers.
  • Methods for obtaining the tissue injury healing factor, indulin, of the present invention include tissue and blood components of animals such as rats subjected to carbon tetrachloride-treated heminephrectomy surgery, or patients with hepatitis, nephritis or immediately after surgery. It can be purified using the tissue or blood components of a mouse as a raw material by the gel filtration method shown in Example 2 or the FPLC or SDS polyacrylamide gel electrophoresis shown in Example 4.
  • tissue injury-healing factor of the present invention indurin is useful for healing injuries to tissues and organs of humans and other mammals, and is usually prepared in the form of general pharmaceutical preparations, and Can be administered topically or orally.
  • the pharmaceutical preparation used in the above administration may contain an effective amount of the active ingredient indulin and a pharmaceutically acceptable carrier or excipient.
  • preparations for oral administration include solid or liquid dosage forms, specifically tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (soft capsules) And syrups, milks, suspensions and the like.
  • Such preparations are produced by a method known per se, and are used in the field of preparations as carriers or excipients that are practically used. It contains a fixative.
  • carriers and excipients for tablets include lactose, starch, sucrose, magnesium stearate and the like.
  • Formulations for parenteral administration include, for example, dosage forms such as injections, intramuscular injections, and infusions. Such injections are prepared by a method known per se, that is, by dissolving, suspending or emulsifying indulin in a sterile aqueous or oily liquid commonly used for injections.
  • aqueous solution for injection include physiological saline, isotonic solution containing glucose and the like and other scavengers, and suitable dissolution aids such as alcohol (eg, ethanol) and polyalcohol (eg, Propylene glycol), a nonionic surfactant (for example, polysorbate 80), a preservative, and a soothing agent may be used in combination.
  • oily liquid examples include sesame oil and soybean oil.
  • Benzyl benzoate, benzyl alcohol and the like may be used in combination as a solubilizer.
  • the prepared injection solution is usually filled in an appropriate ampoule and sterilized by a conventional method such as high-pressure steam sterilization.
  • the above-mentioned oral or parenteral pharmaceutical preparation is preferably adjusted to a dosage unit form suitable for the dose of the active ingredient.
  • dosage unit dosage forms include tablets, pills, capsules, injections, and lotions.
  • the amount of indulin which should be contained in the above-mentioned pharmaceutical preparation is not particularly limited and may be selected in a wide range, but usually 5 to 95%, particularly 10 to 70% is appropriate in the whole composition. .
  • the administration method of the above-mentioned preparation is not particularly limited, and is administered by a method according to various preparation forms, patient's age, gender and other conditions, degree of disease and the like.
  • tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered.
  • it is administered intravenously, alone or in combination with a normal liquid sampling solution such as glucose or amino acid.
  • a normal liquid sampling solution such as glucose or amino acid.
  • it is administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally.
  • the dosage of the pharmaceutical preparation is appropriately selected depending on the usage, the age of the patient, gender and other conditions, the degree of the disease, and the like.
  • the product should be administered in 2 to 4 divided doses per day Can be.
  • rats used in the following experimental examples and examples are mature male normal rats of the Wistar strain (130 to 150 g).
  • a normal rat underwent a 70% partial hepatectomy by laparotomy or partially ligated the portal vein blood vessel to make it ischemic and injured the liver. 2 ml of blood was collected over time from these liver injury rats and administered intraperitoneally to normal rats. As controls, normal rat peripheral blood and physiological saline were administered. Six hours after the administration, the rats were dissected, the lungs were excised, and subjected to HGF mRNA measurement. More specifically, RNA was extracted from the excised lung by the acid-guanidine-phenol-chloroform method (AGPC method), and poly (A) RNA was purified using Oligotex dT-30.
  • AGPC method acid-guanidine-phenol-chloroform method
  • Figure 1 shows the results. As shown in FIG. 1, it was observed that the expression of HGF mRNA in the lung was promoted in both cases of partial hepatectomy and hepatic ischemia. '
  • Human fetal lung-derived fibroblast cell line MRC-5 cells are 10% fetal serum (
  • the cells were cultured in Dulbecco's Eagle's medium (DMEM) supplemented with FCS), penicillin 100 IU / IR1, and streptomycin 100 IU / ml.
  • DMEM Dulbecco's Eagle's medium
  • Indulin activity was measured by quantifying HGF produced by MRC-5 cells.
  • MRC-5 cells were cultured in a 24-well microplate (manufactured by Koingen Co., Ltd.), and when the cell density reached 80-90% saturation, the medium was replaced with DMEM without FCS. Sample serum was added to each well and the culture was continued for an additional 24 hours.
  • the unit of indulin activity was ImU (1/1000 unit activity), which was the activity that gave the maximum HGF concentration of 50 expressed when an acidic extract of porcine lung was added.
  • HGF in the culture supernatant of MRC-5 cells was quantified by enzyme immunoassay (ELISA).
  • ELISA enzyme immunoassay
  • An anti-human HGF polyclonal antibody was obtained by immunizing rabbits with recombinant human HGF and purifying IgG from the resulting serum using Protein A Sepharose gel (Pharmacia). The obtained antibody did not cross-react with rat HGF.
  • the anti-human HGF antibody was dissolved at a concentration of 20 iig / ml in a 50-carbonate buffer solution, dispensed into a 96-well microplate (manufactured by Costar), and incubated at 37 ° C and 15 ° C in a constant-humidity chamber with saturated humidity.
  • the plate was allowed to stand for a period of time to prepare a plate solid phase. After blocking with bovine serum albumin (BSA) prepared at a concentration of 3% in phosphate buffered saline (PBS), the culture supernatant was added to the wells and incubated at 37 ° C for 2 hours. Each well was washed three times with PBS containing 0.025% Tween20 (PBSTeen20), and a biotin-conjugated anti-human HGF antibody dissolved in PBS-Tween20 was added and incubated at 37 ° C for 2 hours.
  • BSA bovine serum albumin
  • PBS phosphate buffered saline
  • Figure 2 shows the results.
  • the results are shown for rats treated with kanamycin (mouth).
  • indulin activity was very high 3 hours after each treatment and peaked after 6-12 hours.
