• 제목/요약/키워드: Recombinant Human Erythropoietin

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유전자재조합 CHO 세포에서 Histone Deacetylase Inhibitor를 이용한Albumin-erythropoietin 생산성 증진 (Enhanced Production of Albumin-erythropoietin by Histone Deacetylase Inhibitors in Recombinant CHO Cells)

  • 김수진;서준석;최성훈;차현명;임진혁;신수아;신연경;김동일
    • KSBB Journal
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    • 제30권1호
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    • pp.44-51
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    • 2015
  • Chinese hamster ovary (CHO) cells are the most widely used mammalian host for the commercial production of recombinant proteins. However, they show relatively low yields of recombinant proteins in comparison with microbial cells. Various strategies have been tried to overcome this drawback. The acetyl moieties are attached to the N-terminus of histone by histone acetyltransferase (HAT) while histone deacetylase (HDAC) removes histone-bound acetyl groups. HDAC inhibitor (HDACi), such as sodium butyrate, sodium propionate and valproic acid, can enhance specific productivity of CHO cells. Human albumin-erythropoietin (Alb-EPO) is a novel 105 kDa protein comprising recombinant human EPO fused to human albumin. In this study, we examined the effects of HDACi on the production of Alb-EPO in CHO cells with various concentrations in the range of 0-1 mM. The results showed that sodium butyrate was found to be the best HDACi for enhancing productivity. It enhanced not only the production of Alb-EPO but also the apoptosis of recombinant CHO cells.

CHO 세포에서 생산된 재조합 Erythropoietin (EPO)의 약효 (Efficacy of Recombinant Erythropoietin from CHO Cells)

  • 김석준;하병집;이동억;오명석;김달현;박관하;김현수
    • Biomolecules & Therapeutics
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    • 제2권4호
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    • pp.343-346
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    • 1994
  • In vivo activity of recombinant human erythropoietin (rh-EPO) has been examined using polycythemic model in mice and acute hemorrhage model in rats. The number of reticulocytes in blood stream was increased after a single injection of rh-EPO depending on the dosage of rh-EPO in polycythemy model. It seemed that optimal dose of rh-EPO for polycythemic mice was around 1-10 U/kg. Rh-EPO also showed the effectiveness for increase of reticulocyte numbers both in male and female rats after bleeding. The number of reticulocytes and the change of hemoglobin concentration in the blood stream of normal rats has been examined after injection of rh-EPO. The maximum value of reticulocyte was observed on the 6th day of the injection in these normal rats. In addition, the increase of reticulocyte and the concentration of hemoglobin were dependent on the dosage of rh-EPO. The increase of hemoglobin concentration was continued to the 9th day after injection. In this study, the efficacy of rh-EPO was confirmed in both mice and rats.

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재조합 사람 적혈구 조혈인자 DA-3585의 랫드에 대한 단회 및 4주반복 정맥투여 독성시험 (Single and Four-week Intravenous Toxicity Studies of DA-3585, a Recombinant Human Erythropoietin, in Rats)

  • 김동환;조현;강경구;백남기;김원배
    • Biomolecules & Therapeutics
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    • 제6권2호
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    • pp.182-190
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    • 1998
  • DA-3585 is a recombinant human erythropoietin produced by Dong-A pharmaceutical Co. Ltd. using recombinant DNA technique. Recently, recombinant human erythropoietin (rHu-EPO) has been used to treat various types of anemia. In this study, we examined acute and subacute toxicity of DA-3585 in rats. DA-3585 was intravenously administered to rats at dose levels of 0, 6,250, 12,500 and 25,000 lU/kg for single dose toxicity study and at dose levels of 0,100,500 and 2,500IU/kg daily for 4 week-repeated dose toxicity study. In the single dose toxicity study, there were no death, clinical signs and changes in body weight gain related to the treatment. Necropsy revealed no evidence of toxicity related to DA-3585, In the repeated dose toxicity study, all the rats survived throughout the study. There were no treatment-related changes in clinical signs, food and water intake, and body weight. Hematological examination showed increases in the number of erythrocytes, hemoglobin concentration, hematocrit value and mean corpuscular volume, and decrease in the number of platelet in 500 and 2,500 lU/kg dosed groups. Extramedullary hematopoiesis in the spleen and erythroid hyperplasia in the bone marrow were noted as treatment-related histological changes. Toxicologically significant changes were not observed in blood biochemistry, urinalysis, organ weights and in any other examinations. The treatment-related changes observed in this study were hematological or histological changes associated with pharmacological effects of DA-3585. On the basis of the results of this study, LD5n value of DA-3585 was above 25,000 lU/kg and the no-observed-adverse-effect-level was estimated to be 100 lU/kg.

