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Biomedical subjects

K Havemann

Publications and source records attributed to K Havemann.

At least 73 records · Page 4Linked to original sources
PubMed1993

Granulocyte-monocyte colony-stimulating factor levels during hemodialysis-induced leukopenia.

Hemodialysis (HD), especially with cellulosic membranes, leads regularly to a transient but marked drop of peripheral neutrophils. Such neutropenia during the initial 10-30 min of HD is followed by a reincrease in granulocyte count up to a mild leukocytosis. Although this phenomenon accounts for the best documented side effect of HD, little is known about the underlying regulatory mechanisms. Therefore in this study the blood levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured during HD. Previous investigations have demonstrated that GM-CSF plays the central role in controlling the homeoiostasis of leukocytes by up- and downregulation of proliferation and efflux of cells out of the maturation compartment within the bone marrow. Three patients with chronic renal failure underwent HD with cuprophane membranes. In all cases a significant drop of peripheral granulocytes occurred, but GM-CSF levels remained unchanged and were found in the normal range during the whole period of the treatment. It is therefore concluded that GM-CSF may not be significantly involved in the regulation of peripheral leukocytes during HD.

Cellulose↗
PubMed1993

Protein S degradation in vitro by neutrophil elastase.

Human protein S is degraded by neutrophil elastase. The characteristics of cleavage are compared in a purified protein S preparation, a concentrate of vitamin K-dependent proteins (PPSB) and in normal plasma as well as in alpha-proteinase inhibitor (alpha PI)- deficient plasma. Elastase incubation of purified human protein S (molar enzyme-to-substrate-ratio 1:5500-1:55) reduces the molar mass of the native protein S (81-83 kDa) to about 79 kDa by cleavage of a small peptide. Incubation with very high elastase concentrations (molar enzyme-to-substrate-ratio 1:5.5) completely degrades protein S into small fragments. The elastase incubated protein S has a higher isoelectric point than the native form (Ip 5.9 vs. 5.3). Protein S in a PPSB coagulation factor concentrate is degraded in the same way as isolated protein S. By immunoblotting also smaller split products of molar masses between 34 and 70 kDa are demonstrated. In normal plasma protein S is not degraded by elastase concentrations up to 14 mumol l-1. In plasma of a patient with alpha 1-proteinase inhibitor deficiency protein S can be degraded by elastase. The native 82 kDa protein is degraded to a 72 kDa protein. PEG precipitation of the protein S- C4b- binding protein-complex shows that elastase predominantly splits the free protein S.

Blood Coagulation Factors↗
PubMed1993

Biochemical characterization of a novel autocrine transferrin-like growth factor in acute myeloblastic leukemia.

Serum-free conditioned media (CM) of acute myelogenous leukemia cell lines induce growth stimulation of other leukemic cell lines. A transferrin (Tf)-like iron binding kD 50 protein was found to be the main growth factor of these CM's. Purification and further characterization of this protein was performed by chromatographic methods, SDS-PAGE, peptide mapping and amino acid analysis. In addition m-RNA of leukemic cell lines was analysed by Northern blot analysis with oligonucleotide probes specific for human serum Tf and melanotransferrin (p97) respectively. No hybridization signals for these probes have been detected. Biochemical results show significant differences between human serum Tf and kD 50 growth factor with respect to retention time on reversed phase FPLC, pattern of digestion peptides in SDS-PAGE and amino acid composition, which suggests, that this protein is an additional tumor associated member of the transferrin superfamily.

Amino Acids↗
PubMed1993

Secretion of a latent, acid activatable cathepsin L precursor by human non-small cell lung cancer cell lines.

