Granulocyte colony-stimulating factor production and rapid progression of gastric cancer after histological change in the tumor

Granulocyte colony-stimulating factor (G-CSF)-producing malignancies are thought to be rare and associated with advanced disease and poor prognosis. Here, we report on a 77-year-old patient with G-CSF-producing gastric cancer. We observed this patient from the stage prior to the diagnosis of gastric cancer when leukocyte count was normal to the stage of advanced disease associated with remarkable leukocytosis. Immunohistochemical analysis demonstrated G-CSF expression in the advanced-stage, poorly differentiated adenocarcinoma, but not in the early-stage, well-differentiated adenocarcinoma. G-CSF receptor was not detected to be expressed in the advanced-stage tumor. Based on these results it appears that a histological change in the tumor may influence G-CSF production and the concomitant rapid progression in gastric cancer.     

Granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor in the treatment of acute myeloid leukemia and acute lymphoblastic leukemia

The role of G-CSF, GM-CSF and M-CSF in the treatment of AML and ALL was reviewed. These CSFs significantly accelerate the neutrophil recovery after intensive chemotherapy, and reduce febrile neutropenia and documented infections. There is no clear evidence that CSFs accelerate early regrowth of AML cells at the doses and schedules presently used clinically except one study. Patients who have received CSFs tend to have a higher CR rate, which does not seem to be translated into definite survival benefit. There has been no prospective randomized study showing any beneficial priming effect of CSFs on AML cells with better clinical outcomes.     

Attempted dose intensified cyclophosphamide,etoposide, and granulocyte colony-stimulating factor for treatment of malignant astrocytoma

Summary Patients with malignant astrocytoma continue to respond poorly to chemotherapy and have a dismal prognosis. Cyclophosphamide (CTX) and etoposide demonstrate activity against malignant astrocytoma at standard dosages, with bone marrow suppression as the limiting toxicity. In order to allow dose intensification, minimize leukopenia, and improve efficacy granulocyte colony-stimulating factor (G-CSF) was used in combination with CTX and etoposide. The protocol consisted of CTX (2 mg/m²/d, days 1, 2), etoposide (200–300 mg/m²/d, days 1–3), and G-CSF (5–10 g/d subcutaneously, days 4–18), every 4 weeks. Nine evaluable patients (7 glioblastoma multiforme, 2 anaplastic astrocytoma) were treated, ranging in age from 26–67 (mean 41). One of 9 patients responded (11%) with a partial response (13+ months), 3 had stable disease (33%; 8, 5, 2.5 months), and 5 had progressive disease (3, 2.5, 2, 1.5, 1 months). The median time to progression for responders was 6.5 months, while overall it was 2.5 months. Overall median survival was only 7.0 months. Toxicity was frequent and severe, typically delaying treatment cycles. The most common complications were severe myeolosuppression (9), sepsis (8), rash (6), urinary infection (5), and anorexia (5). Treatment delays caused by infections and other complications occurred often, abrogating the intended dose intensification. The received dose intensity (DI) for CTX was 400–425 mg/m²/week (relative DI 0.41), while for etoposide it was 75 mg/m²/ week (relative DI 0.42). In summary, as used in this protocol, dose intensive chemotherapy with CTX, etoposide, and G-CSF does not improve efficacy over standard regimens and results in excessive toxicity.     

Regulation of granulocyte and macrophage colony-stimulating factor production by phytohaemagglutinin-treated blood mononuclear cells

The colony-stimulating activity (CSA) of medium conditioned by phytohaemagglutinin (PHA)-stimulated blood mononuclear cells was tested using granulocyte-macrophage colony-forming cells (GM-CFC) from normal bone marrow. Low concentrations of the conditioned medium stimulated granulocytic colony-forming cells (CFC) which formed colonies by the seventh day of incubation; higher concentrations stimulated the formation of macrophage colonies which were not seen until the end of the second week in culture.The colony-stimulating activities could not be demonstrated in adherent cell-depleted bone marrow cultures. This dependence of activity on adherent cells was confirmed by incubating different concentrations of conditioned medium with isolated adherent cells and then testing for colony-stimulating activity in cultures of non-adherent bone marrow cells. The activities of conditioned media following exposure to adherent cells corresponded to the results seen when the conditioned medium from PHA-stimulated mononuclear cell cultures was used to stimulate agar cultures of unseparated marrow. The results suggest that PHA-responsive mononuclear cells (probably T lymphocytes) may modulate the regulation of colony-stimulating factor (CSF) production by adherent colony-stimulating cells (CSC).     

