颗粒-单核细胞集落生成因子在肺癌治疗中的应用

颗粒—单核细胞集落生成因子是一种糖蛋白对血细胞的产生有调节作用。其中通过基因工程重组的集落刺激因子(CSF)已被公认的有4种:颗粒—单核细胞集落刺激因子(GM—CSF),粒细胞集落刺激因子(G—CSF),单核细胞集落刺激因子(M—CSF)和白细胞介素3(IL_3)。前两种可供临床试用。动物实验提示:G—CSF能升高粒细胞,GM—CSF可使巨噬细胞、粒细胞、嗜酸细胞和红细胞增生。临床对需要加强化疗和放疗的恶性肿瘤患者,在必须增加细胞毒药物剂量、缩短疗程情况下,CSF可缩短白细胞减少的时间,增加抵抗力,减少感染率     

重组人粒系细胞集落刺激因子临床应用进展

重组人粒系细胞集落刺激因子（G－CSF）刺激中性粒系细胞的增殖与分化，并促进其超化活性和周围血粒细胞增多。因此G－CSF已被用于各种原因所引起的中性粒细胞减少症。本文就近年来G－CSF或基因重组人粒单系细胞集落刺激因素（GM－CSF）临床应用的进展概要综述如下：1粒细胞减少（缺乏）症1．1药物所致粒细胞缺乏症白1989年以来，G－CSF用于药物所致粒细胞缺乏症日益增多。为了评价G－CSF及GM－CSF治疗药物所致粒细胞缺乏症（＜O．IX10’几）的疗效，SPrikkelm等“‘总结7O例临床资料，结果表明外周血粒细胞均迅速恢复，死亡…     

粒细胞——巨噬细胞集落刺激因子的研究现状及临床应用

集落刺激因子(Colony Stimulating Factors)是一组控制粒细胞、单核一巨噬细胞和某些有关的造血细胞增殖和分化的糖蛋白,根据不同的分化阶段和造血祖细胞,分为粒细胞一巨噬细胞集落刺激因子(GM—CSF)、粒细胞集落刺激因子(G—CSF)、巨噬细胞集落刺激因子(M—CSF)以及多潜能集落刺激因子(Multi—CSF)又称白细胞介素—3(IL—3)。现就近年来GM—CSF研究进展及临床应用综述如下。     

造血生长因子的临床应用

近年来,重组DNA技术已能生产5种造血生长因子,包括促红细胞生成素(EPO),粒—巨噬细胞克隆刺激因子(GM—CSF),粒细胞克隆刺激因子(G—CSF),巨噬细胞克隆刺激因子(M—CSF)及白细胞介素Ⅲ(IL—3)。其中EPO、     

粒细胞-巨噬细胞集落刺激因子受体的研究进展

集落刺激因子（Colony Stimulating Factor）是一组控制粒细胞、单核一巨噬细胞和某些有关的造血细胞增殖和分化的糖蛋白，根据不同的分化阶段和造血祖细胞，可分为粒细胞-巨噬细胞集落刺激因子（GM—CSF）、粒细胞集落刺激因子（GCSF）、巨噬细胞集落刺激因子（M-CSF）以及多潜能集落刺激因子（Multi—CSF）叉称白细胞介素-3（IL-3）、红细胞生成素（Epo）、血小板生成素（Tpo）及干细胞因子（SCF）等。GM—CSF是一个多效性细胞因子，它促进多种造血细胞的存活，增殖、分化，     