Secretion of pro-cathepsin L, the precursor of a lysosomal cysteine proteinase, has been described for ras-transfected mouse fibroblasts and several human cancer cell lines. The secretion of a latent but stable precursor might be a means for tumor cells to involve this proteinase in extracellular matrix breakdown. Since lung cancer is the leading cause of cancer death in the industrialized countries, we therefore studied the secretion of pro-cathepsin L in 11 human non-small cell lung cancer cell lines (EPLC 32M1, NCI H157, EPLC 272H, U1752, LCLC 103H, LCLC 97TM1, U 1810, NCI H661, NCI H23, NCI H125, and NCI H596) and 8 human small cell lung cancer cell lines (SCLC 22H, NCI H60, NCI H82, NCI H526, NCI H146, NCI H841, NCI H510, and DMS 79). Immunoblot analysis of cell conditioned media showed that latent pro-cathepsin L (M(r) 42 kDa) was secreted in all 11 non-small cell lung cancer cell lines. Three of these cell lines secreted an additional inactive form of cathepsin L of M(r) 24 kDa. In contrast, the 8 small cell lung cancer cell lines did not secrete any detectable cathepsin L-immunoreactive material. Phorbol-12-myristate-13-acetate increased the secretion of pro-cathepsin L in 6 of the non-small cell lung cancer cell lines. The cathepsin L precursor could be activated in vitro at pH 3, accompanied by a shift in molecular mass to 34 kDa. Chicken egg white cystatin prevented the acid activation. Specific antibodies against a synthetic peptide from the pro-sequence of cathepsin L reacted with the nonsmall cell lung cancer cathepsin L precursor. Extracellular pro-cathepsin L may be important in the tumor biology of non-small cell lung cancer and would be a good target for novel diagnostic and therapeutic approaches, since the majority of physiological lysosomal proteinases are contained in intracellular compartments only.

Adenocarcinoma↗
PubMed1993

Assay of complexed alpha 1-antichymotrypsin in plasma.

We introduce an assay to measure complexed alpha 1-antichymotrypsin in human plasma. The assay works on the principle that the target proteinase cathepsin G has a very high affinity to the surface of microtiter plates, even if these surfaces are blocked with albumin and Tween 20. alpha 1-Antichymotrypsin, when complexed to cathepsin G, is thus immobilized and can be detected with specific antibodies. The mean (SD) concentration of alpha 1-antichymotrypsin in 50 healthy individuals was 1.73 (0.58) nmol/L. The detection limit was 0.84 nmol/L. The results of the assay are linear to at least 14 nmol/L. We propose to use this assay for diseases in which increased turnover of alpha 1-antichymotrypsin or cathepsin G can be expected to clarify further the function of this enzyme-inhibitor system.

Adult↗
PubMed1992

Characterization of insulin-like growth factor I receptors and growth effects in human lung cancer cell lines.

Small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) cell lines were studied for insulin-like growth factor I (IGF-I) receptor expression and with regard to the influence of IGF-I on cell proliferation. IGF-I receptors on the cells were characterized by competitive binding assays, chemical crosslinking and northern blot hybridization of IGF-I receptor mRNA. All SCLC and NSCLC cell lines showed specific IGF-I binding sites with an affinity (KD) of 0.69-5.21 nM. The amount of binding sites ranged from 59 fmol/mg to 1230 fmol/mg protein. The IGF-I binding was inhibited by the IGF-I receptor antibody (alpha-IR-3). Northern blot hybridization indicated that IGF-I receptor mRNA was being produced by all SCLC and NSCLC cell lines. We used the soft-agarose clonogenic assay to evaluate the influence of IGF-I on the in vitro proliferation of the cells. Our results have shown that IGF-I stimulates the growth of all tested cell lines ranging from a factor of 1.6 to 4.2 in SCLC and from 1.1 to 2.7 in NSCLC. The data indicate that the IGF-I receptor thus appears to be the common pathway for the mitogenic activity of IGF-I and IGF-II with regard to human lung cancer cells.

Binding, Competitive↗
PubMed1992

Experience with GM-CSF in the treatment of solid tumors.

The efficiency of GM-CSF to reduce myelosuppression after chemotherapy depends on the schedule of administration and the dose of chemotherapy. If conventional chemotherapy doses are given, a seven to ten day administration starting one day after the end of chemotherapy is able to reduce both degree and duration of leucopenia. A later onset is less effective, an earlier one aggravates leuco- and thrombocytopenia. The reduction of myelosuppression is accompanied by a reduction of infection rates and hospitalisation of patients due to these complications. If high-dose chemotherapy is given, GM-CSF does not markedly affect nadir values for leuco- and thrombocytes, but still shortens the duration of leucopenia. This effect is consistently seen after the initial cycles of chemotherapy, but seems to be less pronounced in later cycles. Thus, the growth factor administration allows a treatment intensification mainly by shortening of treatment intervals. Whether these modifications will improve the prognosis of patients with solid tumors is currently being investigated in small cell lung cancer in a German multicenter randomized trial.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Differential expression of insulin-like growth factor binding proteins in human non-small cell lung cancer cell lines.

