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PubMed1989

Hematopoietic responses in patients with advanced malignancy treated with recombinant human granulocyte-macrophage colony-stimulating factor.

The in vivo effect of yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor (rh GM-CSF) was investigated in 30 patients with advanced malignancy in a phase Ib trial. Patients were treated at four different dose levels (120 to 1,000 micrograms/m2/d) by either daily intravenous (IV) bolus injection or 24-hour continuous infusion. Administration of rh GM-CSF resulted in a broad spectrum of dose- and schedule-dependent hematopoietic effects. Sustained infusion of rh GM-CSF elicited a maximum 17-fold average peak increase of the total WBC count with mainly neutrophils, eosinophils, and monocytes accounting for this rise, and increases in bone marrow cellularity with a shift to immature myeloid elements. Elevation of lymphocytes, platelets, and reticulocytes was not induced. Within five days after discontinuation of treatment the leukocytosis had disappeared. Adverse reactions encountered with rh GM-CSF seen in 65% of the patients studied were never life-threatening and always rapidly reversible. They included mild myalgias, facial flushing, low-grade fever, headache, bone discomfort, nausea, dyspnea, and transient decline of platelet counts. These results suggest that rh GM-CSF can be safely administered at the doses and schedules used and that it can induce in vivo some of the biological effects reported in in vitro studies. Although no objective antitumour responses have been seen, the ability of rh GM-CSF to increase number and function of leukocytes in vivo may prevent neutropenia and infections when GM-CSF is added to cytotoxic cancer therapy.

Adolescent↗
PubMed1991

In vitro functions of neutrophils induced by treatment with rhG-CSF in severe congenital neutropenia.

Neutrophils (and monocytes) from 5 patients suffering from severe congenital neutropenia (SCN) were investigated in vitro after induction of this cell type by treatment with recombinant human granulocyte colony-stimulating factor (rh G-CSF) in vivo. Some abnormal morphological features were seen, such as anomalies of nuclei of phagocytes. No limitations were found 1) in the ability of neutrophils and monocytes to produce reactive oxygen intermediates (ROI) following stimulation with phorbol-myristate-acetate (PMA), 2) in the ability of neutrophils to phagocytose particles of zymosan A and to produce ROI simultaneously and 3) in the ability to kill bacteria of the species staphylococcus aureus. However the specific migration of neutrophils in a gradient of FMLP under soft agar was decreased to approximately 50% in all patients tested as compared to healthy controls. In addition, spontaneous motility was decreased in one patient. Nevertheless, the good clinical improvements of patients suffering from SCN after treatment with rh G-CSF appeared to be due to induction of neutrophils displaying overall good functional activities with respect to natural defense.

Blood Bactericidal Activity↗
PubMed1986

Biologic properties in vitro of a recombinant human granulocyte-macrophage colony-stimulating factor.

Recombinant human granulocyte-macrophage colony-stimulating factor (rH GM-CSF) was purified to homogeneity from medium conditioned by COS cells transfected with a cloned human GM-CSF cDNA and shown to be an effective proliferative stimulus in human marrow cultures for GM and eosinophil colony formation. The specific activity of purified rH GM-CSF in human marrow cultures was calculated to be at least 4 X 10(7) U/mg protein. Clone transfer experiments showed that this proliferation was due to direct stimulation of responding clonogenic cells. Acting alone, rH GM-CSF did not stimulate erythroid colony formation, but in combination with erythropoietin, increased erythroid and multipotential colony formation in cultures of peripheral blood cells. rH GM-CSF had no proliferative effects on adult or fetal murine hematopoietic cells, did not induce differentiation in murine myelomonocytic WEHI-3B cells, and was unable to stimulate the survival or proliferation of murine hematopoietic cell lines dependent on murine multi-CSF (IL 3). rH GM-CSF stimulated antibody-dependent cytolysis of tumor cells by both mature human neutrophils and eosinophils and increased eosinophil autofluorescence and phagocytosis by neutrophils. From a comparison of these effects with those of semipurified preparations of human CSF alpha and -beta, it was concluded that rH GM-CSF exhibited all the biologic activities previously noted for CSF alpha.