重组人粒细胞集落刺激因子联合抗生素治疗急性白血病化疗后中性粒细胞缺乏合并感染患者的疗效

目的探讨重组人粒细胞集落刺激因子联合抗生素治疗急性白血病化疗后中性粒细胞缺乏合并感染患者的疗效。方法选取急性白血病化疗后中性粒细胞缺乏合并感染患者60例,采用随机数字表法分为两组,各30例。观察组采用重组人粒细胞集落刺激因子联合抗生素治疗;对照组采用抗生素治疗,比较两组患者临床疗效的差异。结果观察组治疗总有效率明显高于对照组(P0.05);外周血中性粒细胞最低值明显高于对照组,外周血中性粒细胞缺乏持续时间、退热时间与抗生素应用时间均明显短于对照组(P0.05)。观察组出现皮疹3例,对照组出现皮疹4例,两组比较无统计学差异(P0.05)。治疗前,两组卡氏体力状况(KPS)评分无统计学差异(P0.05);治疗后,全部患者KPS评分均明显高于治疗前(P0.05),其中观察组KPS评分明显高于对照组(P0.05)。结论重组人粒细胞集落刺激因子联合抗生素治疗急性白血病化疗后中性粒细胞缺乏合并感染患者的疗效显著,有助于提高患者的生活质量,且药物副作用较少,值得临床推广。     

粒-巨噬细胞集落刺激因子在肺表面活性物质稳态调节中的作用

粒 巨噬细胞集落刺激因子 (GM CSF)是一种细胞生长因子 ,常用于化疗及骨髓移植后刺激造血恢复。近年通过转基因动物的研究发现 ,GM CSF或其受体基因敲除鼠并未出现造血系统紊乱 ,唯一的病理改变是肺内表面活性物质磷脂和蛋白的蓄积。该研究提示GM CSF在造血系统稳态调节中作用甚微 ,而在肺表面活性物质的代谢平衡中却起着至关重要的作用。这为临床上肺泡蛋白沉积症的诊断及治疗提供了有益的启示     

G-CSF液漱口治疗化疗后口腔粘膜炎30例疗效观察

2002年2月～2003年2月，我科采用粒细胞集落刺激因子(G—CSF)液漱口治疗化疗所致口腔粘膜炎30例，取得了满意疗效。现报告如下。     

两种免疫抑制疗法治疗重型再生障碍性贫血比较研究

目的 :探讨重型再生障碍性贫血的适宜治疗方案。方法 :回顾性比较猪 -抗胸腺细胞球蛋白( P- ATG)单用 ( IST方案 )与联合方案兔 -抗人 T淋巴细胞球蛋白 ( R- ATL G)、环孢霉素 A( Cs A)、重组人粒 -巨噬细胞集落刺激因子 ( rhu GM- G- CSF) /重组人粒细胞集落刺激因子 ( rhu- G-CSF)及重组人红细胞生成素 ( rhu EPO) ( IST方案 )治疗 SAA疗效。结果 :IST方案 组不仅疗效高于 IST方案 组 ,且其有效者造血功能恢复更为迅速及良好。结论 :SAA患者更适宜于 IST方案 。     

动员自体骨髓干细胞促进大鼠急性脑缺血损伤后血管新生的实验研究

目的　探讨应用粒细胞集落刺激因子 (G CSF)动员自体骨髓干细胞对大鼠急性脑缺血 /再灌注损伤后血管新生的影响。方法　采用大鼠大脑中动脉栓塞 /再灌注模型 (MCAO/R) ,应用粒细胞集落刺激因子 (G GSF)动员自体骨髓干细胞 ,观察不同时间大鼠的神经病学评分。应用HE染色和免疫组化方法检测动物模型脑缺血区病理改变、CD34 阳性细胞 ,应用 5 溴脱氧尿核苷 (Brdu)标记新生血管。结果　手术动员组大鼠脑缺血 /再灌注后脑局部缺血组织缺血坏死渐进加重 ,缺血 /再灌注 2 4h ,有大量淋巴细胞、单核细胞浸润 ;48h ,脑组织缺血坏死区可见CD34 阳性细胞 ,并可见新生毛细血管 (Brdu染色阳性 )生成 ;72h后 ,新生毛细血管数目更明显多于手术非动员组。结论　应用G CSF动员自体骨髓干细胞治疗MCAO/R大鼠 ,可以促进微血管的新生     

Antithyroid drug-induced agranulocytosis: how has granulocyte colony-stimulating factor changed therapy?