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게잡이 원숭이에서 Recombinant Human Erythropoietin의 4주간 투여 후 비장 유전자 발현 연구 (Effects of Recombinant Human Erythropoietin Treatment in Male Cynomolgus (Macaca fascicularis) Monkeys (II): Gene Expression Profiling in Spleen)

  • 윤석주;황지윤;임정선;정선영;김용범;김달현;권명상;한상섭;김충용
    • Toxicological Research
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    • 제21권3호
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    • pp.209-218
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    • 2005
  • We investigated effects of recombinant human erythropoietin (rHuEPO) on profiles of mRNA transcripts in 6 male cynomolgus (M. fascicularis) monkey's spleen for 4 weeks. Six monkeys, composed of control and treatment group (Control : M1, M2, M3: Treatment : M4, M5, M6) were intravenously administered 3 times per week without or with a dose of rHuEPO 2730 IU/0.1 ml/kg. After 4 weeks rHuEPO treatment, spleen was removed for RNA isolation. Splenic gene expression was assessed using Affymetrix U133A 2.0 arrays containing 18,400 transcripts and variants, including 14,500 well-characterized human genes. Gene expression pattern was very different between individuals even in same treatment. In rHuEPO treated groups showed number of genes were up- or down-regulated (M4: 79: M5: 48; M6: 73 genes). Six genes (epidermal growth factor receptor, calgranulin A, estrogen receptor binding site associated antigen, matrix metalloproteinase 19, zinc finger and BTB domain containing 16, progestin and adipoQ receptor) were commonly expressed in rHuEPO treated group. The different individual response could be major considering factor in monkey experiment. Further study is needed to clarify the different individual response to rHuEPO in molecular level. This study will be valuable in the fundamental understanding and validation of molecular toxicology for bio-generic drugs including rHuEPO in cynomolgus monkey.

새로운 인체 재조합 적혈구 조혈인자 LB00014의 생식독성연구: 랫드 최기형성시험 (Reproductive Toxicity Study of LBO0014, A New Recombinant Human Erythropoietin: Teratogenicity Study in Rats)

  • 정문기;양병철;김종춘;송시환;이상구
    • Biomolecules & Therapeutics
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    • 제6권1호
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    • pp.82-88
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    • 1998
  • LBO0014, a new recombinant human erythropoietin, was at dose levels of 0, 120, 600, and 3,000 IU/kg/day administered intravenously to pregnant Sprague-Dawley rats during the organogenetic period. All dams were subjected to caesarean section on day 20 of pregnancy, Effects of test substance on dams and embryonic development of Fl fetuses were examined. No treatment-related changes in clinical signs, body weight, and food consumption were observed at all doses tested. At necropsy spleen enlargement was found at 3,000 lU/kg. There was an ulcrease in the spleen weight at 600 and 3,0007/kg. Developmental toxicity was evident as increased resorptions at 3,000 lU/kg. At 600 and 3,000 RJ/kg, retarded ossification of fetuses occurred at an incidence of 31.3% and 64.7%, respectively. In addition, there was a delay in ossification of sternebrae and sacrocaudal vertebrae at 600 and 3,000 lU/kg. A decrease in the number of metacarpi and metatarsi was also seen at 3,000 nJ/kg. The results show that the no observed adverse effect dose level (NOAEL) for material toxicity was over 3,000 IU/kg/day and the NOAEL for developmental toxicity was 120 IU/kg/day.

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랫드에서 인체 재조합 적혈구 조혈인자, rHu-EPO의 급성정맥독성시험 (Acute Toxicity Study of Recombinant Human Erythropoietin(rHu-EPO) in Rats)

  • 곽승준;김형식;임소영;천선아;홍채영;박현선;김원배;김병문;안병옥
    • Biomolecules & Therapeutics
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    • 제4권4호
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    • pp.330-333
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    • 1996
  • Acute intravenous toxicities of rHu-EPO (recombinant human erythropoietin) were investigated in Sprague-Dawley rats. Seven days after administration of rHu-EPO, we examined the clinical signs, mortalities, body weight and etc. No clinical signs and mortalities of toxicity were observed in animals. Also, a significant change of body weights was not observed. These results suggest that LD$_{50}$ value was >25,000 unit/ kg in Sprague-Dawley rats and the acute intravenous toxicities of rHu-EPO were not significant.t.