Animals↗
PubMed1987

Immunomodulatory and immunotherapeutic properties of recombinant gamma-interferon and recombinant tumor necrosis factor in mice.

These studies were designed to examine the immunodulatory and immunotherapeutic properties of recombinant murine interferon gamma (rM IFN-gamma) and recombinant human tumor necrosis factor (rH TNF). We report that rM IFN-gamma activated murine natural killer cells and macrophages in a dose-dependent manner in vivo. The rM IFN-gamma, which demonstrated a bell-shaped therapeutic response curve, must be administered at specific doses and schedules to produce optimal therapeutic activity. Optimal activity was observed after i.v. administration of 50,000 U/animal rM IFN-gamma three times per week. In contrast, rH TNF produced its major therapeutic activity in the treatment of metastatic disease after i.v. but not i.p. administration. The therapeutic effects of rH TNF were as great in these in vivo systems as those of rM IFN-gamma. Furthermore, rH TNF had additive therapeutic activity when administered in conjunction with suboptimal doses of rM IFN-gamma. Unlike rM IFN-gamma, rH TNF did not activate natural killer cells in vivo or in vitro but did augment in vivo and in vitro macrophage tumoricidal activity. It also had synergistic cytostatic properties with rM IFN-gamma for some murine tumor cell lines in vitro. High levels of rH TNF were readily detected in the serum with a half-life of approximately 30 min after i.v. administration. In contrast, only minimal serum TNF activity occurred after i.p. administration, suggesting that i.v. administration may more efficiently facilitate systemic therapeutic activity. In summary, rH TNF and rM IFN-gamma have therapeutic activity for metastatic disease as individual agents and additive therapeutic activity when used in combination. Furthermore, it appears that in addition to therapeutic potential as cytostatic agents, the immunomodulatory properties of rH TNF have a role in its therapeutic properties.

Animals↗
PubMed1983

[Successes and failures in rhesus-prophylaxis].

The medical history of hemolytic disease of the newborn (h. d. n.) due to Rh is reviewed from 1928-1963 and a very common and widespread error in the international literature on statistical data of h. d. n. has been critically analysed and corrected on the basis of the Viennese material over a period of 25 years. It is shown the first time that the morbidity is not as high as 6 to 7 in 1000 newborns but approximately 3 to 4 taking into account the origin of their mothers. The frequency of h. d. n. in Vienna is strongly influenced by mothers who come from abroad with and without foreign citizenship. In 13,34% of h. d. n. the women produce Rh antibodies during pregnancy, and therefore the Rh prophylaxis given after birth is not able to prevent the immunization which means that 0,55 per thousand of the h. d. n. rate of 4,1 per thousand is caused by Rh antibodies developed intra graviditatem and 3,55 per thousand post partum. These figures are derived from observations between 1948 and 1971 in the Pre-Prophylaxis-Time. The success of the Anti-D-IgG application dropped the h. d. n. rate from 4,1 per thousand to 1,7 per thousand in 1981. If the figure of 0,55 per thousand is taken into account as a wrong "failure" of the post partum prophylaxis, 1,15 per thousand (1,7-0,55) of h. d. n. have to be noted as true failures. There are many causes possible for the high rate of failure in the post partum prophylaxis which is to be eliminated before one could think of a systematic ante partum Rh prophylaxis. In our population 17% are Rh negative, 10% of all mothers are Rh negative giving birth to a Rh positive child and 3,5 per thousand of mothers of h. d. n. develop Rh antibodies post partum, 0,55 per thousand before. Out of 1000 Anti-D-IgG injections given after birth 965 are without any consequence and therefore only 35 are effective. Making use of the ante partum prophylaxis (mother Rh negative, baby's Rh factor unknown) 17% of all pregnant women have to be treated for prevention of only 0,55 per thousand h. d. n. and only 3 injections of 1000 Anti-D-doses are of preventive value whereas 997 are useless.