This study examined whether granulocyte colony-stimulating factor (G-CSF) is beneficial for the treatment of antithyroid drug-induced agranulocytosis. From January 1975 to December 2001, 30,798 patients with Graves' disease were treated with antithyroid drugs at Noguchi Thyroid Clinic & Hospital Foundation. During this period, 109 patients (0.35%) were found to have agranulocytosis caused by antithyroid drugs. In the symptomatic group, the recovery time from agranulocytosis was significantly shorter after the introduction of G-CSF (5.5 +/- 3.5 days, n = 19) compared to the symptomatic group before its introduction (9.2 +/- 4.4 days, n = 37, p < 0.01). In the asymptomatic group, the recovery time from agranulocytosis was significantly shorter after the introduction of G-CSF (2.3 +/- 1.9 days, n = 15) compared to the asymptomatic group before the introduction of GCSF (5.4 +/- 4.3 days, n = 34, p < 0.05). However, G-CSF therapy was ineffective in severe cases with granulocyte count below 0.1 x 10(9)/L and symptoms. We recommend that G-CSF therapy should be applied only in asymptomatic patients and symptomatic patients with granulocyte count above 0.1 x 10(9)/L, and not for symptomatic patients with granulocyte count below 0.1 x 10(9)/L. In conclusion, G-CSF therapy shortens the period of recovery from antithyroid drug-induced agranulocytosis and benefits patients, except those with symptoms and a granulocyte count below 0.1 x 10(9)/L.     

Granulocyte colony-stimulating factor (G-CSF) does not improve recovery from antithyroid drug-induced agranulocytosis: a prospective study.

Agranulocytosis is the most serious side effect of antithyroid drug (ATD) therapy. We conducted prospective and randomized studies to examine whether granulocyte colony-stimulating factor (G-CSF) is actually effective for ATD-induced agranulocytosis. Twenty-four patients with Graves' disease who developed agranulocytosis during ATD therapy were randomly divided into a G-CSF group (n = 14) and an untreated group (n = 10). Subcutaneous injection of G-CSF (100 to 250 microg) was given daily until neutrophil counts rose to greater than 1000/microL. The untreated group received antibiotic therapy only. Recovery time, which is defined as the number of days required for neutrophil counts to exceed 500/microL, was monitored by daily complete blood count (CBC). Recovery time in the G-CSF-treated group did not differ from that of the untreated group in those patients with moderate and severe agranulocytosis; thus, prolonged use of G-CSF treatment is generally ineffective for ATD-induced agranulocytosis.     

Thymoma and agranulocytosis: two case reports and literature review

Thymoma with agranulocytosis is a rare association. We describe two cases of agranulocytosis presenting with sepsis which were both found to have coincident benign spindle cell thymomas. One case, associated with promyelocyte arrest and hypogammaglobulinaemia, was treated successfully with granulocyte colony-stimulating factor (G-CSF). Thymectomy had no effect. The other case, associated with complete myeloid aplasia, proceeded to a fatal outcome after failure of treatment with granulocyte-macrophage colony stimulating factor (GM-CSF), plasmapheresis, thymectomy, intravenous immunoglobulin, cyclophosphamide and methylprednisolone. We also review the literature of thymoma in association with agranulocytosis.     

Effects of immunosuppressive drugs and antibiotics on GM-CSF and G-CSF secretion in vitro by monocytes, T lymphocytes and endothelial cells

We studied the effects of eight antibiotics, cyclosporin and corticosteroids on the in vitro secretion of GM-CSF and G-CSF by monocytes, T lymphocytes and endothelial cells. The aim was to evaluate a possible mechanism for these drugs in the delay of haemopoietic recovery after high-dose chemotherapy or bone marrow transplantation. Corticosteroids were prominent inhibitors of GM-CSF secretion by monocytes and T lymphocytes, but not by endothelial cells. In contrast, G-CSF secretion by monocytes was unchanged whereas that of endothelial cells was enhanced in the presence of corticosteroids. Cyclosporin efficiently down-regulated GM-CSF secretion by T lymphocytes and had also a minor effect on CSF secretion by endothelial cells, whereas monocyte secretion was unaffected. Stimulated T lymphocytes derived from patients under treatment with cyclosporin had impaired capacity to secrete GM-CSF compared to controls. Among the antibiotics, cephalosporins inhibited GM-CSF secretion by T lymphocytes, and GM- and G-CSF secretion by endothelial cells. Ciprofloxacin and sulphmethoxazole had minor effects on GM-CSF secretion by T lymphocytes and endothelial cells. No antibiotic significantly influenced GM-CSF secretion by monocytes.     