Co-expression of macrophage colony-stimulating factor with its receptor in human hepatoma cells and its potential roles

Recently,theanti-cytokinetherapyandantireceptortherapyisbeingidentifiedasanefficacioustreatmentinthefieldofbiologicaltherapyagainstcancerandrelateddiseases.[llPathogenesisofhepatomaisquitecomplicateinwhichmulti-factors,multi-genesandmulti-processesareinvolved.Activationofcertainoncogenes,inactivationofsometumorsuppressergenes,orabnormalexpressionofcancerrelatedgenesmightcontributetothedevelopmentofthetumor.TheN-ras,c-myc,p53,cfmsandIGF-2/IGF-ZRarerecognizedasoncogenesorcancerrelatedgenesof…     

基因重组人粒细胞集落刺激因子防治CHOP和CAF方案化疗所致白细胞减少症的临床研究

作者采用随机分组、自身交叉对比的方法，观察了基因重组人粒细胞集落刺激因子（ＲｅｃｏｍｂｉｎａｎｔＨｕｍａｎＧｒａｎｕｌｏｃｙｔｅＣｏｌｏｎｙ－ＳｔｉｍｕｌａｔｉｎｇＦａｃｔｏｒ，ｒｈＧ－ＣＳＦ，以下简称ｒｈＧ－ＣＳＦ）对２３例肿瘤患者ＣＨＯＰ和ＣＡＦ方案化疗所致白细胞和中性粒细胞减少的防治作用及毒副反应。结果表明，ｒｈＧ－ＣＳＦ可以减轻化疗过程中白细胞和中性粒细胞下降的程度，缩短白细胞和中性粒细胞降至正常值以下的持续时间，促进其早日恢复，使化疗可以如期进行。ｒｈＧ－ＣＳＦ副反应轻微，安全可靠。     

重组人粒细胞集落刺激因子治疗急性放射性口腔黏膜损伤的临床观察

目的　观察重组人粒细胞集落刺激因子（ｒｈＧ-ＣＳＦ）对鼻咽癌急性放射性口腔黏膜损伤的作用。方法　将５０例鼻咽癌住院患者随机分为对照组和ｒｈＧ ＣＳＦ治疗组,每组２５例。对照组用生理盐水每次１０ｍｌ含漱,治疗组用生理盐水１００ｍｌ＋ｒｈＧ-ＣＳＦ９００μｇ溶液每次１０ｍｌ含漱;每日３～５次,每次１０分钟。两组均采用标准分割方式放疗,观察急性口腔黏膜损伤的发生率、严重程度及其疗效。结果　放疗２０Ｇｙ时治疗组的黏膜损伤发生率为４０％,对照组为６８％（Ｐ＝０.０４７）。放疗结束治疗组的１～４级黏膜损伤发生率分别为４４％、２４％、１２％和０,对照组分别为１６％、２８％、４４％和８％（Ｐ＜０.０５）。治疗组患者的生活质量各项指标均较对照组有明显改善（Ｐ＜０.０５）。结论　ｒｈＧ-ＣＳＦ能够降低鼻咽癌急性放射性黏膜损伤的发生率,并减轻其损伤程度,值得推广。     

Subcutaneous Administration of Recombinant Human Granulocyte Colony-stimulating Factor (KRN8601) in Intensive Chemotherapy for Patients with Advanced Lung Cancer