Austria↗
PubMed1990

Tumor necrosis factor in advanced colorectal cancer: a phase II study. A trial of the phase I/II study group of the Association for Medical Oncology of the German Cancer Society.

In a phase II study, the efficacy and toxicity of human recombinant tumor necrosis factor (rh TNF-alpha) were evaluated in patients with advanced colorectal carcinoma. Rh TNF-alpha was given as short term infusion at a dose of 3 x 10(5) U/m2 on three successive days. Treatment was repeated after a two week interval. The response was evaluated after four treatment cycles. In 15 patients entering the study, we found one partial response, one stable disease, 9 progressive diseases, and four patients who were not evaluable for tumor remission. There were numerous side effects of the treatment, mainly fever, chills, loss of appetite, leukopenia, and hepatotoxicity. In this regimen, rh TNF-alpha does not suggest a therapeutic advantage for treatment of advanced colorectal carcinoma.

Adenocarcinoma↗
PubMed1990

Tumor necrosis factor induces necrosis of human carcinoma xenografts in the presence of tricyclodecan-9-yl-xanthogenate and lauric acid.

Recombinant human tumor necrosis factor (rh TNF) when administered intravenously together with the phospholipase C inhibitor tricyclodecan-9-yl-xanthogenate (D609) and lauric acid (C12), leads to the partial regression of various human tumor transplants in athymic mice. Extensive necrosis occurred after a single intravenous infusion, with no detectable side effects. TNF-mediated cytotoxicity was found to be correlated with the depletion of energy in HeLa cells. The activity of rh TNF was enhanced by the absence of glucose, while it was reduced by addition of extraneous ATP. In the presence of rh TNF, D609, and C12, cellular energy metabolism was almost completely switched to glycolysis. Under these conditions the cytocidal activity of rh TNF on HeLa cells was amplified at least 60-fold.

Animals↗
PubMed1993

Evaluation of opsonophagocytic dysfunctions in severely burned patients by luminol-dependent chemiluminescence.

We compared the luminol-dependent chemiluminescence (CL) response of peripheral blood from severely burned patients with that from normal controls to evaluate the primary defense level against bacterial infection in the patients. The CL was measured upon addition to diluted whole blood of a soluble stimulus, phorbol myristate acetate (PMA) or particulate stimuli such as bacteria or zymosan without special opsonization. In the early post-burn days, the initial rate of whole blood CL induced with the particulate stimulus was much lower than that in the normal controls, whereas the rate was higher when PMA was used as a stimulus. The number of granulocytes in the patients' blood had increased and isolated polymorphonuclear leukocytes (PMNs) from the patients exhibited higher CL responses to the particulate or soluble stimulus as compared with those of normal controls. The results suggest that the PMNs in burn patients were activated and normally mobilized in the early post-burn period but the opsonizing capacity in the blood decreased. In fact, the serum levels of complement, immunoglobulins and fibronectin were found to be lower in the blood from the patients than those from normal controls and a supplement of freshly frozen plasma of human immunoglobulin preparations restored the initial rate of the whole blood CL upon phagocytosis. The prognosis is still poor when severe infection occurs in the patients with decreased CL response of whole blood. Recombinant human granulocyte colony-stimulating factor (rh G-CSF) enhanced the CL response of PMNs from burn patients. The administration of rhG-CSF may be useful for decreasing the morbidity of severe infection following burn injury in the near future.

Adolescent↗
PubMed1978

Genetics in keratoconus: A, B, O blood groups.

A, B, O blood group frequencies and Rh factors were studied in 69 white keratoconus patients and compared with 1,465 healthy white individuals. We did not detect a significant excess of any particular blood group among keratoconus patients. It was concluded that blood groups were not associated with keratoconus.

ABO Blood-Group System↗
PubMed1992

Glucose depletion enhances the anti-tumor effect of TNF.