The possible expression and secretion of insulin-like growth factor binding proteins (IGFBPs) by non-small cell lung cancer (NSCLC) cell lines was investigated and compared with possible IGFBP expression by primary NSCLC tumours. Cells growing under serum-free conditions released binding proteins with apparent molecular masses of 26-43 kD when analysed by a ligand blotting method under non-reducing conditions. Additionally, northern blot analysis of total RNA from NSCLC cell lines and tumours was performed using cDNAs coding for each of IGFBP-1, IGFBP-2, and IGFBP-3. This analysis revealed expression of all three mRNAs to varying degrees by all cell lines. In contrast all primary tumours analysed expressed predominantly IGFBP-2 and IGFBP-3 and none showed any evident expression of IGFBP-1. Both NSCLC cell lines and tumours synthesise IGFBPs but the pattern of expression differs significantly between cell lines and primary tumours.

Blotting, Northern↗
PubMed1992

Adrenal masses in lung cancer: sonographic diagnosis and follow-up.

Ultrasound has become an important diagnostic modality in the staging of patients with lung cancer. Between 1980 and 1990, 410 patients with histologically proved lung cancer were evaluated. In 44 patients (11%) an adrenal mass was discovered on ultrasound; in 13 patients it was isolated, and in 31 further evidence of abdominal disease was shown. Sonographic follow-up examinations of adrenal masses showed changes of size in all but 2 patients, and were therefore found to be adrenal metastases. In the 2 patients with isolated and stable adrenal disease, fine-needle biopsy revealed adenomas. Adrenal masses in patients with lung cancer are more likely to be metastatic than benign. The existence of neoplastic adrenal disease can be retrospectively confirmed by changes of size during sonographic follow-up examinations in almost all patients. Histologically verification would only appear necessary in stable adrenal disease and in cases with isolated adrenal disease in which prompt diagnosis affects treatment decision.

Adrenal Gland Neoplasms↗
PubMed1992

Preclinical and clinical experience with cisplatin and carboplatin and simultaneous radiation in non-small cell lung cancer.

Preclinical experiments with cisplatin and carboplatin showed radiosensitizing capability for these drugs against non-small cell lung cancer (NSCLC) cell lines and phase II clinical investigations were undertaken in patients with stage IIIA/B NSCLC. In the first trial, cisplatin 20 mg/m2 was infused on the first day of every treatment week, followed in about 1 hour by radiotherapy. Radiotherapy was given in single daily 2-Gy doses 5 days a week for 3 weeks, and, after a 2-week interval, for an additional 2 weeks. There were 5 complete responses (CRs) and 15 partial responses (PRs), while 6 patients had no change and 4 progressive disease, for a 67% overall response. Median survival was 14 months; the 2-year survival rate was 20%. To investigate the maximum tolerated dose of carboplatin, escalating doses were given on day 1 of each treatment week; simultaneous radiotherapy was administered as in the cisplatin study. Drug doses began at 100 mg/m2 and were increased by increments of 10 or 20 mg/m2 to a maximum of 200 mg/m2, with 5 patients treated at each dose level. Dose escalation was to stop when 3 of 5 patients developed intolerable World Health Organization (WHO) grade 3 myelosuppression. No grade 3 or 4 leukopenia occurred at carboplatin doses less than or equal to 140 mg/m2. Grade 3 leukopenia was seen in only 1 patient from the groups receiving 150, 160, or 180 mg/m2. Of the 35 patients evaluable thus far, 1 achieved CR and 18 PR, while 10 had no change and 6 progressive disease despite treatment, for a 54% overall response rate. Response rate in patients with stage IIIB disease was 48%.(ABSTRACT TRUNCATED AT 250 WORDS)

Carboplatin↗
PubMed1992

Felty's syndrome: favorable response to granulocyte-macrophage colony-stimulating factor in the acute phase.

We report a case of Felty's syndrome in which infectious complications due to severe neutropenia could be overcome by short-term treatment with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF, 7 micrograms/kg/day s.c.). Leukocyte counts rose from 1,050/mm3 at presentation to 4,470/mm3 after 15 days of treatment. A flare-up of arthritis was not noted. Defects in granulocyte function and clinical improvement prior to leukocyte rise suggest that the beneficial effect of GM-CSF is mainly due to an improvement of granulocyte function.