Serum concentrations of granulocyte colony-stimulating factor (G-CSF) in antithyroid drug-induced agranulocytosis

Granulocyte colony-stimulating factor (G-CSF) levels in serum were determined by a highly-sensitive chemiluminescent enzyme immunoassay (limit of detection, 0.5 pg/ml) in 54 patients with Graves' disease including 6 patients complicated with methimazole-induced agranulocytosis. Serum G-CSF levels in patients with Graves' disease were not different from normal subjects and did not correlate with serum FT4 level or circulating neutrophil counts. Before the onset of agranulocytosis, there was no difference in serum G-CSF level between the patients complicated with agranulocytosis and the uncomplicated patients. When circulating neutrophil counts decreased to less than 0.5 x 10(9)/L, serum G-CSF level elevated with the mean of 106.8 +/- 82.2 (SD) pg/ml, but the level did not correlate with the duration of agranulocytosis. Interestingly, maximum serum G-CSF level during the treatment with recombinant human G-CSF (100 microg/day) was related to bone marrow finding at the onset of agranulocytosis and correlated with the duration of agranulocytosis (r = 0.824, p < 0.05). In conclusion, measuring serum G-CSF levels with a highly-sensitive chemiluminescent enzyme immunoassay revealed that 1) thyrotoxicosis does not affect serum G-CSF level, 2) serum G-CSF level during antithyroid drug treatment does not play an important role in development of agranulocytosis, 3) the maximum serum G-CSF level in the course of agranulocytosis is related to the responsiveness of bone marrow to G-CSF and the recovery time from agranulocytosis.     

Growth factors and hemostasis: differential effects of GM-CSF and G-CSF on coagulation activation – laboratory and clinical evidence

Granulocyte-macrophage (GM-CSF) and granulocyte colony-stimulating factors (G-CSF) are equally effective hematopoietic growth factors in terms of their potential to shorten the period of neutropenia following high-dose chemotherapy or to mobilize hematopoietic stem cells. Thus the choice between the two preparations must be based on a comparison of adverse effects. Both GM-CSF and G-CSF have been implicated in disturbances of the hemostatic system, resulting in both hemorrhagic and thrombotic complications. We therefore studied the effects of GM-CSF and G-CSF therapy on hemostasis both ex vivo and clinically. In a prospective, non-randomized study 34 patients who were treated with a myeloablative regimen according to the hyper-ME+/-C protocol and stem cell or bone marrow transplantation received posttransplantation hematopoietic support with GM-CSF (n=15) or G-CSF (n=19). The patients were monitored for alterations in plasmatic coagulation parameters and clinical evidence of hemorrhagic or thrombotic events. GM-CSF, but not G-CSF, induced a significant, albeit usually mild activation of the coagulation cascade. We observed an increased frequency of veno-occlusive disease in the GM-CSF group (3/15 vs. 1/19 on G-CSF, n.s.). Other thrombotic events were rare. At the same time, hemorrhage was both more common and more severe in GM-CSF treated patients than in those on G-CSF (macroscopic hemorrhage 11/15 vs. 10/19, III hemorrhage 7/15 vs. 1/19 on GM-CSF or G-CSF, respectively). In conclusion, unlike G-CSF, if given after hyper-ME chemotherapy plus stem cell or bone marrow transplantation, at the dosage used here GM-CSF induced an activation of the coagulation system and was associated with an increased risk of hemostasis associated treatment complications.     