The efficacy and toxicity of recombinant human granulocyte colony-stimulating factor (rh G-CSF, KRN8601) given subcutaneously was evaluated in patients with advanced lung cancer undergoing intensive chemotherapy. Twenty-nine and 30 patients with or without prior therapy were enrolled in this study. At dose levels of 50, 90 and 130 μg/m² of rh G-CSF for 14 consecutive days after chemotherapy, the mean neutrophil nadir counts, the mean neutrophil nadir ratios and the duration of neutropenia (days of < 1000/mm³) were significantly improved. No significant differences were seen in frequency and duration of febrile episodes (>38°C). When rh G-CSF is given subcutaneously, the dose required for an equal effect in alleviating neutropenia is 50% of that required when it is given intravenously. The monocyte counts in the peripheral blood were also significantly increased after chemotherapy cycles with rh G-CSF. The cumulative plasma concentration of rh G-CSF showed a decrement after 7–9 days despite maintenance of the same dose of rh G-CSF for the entire 14 days. In conclusion, 50–130 μg/m² of sc rh G-CSF increased the neutrophil nadir count and shortened the duration of neutropenia in patients undergoing intensive chemotherapy for lung cancer without intolerable side effects.     

Protective effect of human granulocyte colony-stimulating factor (hG-CSF) on Cryptococcus and Aspergillus infections in normal and immunosuppressed mice

Prophylactic treatment with human granulocyte colony-stimulating factor (hG-CSF) affords significant protection against systemic aspergillosis or pulmonary aspergillosis in neutropenic (cyclophosphamide-treated) mice but not in cortisone-treated animals. Cryptococcosis does not respond to hG-CSF therapy. Our data show that granulocytes play an important role in the immune defense against aspergillosis, but not against cryptococcosis. Combined treatment using hG-CSF and conventional antimycotics shows a significant beneficial effect in systemic or pulmonary aspergillosis.     

ANTITUMOR EFFECT OF GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR(GM-CSF)-GENE ENCODED VACCINIA MELANOMA ONCOLYSATE AND ITS IMMUNOLOGICAL MECHANISMS

ＡＮＴＩＴＵＭＯＲＥＦＦＥＣＴＯＦＧＲＡＮＵＬＯＣＹＴＥＭＡＣＲＯＰＨＡＧＥＣＯＬＯＮＹＳＴＩＭＵＬＡＴＩＮＧＦＡＣＴＯＲ（ＧＭＣＳＦ）ＧＥＮＥＥＮＣＯＤＥＤＶＡＣＣＩＮＩＡＭＥＬＡＮＯＭＡＯＮＣＯＬＹＳＡＴＥＡＮＤＩＴＳＩＭＭＵＮＯＬＯＧＩ...     

大剂量粒系集落刺激因子使老年急性髓系白血病患者受益

目的 探讨老年急性髓系白血病（AML）化疗期间预防性大剂量（>5 μg/kg）和标准剂量（5 μg/kg）使用G-CSF对感染、输血情况的影响。方法 回顾性对比分析82例老年AML 273个化疗周期中两组G-CSF进行支持治疗中抗生素和抗真菌药物使用情况、发热天数、发热程度、粒缺时间、输血情况等。结果 273个化疗周期中合并感染223次（81.7%）,因感染中断治疗11例（13.4%）;标准剂量组中2例（2.3%）患者在诱导治疗期间死亡。亚组分析发现,大剂量组可明显缩短巩固治疗期间粒缺时间、发热天数及减少抗真菌药物的使用。结论 大剂量G-CSF可提高老年AML患者化疗期间的安全性、耐受性。     

Synthesis by mouse peritoneal cells of G-CSF, the differentiation inducer for myeloid leukemia cells: stimulation by endotoxin, M-CSF and multi-CSF