Treatment of human carcinoma xenotransplants in athymic mice with recombinant human tumor necrosis factor (rh TNF) causes necrosis mainly in the central parts of the tumors, while peripheral sections remain mitotically active. As tumors are known to be supplied with adequate glucose exclusively in their periphery, the influence of the lack of glucose on the cytotoxic activity of rh TNF was studied. The absence of glucose enhanced the killing of tumor cell lines by rh TNF in tissue culture. Meth-A, a cell line known to be resistant to TNF in vitro but highly sensitive to it in vivo, was readily killed in tissue-culture medium lacking glucose. All non-transformed cell lines tested were found to be resistant to rh TNF, regardless of the presence or absence of glucose. In tumor-bearing mice a reduction of the blood glucose content augmented by insulin led to increased anti-tumor efficiency of rh TNF. The enhanced anti-tumor activity was reflected both in histological sections of the tumor xenotransplants, by extensive central necroses, and by reduction of the tumor volumes.

Animals↗
PubMed1994

A phase I/II trial of recombinant human granulocyte-macrophage colony-stimulating factor in the intensification of cisplatin and cyclophosphamide chemotherapy for advanced ovarian cancer.

A pilot study was undertaken in eight patients to assess the feasibility of recombinant human granulocyte-macrophage colony-stimulating factor (rH GM-CSF) support to intensify standard chemotherapy for advanced ovarian cancer using a shortened 15 day treatment interval. Only four patients completed the course of six cycles of cisplatin 75 mg m-2 and cyclophosphamide 750 mg m-2 with rH GM-CSF, 3-5 micrograms kg-1 day-1, days 3-14, but one of these suffered a toxic death on study. Another died of disease progression. There were two episodes of life-threatening infection (WHO grade 4), and three patients were withdrawn because of various rH GM-CSF-related problems. Although potentially affording some patients the hypothetical benefits of dose intensification, as well as the possible attraction of a shorter duration of chemotherapy, this regimen is not without problems.

Adenocarcinoma↗
PubMed1978

A linkage study of the loci for Huntington's disease and some common polymorphic markers.

The phenotypic frequencies of 24 polymorphic blood markers in a sample of patients with Huntington's disease (HD) have been compared with those in a sample of healthy Australian volunteers in an effort to detect any associations between HD and the markers concerned. The Rh factor, c, has a significantly lower frequency in the HD sample while ACP1c and Gm1,2 have a significantly higher frequency. The linkage relations of the HD locus have been analysed with respect to the various marker loci concerned. This analysis involved the development of methods to overcome the general lack of genetic data concerning the affected parent and the possibility that presently unaffected offspring may be asymptomatic carriers of the HD gene. The results suggest that close linkage between the HD locus and Fy, ADA, ACP1, Gc or Bg is highly unlikely. They also suggest a low probability of close linkage to ABO, Rh, Jk, Lu, AK1, PGM1 or C3. Positive linkage scores were obtained for P, Hp and Gm. The results are inconclusive for MNSs, K, Le, Se, GPT and Inv. The available data were uninformative for linkage between the HD locus and Co, 6-PGD or E1.

Australia↗
PubMed1991

[Prognostic parameters in peptic ulcer disease].

Tendency of peptic ulcer to frequent recurrence and spontaneous healing as to life-threatening complications are apart of the natural history of ulcer disease. In a retrospective study of 7 years, we examined 27 simple factors for their prognostic value by 218 patients suffering from ulcer disease which were diagnosed by fibroscopy. The interpretation with help multi analysis, the variant and discriminant analysis showed by patients with stomach ulcer that, the prognosis of the combination between renunciation of nicotine the begin of the disease until 30th years of the people, more than three foods daily, stomach cancer in the family, blood group A and left finger position would be suitable. The prognosis was better for patients with duodenal ulcer who have nicotine abstinence, childlessness negative history of the family with view to ulcer disease, blood group 0, positive Rh-factor and the working time.

Analysis of Variance↗
PubMed1990

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 micrograms/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 less than 1000/mm3) were significantly improved. No significant differences were seen in frequency and duration of febrile episodes (greater than 38 degrees 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 micrograms/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.

Adult↗
PubMed1988

Phase I clinical study for recombinant human granulocyte colony-stimulating factor.