Acute Disease↗
PubMed1992

Carboplatin and simultaneous radiation in the treatment of stage IIIA/B non-small cell lung cancer.

The radiosensitizing properties of carboplatin were investigated in preclinical and clinical studies. In human non-small cell lung cancer (NSCLC) cell lines (EPLC 65 H and LCLC 97 TM1) combined carboplatin and radiation therapy was superior to chemotherapy or radiotherapy alone, indicating the existence of additive effects for both treatment modalities. In a subsequent clinical phase II trial, escalating doses of carboplatin were given concurrently with radiation to patients with stage IIIA/B NSCLC. Radiotherapy was given in daily doses of 2 Gy, 5 days a week, during weeks 1-3 and 6 and 7. Carboplatin was given on day 1 in weeks 1-3 and 6 and 7. The starting dose level was 100 mg/m2, followed by dose escalations to 120, 130, 140, 150, 160, 180, and 200 mg/m2. Five patients were to be treated at each dose level until intolerable toxicity (World Health Organization grade 3 or 4 leukopenia) occurred in 3 of the 5. To date, 34 patients have been entered into the study. Toxicity was mild and, even at the 180-mg/m2 dose level, no severe myelosuppression was observed. Thus, the maximum tolerated dose of carboplatin has not yet been reached. Preliminary analysis of response and survival shows an overall response rate of 53% and a median survival of 10 months. Patients receiving higher carboplatin doses (140-160 mg/m2) survived longer than patients who received lower doses (100-130 mg/m2). These preliminary results indicate that combination carboplatin and radiation therapy is a well-tolerated, active regimen in patients with locally advanced NSCLC. Splitting carboplatin administration may reduce its hematologic toxicity.

Carboplatin↗
PubMed1992

Hemophan versus hemophan--a philippic against the suggestion of constant membrane quality.

All statements referring to biocompatibility of dialyzers depend on the suggestion of a constant and reproducible structure of the investigated membrane material. The data presented here strike this concepts in case of hemophane. Two commercially available hemophane dialyzers, the GF MC 120 (Gambro) and the MO 450 (SMAD) membranes, were compared. Significant differences could be seen in the induction of leukopenia and leukocyte sequestration reaction within patients lungs, but also in capacity to influence granulocyte oxidative metabolism and release of granular enzymes. According to these data it seems questionable whether hemophane is a membrane material with constant structure and quality normally expected for products bearing trade names. Excluding other differences (like surface-area or sterilization method) variable amounts of DEAE substituents and/or an inconstant distribution of the DEAE groups within the membranes may be the most possible reason responsible for the differences found. The study underlines the urgent need of an exact physico-chemical characterization of dialyzer membranes and is therefore a challenge for free publication of such basic data by the producers.

Biocompatible Materials↗
PubMed1992

Regulation of neutrophil functions by elastase-generated IgG fragments.

IgG is split by neutrophil elastase into Fc and Fab fragments. These IgG fragments influence the functions of stimulated neutrophils such as chemotaxis, oxidative burst, and enzyme release. FMLP stimulated leukocyte chemotaxis is specifically inhibited by the elastase generated Fc fragments. Seven nmol Fc/10(6) PMN totally inhibit the chemotaxis stimulated by 16 to 125 nM FMLP. Native IgG and Fab fragments show no effect. FMLP-stimulated superoxide anion generation is specifically inhibited by Fc fragments with half maximal inhibition by 1.2 nmol/10(6) PMN. The generation of hydrogen peroxide is concomitantly stimulated, resulting in a superoxide dismutase-like effect. FMLP-stimulated elastase and myeloperoxidase release are enhanced by Fab fragments (10 nmol/10(6) PMN) to 206 and 155%, respectively, of reference values by 25 nM FMLP, while Fc and native IgG stimulate to a less extent. Consequently, elastase-generated Fc fragments have an inhibitory effect on inflammation by reducing chemotaxis and oxidative burst of stimulated neutrophils. The release stimulating activity of Fab fragments results in an up-regulation of elastase induced IgG degradation.

Chemotaxis, Leukocyte↗