Normal C57BL mouse peritoneal cells were able to synthesize material with the ability to induce differentiation in colonies of the mouse myelomonocytic leukemia cell line, WEHI-3B. The active factor was provisionally identified biochemically as the normal regulator, granulocyte colony-stimulating factor, G-CSF. Thioglycollate-induced peritoneal exudate cells had little or no capacity to synthesize such material. Production of active material was elevated 10-100-fold by exposure of peritoneal cells to endotoxin, detectable elevations being observed after the addition of as little as 0.8 ng/ml. Production of G-CSF was observed using adherent peritoneal macrophages, was a radioresistant process depending on protein synthesis and was not modified by the absence or addition of T-lymphocytes. Addition of unfractionated media containing M-CSF or Multi-CSF, partially purified M-CSF or fully purified Multi-CSF elevated the production of G-CSF by peritoneal cells from both C57BL mice and mice of the endotoxin-unresponsive strain C3H/HeJ, but an involvement of endotoxin in this process could not be excluded absolutely. The experiments provide further evidence that microorganisms and perhaps hemopoietic regulators play an important role in modulating the production of G-CSF and thus have the potentiality to influence the emergence and progressive proliferation of myeloid leukemia populations.     

Granulocyte colony-stimulating factor (G-CSF)-mediated signaling regulates type IV collagenase activity in head and neck cancer cells

Granulocyte colony-stimulating factor (G-CSF), a hematopoietic cytokine, regulates the proliferation and differentiation of granulocytic progenitor cells and functionally activated mature neutrophils. G-CSF also affects nonhematopoietic tumor cells through its binding to the specific receptor (G-CSFR) on the cells. The type IV collagenase [matrix metalloproteinase 2 (MMP-2)] is known to play a main role in the process of invasion and metastasis, but its regulation, for example, in expression or in activation, is not clearly understood. In this study, we investigated the role of G-CSF in the regulation of tumor cell invasion and the synthesis of MMP-2. G-CSFs producing the head and neck carcinoma cell line T3M-1 cells with metastatic ability and no G-CSF receptor (G-CSFR) expression were transfected with G-CSFR expression vector. In vitro treatment of G-CSFR-transfectant T3M-1 cells with recombinant G-CSF (rG-CSF) significantly augmented their invasive potential in a reconstituted basement membrane (Matrigel) system compared with that of parental cells. Moreover, MMP-2 activity of G-CSFR-transfectant T3M-1 cells was enhanced by the stimulation with rG-CSF, as assessed by gelatin zymography. These results identify G-CSF as a regulator of MMP-2 and cellular invasion.     

A single-blind, randomised, vehicle-controlled dose-finding study of recombinant human granulocyte colony-stimulating factor (lenograstim) in patients undergoing chemotherapy for solid cancers and lymphoma

This study evaluated the effect of glycosylated recombinant human granulocyte colony-stimulating factor (rHuGCSF; lenograstim) on neutrophil granulocyte counts and on cells of other haematopoietic lineages in 66 patients with solid cancer or lymphoma who received myelosuppressive chemotherapy. Beginning 1 day after completion of chemotherapy, patients received lenograstim (at dosages of 0.5, 2, 5 or 10 μ/kg) or vehicle subcutaneously once daily for 14 consecutive days. Compared with vehicle, lenograstim significantly accelerated neutrophil recovery after chemotherapy in a dose-dependent manner. Mean neutrophil counts recovered to > 1.0 × 10⁹ cells/l by day 13 in the vehicle group compared with days 11, 10, 8 and 7 in the 0.5, 2, 5 and 10 μg/kg lenograstim groups, respectively. Doses of 0.5 and 2 μg/kg of lenograstim had a significant effect on the duration of neutropenia (< 1.0 × 10⁹ cells/l), the area under the absolute neutrophil count (ANC) curve and the time to ANC nadir. The dose of 5 μg/kg additionally decreased the total area of neutropenia and gave the narrowest range of values for all neutrophil parameters, while the 10 μg/kg dose brought no added benefit. A dose-response effect of lenograstim on time to neutrophil recovery was observed both for patients who received chemotherapy on a single day (n = 35) and for those who received chemotherapy over several days (n = 29). Based on these findings, a dose of 5 μg/kg/day was chosen for further trials.     