  • MRC-5 cells in DMEM containing 10% FCS to 80-90% saturation cell density, normal rat serum in DMEM without FCS and rat serum 12 hours after carbon tetrachloride administration The medium was replaced with a medium containing. After 3 to 48 hours, the medium was sampled, RNA was extracted by the AGPC method, and Northern hybridization was performed according to the method of Experimental Example 1 to track the expression level of HGF mRNA over time. As a control, an example in which the medium was replaced with a serum-free medium is shown.
  • Figure 3 shows the results. As shown in FIG. 3, it was confirmed that the expression level of HGF mRNA in the MRC-5 cells was extremely increased after 3 hours, and was once increased and then increased again 24 hours later.
  • Fig. 4 shows the results. As shown in Fig. 4, indulin activity increased 2-2.5 times immediately after the operation, then gradually decreased, and returned to a normal value in about 2 weeks.
  • Experimental example 5 shows the results. As shown in Fig. 4, indulin activity increased 2-2.5 times immediately after the operation, then gradually decreased, and returned to a normal value in about 2 weeks.
  • Indulin activity present in various organ extracts of pigs was measured by the following method.
  • Each of the excised septum organs was added with 5 volumes (5 ml / g-sample) of 1 M acetic acid (pH 3.5) per 1 weight, and homogenized at 0 ° C for 2 minutes using a polytron homogenizer.
  • the crushed material was centrifuged at 100,000 xg for 1 hour, and the obtained supernatant was neutralized and adjusted to pH 7.0. After further centrifugation at 100, OOOxg for 20 minutes, the supernatant was dialyzed against PBS and filtered through a 0.22 ⁇ mesh filter. According to the method of Experimental Example 2, the obtained extract was measured for lindulin activity by MRC-5 cell MGF production stimulating activity.
  • the protein concentration was measured using a ⁇ CA protein assay kit (Pierce Chemical). The results are shown in Table 1. As shown in Table 1, the indulin activity per protein was high in the cerebellum, lung, and cerebellum, and the total activity per organ was significantly higher in the lung.
  • Example According to the method of Experimental Example 1, the physical properties of the tissue injury healing factor indulin in the serum of the liver injury rat were examined.
  • Serum from a normal rat and serum 3 hours after the operation of a normal rat with a 70% hepatectomy were used as samples.
  • To examine the stability of this factor against acid add 1M acetic acid to pH 3.5, incubate at 4 ° C for 12 hours, centrifuge at 100,000 xg for 1 hour, and discard the supernatant as follows. Tested.
  • the acid-treated sample was heat-treated at 100 ° C for 5 minutes, filtered through a 0.22 ⁇ mesh filter, and the filtrate was subjected to the following test. .
  • the sample was ultrafiltered using an Amicon YM10 membrane filter to check whether the molecular weight was 10 kD or more, and the solution that passed through the filter (including those with a molecular weight of less than 10 kD) and remained in the filter 1 (Including those having a molecular weight of 10 kD or more) were subjected to the following tests.
  • RNA extraction, purification and Northern hybridization were performed.
  • Figure 5 shows the results. As shown in FIG. 5, the indulin activity was not attenuated by the acid treatment and the heat treatment, and it became clear that the indulin of the present invention was resistant to acid and heat and did not pass through a filter having a molecular weight of 10 kD. Was.
  • tissue injury healing factor indiulin of the present invention was purified from serum of a rat to which carbon tetrachloride had been administered by molecular sieving chromatography.
  • Indulin activity was quantified using MRC-5 cells according to the method of Experimental Example 2.
  • Figure 6 shows the results. As shown in FIG. 6, it was found that indulin was eluted in fractions Nos. 43-60.
  • Figure 7 shows the results. As shown in FIG. 7, it was revealed that the indulin of the present invention has a molecular weight of about 10,000 to 30,000 (10 kD to 30 kD).
  • Example 3
  • the pH was adjusted to 5.0 and 3.5 using acetic acid, and adjusted to pH 1.0 using hydrochloric acid.
  • trypsin As a trypsin treatment, trypsin was added to an indulin fraction having a protein concentration of 470 ⁇ / ⁇ 1 at a concentration of 100 ig / ml and incubated at 37 ° C for 3 hours. The enzymatic reaction was stopped by adding soybean-derived trypsin inhibitor at a concentration of 200 g / ml.
  • dithiothreitol was added to O.lmM. It was added at a concentration.
  • the indulin fraction was subjected to electrophoresis.
  • the indulin activity fraction obtained in Example 2- (2) was purified by ion-exchange FPLC, reverse-phase HPLC and preparative SDS-PAGE, and then 10-20% gradient * polyacrylamide gel under non-reducing conditions I did an electric swim.
  • the following five types of proteins were used as molecular weight markers. Phospholipase b (94 kD), BSA (67 kD), ovalbumin (43 kD), soybean-derived trypsin inhibitor (21 kD), lysozyme (14 kD).
  • the gel was cut into small pieces and disrupted with a Teflon homogenizer. Each gel piece was placed in a test tube, PBS was added, and the mixture was shaken at 4 ° C for 15 hours. After centrifugation at l, 000xg for 20 minutes, BSA was added to the supernatant. , R
  • Indulin activity was measured by MRC-5 cell HGF production stimulating activity according to the method of Experimental Example 2.
  • Figure 8 shows the results. As shown in FIG. 8, it was revealed that the induulin of the present invention has a molecular weight of about 10,000 to 20,000. Indulin activity was also observed in fractions with a molecular weight of about 40,000 to 60,000 (40 kD to 60 kD).
  • Example 5 shows the results. As shown in FIG. 8, it was revealed that the induulin of the present invention has a molecular weight of about 10,000 to 20,000. Indulin activity was also observed in fractions with a molecular weight of about 40,000 to 60,000 (40 kD to 60 kD).
  • Indulin in human serum was purified by the following method.
  • the serum obtained from the patient diagnosed with liver cancer obtained in Experimental Example 4 was purified on Biogel P-60 and Sephadex G-150 according to the method of Example 2, and then the method of Example 4 was performed. Purified by ion-exchange FPLC, reversed-phase HP LC, and preparative SDS-PAGE according to the procedure described above, and the obtained indulin-active fraction was subjected to electrophoresis with a 10-20% gradient polyacrylamide gel under non-reducing conditions. . The slices were cut into gel slices according to the method of Example 4, and the indulin activity fraction was purified using the HGF-inducing activity of MRC-5 cells as an index to obtain the tissue injury healing factor of the present invention, indulin. Industrial applicability
  • the tissue injury healing factor of the present invention is a novel factor, and the tissue injury healing factor of the present invention has an effect of promoting the healing of injuries to tissues and organs of a living body.