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FOUR-WEEK INTRAVENOUS TOXICITY EVALUATION OF RECOMBINANT HUMAN ERYTHROPOIETIN, YHB216 IN BEAGLE DOGS

  • Sin, Ji-Soon;Jung, Eun-Yong;Zhang, Hu-Song;Huang, Zai-Zhi;Zheng, Mei-Shu;Kim, Dong-Kyu;Roh,Yong-Woo;Choi, Ehn-Kyung;Nam, Sang-Yoon;Kang, Jong-Koo
    • 한국독성학회:학술대회논문집
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    • 한국독성학회 2001년도 International Symposium on Dietary and Medicinal Antimutgens and Anticarcinogens
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    • pp.168-168
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    • 2001
  • To investigate the safety and toxicity of a recombinant human erythropoietin, YHB216, we performed 4-week repeated dose toxicity test in 4-month-old Beagle dogs. We injected intravenously everyday for 28 days with dosages of 0, 500, 2,500 and 12,500 I.U/kg body weight. There were not observed clinical signs or motality in the animals treated with YHB216. There were no significant changes in body weight, feed, or water consumption.(omitted)

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Recombinant Human Erythropoietin Therapy for a Jehovah's Witness Child With Severe Anemia due to Hemolytic-Uremic Syndrome

  • Woo, Da Eun;Lee, Jae Min;Kim, Yu Kyung;Park, Yong Hoon
    • Clinical and Experimental Pediatrics
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    • 제59권2호
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    • pp.100-103
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    • 2016
  • Patients with hemolytic-uremic syndrome (HUS) can rapidly develop profound anemia as the disease progresses, as a consequence of red blood cell (RBC) hemolysis and inadequate erythropoietin synthesis. Therefore, RBC transfusion should be considered in HUS patients with severe anemia to avoid cardiac or pulmonary complications. Most patients who are Jehovah's Witnesses refuse blood transfusion, even in the face of life-threatening medical conditions due to their religious convictions. These patients require management alternatives to blood transfusions. Erythropoietin is a glycopeptide that enhances endogenous erythropoiesis in the bone marrow. With the availability of recombinant human erythropoietin (rHuEPO), several authors have reported its successful use in patients refusing blood transfusion. However, the optimal dose and duration of treatment with rHuEPO are not established. We report a case of a 2-year-old boy with diarrhea-associated HUS whose family members are Jehovah's Witnesses. He had severe anemia with acute kidney injury. His lowest hemoglobin level was 3.6 g/dL, but his parents refused treatment with packed RBC transfusion due to their religious beliefs. Therefore, we treated him with high-dose rHuEPO (300 IU/kg/day) as well as folic acid, vitamin B12, and intravenous iron. The hemoglobin level increased steadily to 7.4 g/dL after 10 days of treatment and his renal function improved without any complications. To our knowledge, this is the first case of successful rHuEPO treatment in a Jehovah's Witness child with severe anemia due to HUS.

랫드에서 인체 재조합 적혈구 조혈인자, rHuEPO의 13주 정맥투여 아만성독성에 관한 연구 (Toxicity of Recombinant Human Erythropoietin [rHuEPO] in Rats for 13 Weeks)

  • 김형식;곽승준;천선아;박현선;한하수;임소영;안미영;김원배;안병옥;홍성렬;이병무
    • Toxicological Research
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    • 제14권3호
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    • pp.415-425
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    • 1998
  • A recombinant human erythropoietin (rHuEPO) was administered intravenously at dosage levels of 0, 100, 500, and 2500IU/kg/day for a period of 3 weeks. There were no observed clinical signs and deaths related to treatment in all groups tested. Decreases in body weight gain and food consumption were observed only in males of 2,5000IU/kg group after 2 weeks. In hematological parameters, erythrocyte content, hematocrit values and hemoglobin concentration were dose- dependently increased in rHuEPO treated groups. The ratio between kidney weight and whole body weight was significantly increased in females of 500 and 2,500IU/kg groups. The spleen weight was also increased in both sexes of 500 and 2,500IU/kg groups. However, the absolute weight change of other organs was not observed. In histopathological examinations, the renal tubular basophilia was observed only in males and females of 2,500IU/kg groups. From these results, it is concluded that the no-observed adverse effect level (NOAEL) of rHuEPO is 100 IU/kg in rats in the present study.

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