干细胞动员时提前应用粒系集落刺激因子对患者发热及感染的影响

背景与目的：造血干细胞移植一直被广泛应用于恶性肿瘤和恶性血液系统疾病的治疗,甚至在一些良性疾患中也有应用,如再生障碍性贫血等。造血干细胞的动员也同样被广泛应用。由于移植过程中的高风险,任何能够增加造血干细胞的回收率和简化造血干细胞采集的方法都有望提高造血干细胞移植的成功率。因此本文研究旨在观察提前给予粒系集落刺激因子（在白细胞介于1×10^9-2×10^9/L时）,是否影响干细胞采集的数量和患者感染、发热的发生率。方法：对70例恶性肿瘤患者按随机单双号顺序进入A组和B组。全部患者给予环磷酰胺4 g/m2化疗,分别在白细胞≤1×10^9/L后（A组）和介于1×10^9-2×10^9/L（B组）时,皮下注射粒系集落刺激因子（惠尔血）5μg/kg。在白细胞回升至2×10^9/L以上时,分2-3次采集外周血造血干细胞,同时计数单个核细胞和CD34＋细胞数量。结果：A组采集单个核细胞数量平均为4.34×10^8/kg;B组为3.8×10^8/kg（P〉0.75）。CD34＋细胞A组为2.62×10^6/kg;B组为2.97×10^6/kg（P〉0.9）。感染、发热的发生率A组为18/33;B组为8/35（P〈0.01）。结论：提前给予粒系集落刺激因子（G-CSF）不会影响外周血造血干细胞采集的数量,而发热和感染的发生率却显著降低。     

STAT3介导G-CSF对原代APL细胞增殖的调控作用

目的探讨全反式维甲酸(ATRA)诱导后,白细胞介素(IL)-1β和粒细胞集落刺激因子(G-CSF)对原代急性早幼粒细胞白血病(APL)细胞增殖调控的信号传导因子。方法采用酶联免疫吸附试验(ELISA)法测定原代APL细胞培养上清中IL-1β和G-CSF水平的变化,逆转录-聚合酶链反应(RT-PCR)方法测定IL-1β和G-CSF mRNA表达水平。Western blot测定信号转导和转录激活因子(STAT)1α和STAT3表达水平变化。结果ATRA治疗后APL患者外周血白细胞明显升高,平均12天达到高峰,并且以中晚幼粒细胞为主。ATRA治疗后7天和高峰期的APL细胞体外培养24h后,IL-1β( P＜0．05)和G-CSF(P＜0．05)分泌水平显著升高。RT-PCR结果表明分泌IL-1β和(或)G-CSF升高的原代APL细胞,IL-1β和(或)G-CSF mRNA表达升高。所有患者原代APL细胞的STAT1α蛋白表达均升高,与IL-1β或G-CSF的表达无关。但STAT3的升高却与G-CSF表达和分泌水平变化相一致。结论ATRA诱导高表达的G-CSF,通过STAT3发挥对原代APL细胞的调节作用。     