The pharmacokinetics, the safety and the efficacy of purified recombinant human granulocyte colony-stimulating factor (rh G-CSF) expressed in Chinese hamster ovary (CHO) cells were studied in normal healthy adults. Following the single subcutaneous dose, G-CSF levels in sera elevated in a dose-dependent way, with C-max of approximately 140 pg per ml, T-max of 4 hours and T-half of 5 hours at a dose of 10 micrograms per ml. In accord with the elevation, blood neutrophil counts rose promptly and transiently without any changes in the other blood cell counts. Degree and duration of the neutrophilia were apparently proportional to the rh G-CSF dose and, in turn, the G-CSF levels in sera. Single daily injections of rh G-CSF at a dose of 10 micrograms per body per day for 7 consecutive days did not bring on any accumulation of rh G-CSF in sera, and repeatedly induced neutrophilias following every injection. During the course of the injections, the chemiluminescence generating ability of blood neutrophils also rose. Peak value of the transient neutrophilias and level of the abilities tended to go down after 3 or 4 consecutive injections, presumably due to the limited number of mature neutrophils which can be released from the bone marrow in response to rh G-CSF. However, it was found that the M/E ratio becomes higher after the repeated dosing with an increased proportion of myeloid immature cells as well as increase in the levels of both erythroid and myeloid precursor cells in the bone marrow.(ABSTRACT TRUNCATED AT 250 WORDS)

Colony-Forming Units Assay↗
PubMed1987

Toxicity of tumor necrosis factor is synergistic with gamma-interferon and can be reduced with cyclooxygenase inhibitors.

In recent studies, we have demonstrated that recombinant human tumor necrosis factor (rH TNF), as a single agent, has only minimal therapeutic activity for the treatment of metastatic disease, but when combined with recombinant murine gamma-interferon (rM gamma-IFN), we observed significantly more therapeutic activity than when either agent was administered alone. However, this combination also resulted in increased toxicity. Thus, we undertook a systematic toxicologic study of rH TNF alone or in combination with rM gamma-IFN. Briefly, the toxicity was similar to the generalized Shwartzman's reaction seen during endotoxin shock, with multifocal microthrombi and ischemic necrosis as sequelae. Lesions were observed in the lungs, liver, gastrointestinal tract (preferentially in the duodenum and cecum), testes or uterus, and bone marrow. Our results suggest that TNF (either directly administered or induced in situ) and its induction of arachidonic acid metabolites form one element of toxicity in this model. This conclusion is supported by studies revealing that the toxicity of rH TNF in combination with rM gamma-IFN can be reduced by inhibitors of the cyclooxygenase/lipoxygenase pathway.

Animals↗
PubMed1991

Recombinant human granulocyte-macrophage colony-stimulating factor promotes megakaryocyte maturation in nonhuman primates.

Megakaryocytes are responsive to several nonlineage-specific cytokines in vitro. In this study, we examined the in vivo effects of recombinant human granulocyte-macrophage colony-stimulating factor (rh GM-CSF) on late stages of megakaryocytopoiesis in the rhesus monkey. Four rhesus monkeys were given 10 micrograms/kg body weight/day of rh GM-CSF s.c. in two divided doses daily for 8 days. Megakaryocyte maturation was evaluated serially by measuring nuclear ploidy and cytoplasmic size. GM-CSF-treated monkeys developed significant shifts in ploidy distribution from days 3 through 15 (p less than or equal to 0.001), with increased frequencies of 64N and 128N megakaryocytes. Mean megakaryocyte size increased 92.5% on day 9, paralleling the increase in DNA content, although megakaryocyte size within ploidy groups did not increase. Megakaryocyte number remained unchanged following rh GM-CSF treatment. The platelet count responses were variable, and mean platelet volume did not change. The present study demonstrates that therapeutic doses of rh GM-CSF stimulate megakaryocyte endomitosis and increase mean size. The data indicate that GM-CSF is effective in promoting the maturation stage of megakaryocyte development but does not result in a consistent thrombopoietic response.

Animals↗