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Abstract

Facteur de réparation de lésions cellulaires pouvant stimuler la réparation des lésions subies par les tissus et les organes d'un organisme vivant. Ce facteur (induline) a son origne dans un tissu humain ou animal, ou dans un composant sanguin; sa quantité augmente en fonction de l'étendue des lésions subies par le tissu humain ou animal, et son action consiste à stimuler la production d'un facteur de croissance d'hépatocytes (HGF) dans une cellule produisant ce facteur. Dès lors que ce facteur de réparation stimule la production de HGF qui présente une activité de réparation de lésions tissulaires, il est utile comme agent de réparation de lésions tissulaires.
PCT/JP1992/001286 1991-10-04 1992-10-05 Facteur de reparation de lesions cellulaires Ceased WO1993006853A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP3/285650 1991-10-04
JP3285650A JPH083195A (ja) 1991-10-04 1991-10-04 組織傷害治癒因子

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WO1993006853A1 true WO1993006853A1 (fr) 1993-04-15

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PCT/JP1992/001286 Ceased WO1993006853A1 (fr) 1991-10-04 1992-10-05 Facteur de reparation de lesions cellulaires

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7601365B2 (en) 2000-08-28 2009-10-13 Damavand Wound, AB Synergetic effects of HGF and antibacterial treatment

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6814925B2 (ja) * 2016-10-08 2021-01-20 株式会社ニューロゲン Ｈｇｆ誘導剤

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02134323A (ja) * 1988-11-15 1990-05-23 Agency Of Ind Science & Technol 肝実質細胞増殖因子の製造法
JPH02288899A (ja) * 1988-12-12 1990-11-28 Toyobo Co Ltd 成熟肝実質細胞増殖因子（ｉ）
JPH03130091A (ja) * 1989-06-05 1991-06-03 Toyobo Co Ltd 組換ヒト肝実質細胞増殖因子

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02134323A (ja) * 1988-11-15 1990-05-23 Agency Of Ind Science & Technol 肝実質細胞増殖因子の製造法
JPH02288899A (ja) * 1988-12-12 1990-11-28 Toyobo Co Ltd 成熟肝実質細胞増殖因子（ｉ）
JPH03130091A (ja) * 1989-06-05 1991-06-03 Toyobo Co Ltd 組換ヒト肝実質細胞増殖因子

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7601365B2 (en) 2000-08-28 2009-10-13 Damavand Wound, AB Synergetic effects of HGF and antibacterial treatment

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JPH083195A (ja) 1996-01-09

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