重组人粒细胞集落刺激因子预防乳腺癌化疗后骨髓抑制的疗效分析

背景与目的：骨髓抑制是化疗最严重的不良反应,以中性粒细胞减少最常见。重组人粒细胞集落刺激因子(recombinant human granulocyte colony-stimulating factor,rhG-CSF)能诱导造血祖细胞向中性粒细胞分化,并调节中性粒细胞的功能活性,可用于肿瘤化疗后严重的中性粒细胞缺乏症,以保证原计划化疗方案的完成。本文旨在了解应用rhG-CSF治疗乳腺癌化疗后骨髓抑制的疗效以及预防性作用。方法：采用回顾性调查方法,筛选出在天津医科大学肿瘤医院进行多西紫杉醇(docetaxel)75 mg/m²、表柔比星(epirubicin) 65 mg/m²与环磷酰胺(cyclophosphamide)500 mg/m²(TEC)化疗方案的浸润性乳腺癌患者,在第1个周期末次给药后24~48 h内给予rhG-CSF为预防组,以24~48 h内未给予rhG-CSF为对照组,评估2组化疗后骨髓抑制的发生情况以及用药的安全性。结果：在预防组60例患者中,外周血白细胞(white blood cell,WBC)＜4.0×10⁹/L的发生率为25.0%,中性粒细胞绝对数(absolute neutrophil count,ANC)＜2.0×10⁹/L的发生率为23.3%;在对照组60例患者中,WBC＜4.0×10⁹/L的发生率为78.3%,ANC＜2.0×10⁹/L的发生率为73.3%,差异有统计学意义(P＜0.01)。2组的化疗延迟率分别为5.0%和25.0%(P=0.002),化疗延迟时间分别为(2.33±0.58)d和(3.73±0.80)d(P=0.011),差异均有统计学意义。预防组发热性中性粒细胞减少症(febrile neutropenia,FN)的发生率为1.7%,对照组FN的发生率为20%,预防组明显低于对照组(P=0.001)。2组对血红蛋白(hemoglobin,Hb)与血小板(platelets,PLT)水平均无显著影响(P=0.547;P=0.285)。预防组rhG-CSF用药后不良反应的发生率为8.3%,而对照组为21.6%,差异有统计学意义(P=0.041)。结论：对于浸润性乳腺癌患者,在第一周期化疗后24~48 h内预防性给予rhG-CSF,能降低白细胞减少症的发生,减轻骨髓抑制的程度及持续时间,降低FN的发生风险,并且能减少rhG-CSF用药不良反应的发生。     

Clinical effect of granulocyte colony-stimulating factor on neutrophils and leukemic cells in myelogenous leukemia: analysis.

Clinical experiences with recombinant granulocyte colony-stimulating factor (rhG-CSF) in 13 acute (AML) and four chronic (CML) myelogenous leukemia patients are reported. Sixteen patients received rhG-CSF in support of treatment for life threatening infections and one CML patient in support of induction chemotherapy. After their first induction chemotherapy, six out of eight AML patients showed a rapid increase of neutrophils, recovered from infections and achieved complete remission (CR). One patient, in whom both neutrophils and blasts had increased during rhG-CSF administration, achieved CR through the next administration of chemotherapy (CR rate 87.5%). The last of the eight AML patients showed no increase of neutrophils, and died of interstitial pneumonitis. Two of five AML patients who received rhG-CSF after reinduction chemotherapy for relapsed or refractory leukemia achieved CR, a rate of 40%. In one of the two, the administration of rhG-CSF prior to induction chemotherapy seemed advantageous in achieving CR. During rhG-CSF administration, an increase of blastic cells in peripheral blood was observed in four out of all 13 AML patients. One of three CML patients, with a lymphoid crisis, showed an increase only of neutrophils, and recovered from infection. The other two showed increases of both neutrophils and blasts. One patient with CML in blastic crisis, undergoing induction chemotherapy with rhG-CSF administration, returned to the chronic phase. These clinical experiences suggest rhG-CSF to be effective in supporting infection therapy and in possibly enhancing the sensitivity of myelogenous leukemic blasts to antileukemic agents.     

In vitro growth and clinical response of leukemia cells to macrophage colony-stimulating factor (M-CSF) and granulocyte colony-stimulating factor (G-CSF) in acute leukemia

The in vitro growth and clinical response of leukemia cells to macrophage colony-stimulating factor (M-CSF) and granulocyte colony-stimulating factor (G-CSF) were studied in 24 patients with acute leukemia. Among cases of acute myelogenous leukemia, a positive response to M-CSF (stimulation index > or = 2.5) was seen in 27.3% of the cases, and a significantly higher response rate (81.8%) was seen following G-CSF treatment of leukemia cells in vitro. In cases of acute monocytic leukemia, M-CSF showed a higher stimulating index than that observed for non-monocytic leukemia. G-CSF was administered in 19 cases and M-CSF in 5 cases after chemotherapy, and none of the patients showed leukemia cell proliferation in vivo. There was no correlation between in vitro test results and clinical response of leukemia cells to the CSFs administered.