Idiosyncratic drug-induced agranulocytosis

BACKGROUND: Agranulocytosis is a life-threatening disorder that frequently occurs as an adverse reaction to drugs. CURRENT DATA: Idiosyncratic drug-induced agranulocytosis is characterized by a neutrophil count <0.5x10(9)/l, in serious forms <0,1x10(9)/l that currently occurs especially in association with antibiotics, antithyroid drugs ant ticlopidine (>60% of the incriminated drugs). The overall incidence of idiosyncratic agranulocytosis ranges from 2.4 to 15.4 cases per million patients exposed to drugs per year. Although patients experiencing idiosyncratic agranulocytosis may be asymptomatic (50%), the severity of the neutropenia usually leads to severe sepsis: fever of unknown origin, septicemia, septic shock or localized documented infections such as sore throat, various cutaneous infections or pneumonia. Nevertheless, the mortality rate of idiosyncratic agranulocytosis is now around 5% with appropriate management. PERSPECTIVES: In the future, management of drug-induced agranulocytosis may include pre-established procedures using in critically situations, broad-spectrum antibiotic therapy and hematopoietic growth factors (G-CSF).     

Efficacy of granulocyte and granulocyte-macrophage colony-stimulating factors in the induction treatment of adult acute lymphoblastic leukemia: a multicenter randomized study

In all, 236 adults with newly diagnosed acute lymphoblastic leukemia (ALL) were randomly assigned to receive either granulocyte colony-stimulating factor (G-CSF), or granulocyte-macrophage CSF (GM-CSF), or no CSF during a 4-week 4-drugs induction chemotherapy. Two successive trials were performed. CSFs were given from the last infusion of anthracycline in Trial 1 or from day 4 of induction therapy in Trial 2 until neutrophil recovery. A total of 95 patients were included in the G-CSF group, 67 in the GM-CSF group, and 74 in the control group. Overall, CSFs showed a trend for a reduced incidence of severe infections and of days with antibiotics. Median time for neutrophil recovery was 17 days with G-CSF, 18 days with GM-CSF, and 21 days without CSF. In Trial 2, duration of hospitalization was significantly lower in the G-CSF group than in the other groups (P < 0.05). Time to neutrophil recovery was also significantly shorter (P < 0.05) and severe infections were lower in the G-CSF group (P = 0.01). CR rate was higher in the GM-CSF group as compared to the control group. This tended to be confirmed for the most aggressive ALL and was statistically significant for Philadelphia-positive ALL after salvage therapy (P = 0.04). There were no significant differences between the three groups in terms of disease-free survival.     

Transient cyclic neutropenia following GM-CSF in a patient with chronic granulocytic leukemia transplanted with HLA-identical T cell-depleted donor bone marrow

Treatment with GM-CSF or G-CSF is becoming widely used in patients with chronic neutropenia, or who are aplastic following chemotherapy or autologous or allogeneic bone marrow transplantation. Recently, some authors have described a phenomenon analogous to cyclic agranulocytosis following treatment with G-CSF in a patient with chronic neutropenia. We wish to describe the same phenomenon in a patient with chronic granulocytic leukemia who received GM-CSF (Sandoz) after T cell depletion in order to accelerate hematological reconstitution.     

Ticlopidine-induced aplastic anemia: two new case reports,review, and meta-analysis of 55 additional cases

Ticlopidine-induced aplastic anemia (TIAA) is considered very uncommon. We present two new cases, and we review 55 additional cases from the literature. The first case concerns a 70-year-old man who developed severe aplastic anemia 7 weeks after treatment with 500 mg of ticlopidine daily. The patient sustained a severe septic episode, was treated with antibiotics and GM-CSF, and recovered the 14(th) day after ticlopidine withdrawal. The second was an 82-year-old man receiving ticlopidine for 2 years when, during a febrile episode, he was found neutropenic with marrow aplasia. Ticlopidine withdrawal and treatment with antibiotics, transfusions, and G-CSF helped him to recover. When the data of the 57 patients are evaluated, a reversible direct cytotoxic effect of ticlopidine on the pluripotent/bipotent hematopoietic progenitor stem cell is proposed. It is estimated that the real incidence if TIAA is higher, and many cases, initially presented as agranulocytosis +/- thrombocytopenia, might be true aplastic anemias, not proven by marrow aspiration or trephine biopsy. There is no effective monitoring to prevent this side effect. Recombinant growth factors appear not to help in shortening the neutropenic period.