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Biomedical subjects

K Havemann

Publications and source records attributed to K Havemann.

At least 127 records · Page 7Linked to original sources
PubMed1989

Synthesis and secretion of plasminogen activators and plasminogen activator inhibitors in cell lines of different groups of human lung tumors.

Several human lung tumor cell lines derived from large cell, squamous cell, and small cell carcinomas, as well as from mesotheliomas of the lung have been investigated for their gene expression and secretion of urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitors 1 and 2. All bronchogenic non-small cell carcinoma-derived cell lines studied could produce either plasminogen activators, their inhibitors, or both components, whereas in small cell lung carcinoma cell lines and cell lines derived from mesothelioma of the lung, no substantial amounts of any of these substances were synthesized. In detail, a large cell carcinoma-derived cell line, LCLC 97TM1, constitutively secreted large amounts of plasminogen activator. Northern blot analysis revealed RNA specific for u-PA and t-PA. Another large cell carcinoma-derived cell line, LCLC 103H, secreted smaller amounts of plasminogen activator and, additionally, plasminogen activator inhibitor. Specific mRNAs for u-PA and plasminogen activator inhibitors 1 and 2 were found in this cell line. In contrast, squamous cell carcinoma-derived cell lines secreted plasminogen activator only after treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate; enhanced levels of u-PA, t-PA, and plasminogen activator inhibitor 1 mRNAs could then be demonstrated. The different expression of the plasminogen activator enzyme system distinguishes cell lines derived of non-small cell lung carcinoma from those of small cell lung carcinoma and may also reflect significant differences in the biological behavior of these tumor types.

Autoradiography↗
PubMed1989

Neurofibromatosis and acute monocytic leukemia in adults.

A patient with nonfamilial peripheral neurofibromatosis (NF) (von Recklinghausen's disease) is reported who contracted acute monocytic leukemia at 60 years of age. In the course of the illness, myelonecrosis developed and the patient died 4 months later due to a therapy-resistant bone marrow relapse. This association of the two illnesses would appear to confirm reports on an increased incidence of nonlymphatic leukemia and NF. Such an association is seen during childhood as juvenile chronic leukemia, but it is uncommon in adulthood.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Clinical relevance of histologic subtyping in small cell lung cancer.

Histopathologic specimens from 249 patients with small cell lung cancer (SCLC) were reviewed and classified into oat cell-type, pure intermediate cell-type (excluding specimens with mixed small cell/large cell features), and small cell/large cell-type. One hundred seventy (68%) specimens displayed oat cell features (including 30 with mixed oat cell/intermediate cell features), 66 (27%) displayed intermediate cell features, and 13 (5%) displayed mixed small cell/large cell features. No differences among these subtypes were found with respect to stage of disease, sex, age, performance status, and number and distribution of metastases. Complete and partial remission rates for the oat cell-type were, respectively, 31% and 38%, for the intermediate cell-type 20% and 45%, and for the small cell/large cell-type 38% and 31%. Two-year survival rates were 7%, 11%, and 15%, respectively. These data were all statistically insignificant, and comparisons of log-rank analyses of survival curves for these SCLC subtypes also showed no statistically significant differences. We thus conclude that histologic subtypes of SCLC are not distinct entities of clinical relevance, and that prognostic as well as therapeutic decisions cannot be based on histologic subtyping.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Androgen receptors, androgen-dependent proliferation, and 5 alpha-reductase activity of small-cell lung cancer cell lines.

We investigated the influence of testosterone on binding to established small-cell lung cancer (SCLC) cell lines and were able to show specific high-affinity and low-capacity binding sites in some cell lines with a typical receptor size, using sucrose density gradient centrifugation. In addition, we demonstrated marked growth stimulation with testosterone and dehydrotestosterone using different androgen-receptor-positive small-cell lung cancer cell lines. This growth stimulation could be counteracted by the addition of anti-androgens like cyproterone acetate or flutamide. The presence of 5 alpha-reductase activity, 17 beta-hydroxysteroid-dehydrogenase and 3 alpha-hydroxysteroid-dehydrogenase activities could be demonstrated, suggesting testosterone metabolism of small-cell lung cancer cell lines.

Androgen Antagonists↗
PubMed1989

Granulocyte-macrophage colony-stimulating factor binding sites and oxidative metabolism in human granulocytes.

We investigated the interaction between GM-CSF and its receptor on human granulocytes and on several human tumor cell lines. Specific high-affinity binding for GM-CSF was characterized by Scatchard plot analysis. The specific radioactivity of the 125I-labeled derivative of rH. GM-CSF was determined by self-displacement analysis and calculated to be 30 microCi/micrograms. The maximum concentration of binding sites (B max) in granulocytes was 40 fmol/mg protein (2,200 molecules GM-CSF bound/cell) and the dissociation constant (KD) was 0.42 nM. No binding sites for GM-CSF were found in two lung cancer cell lines, SCLC-16HV and NCI-N417 or in the urinary bladder carcinoma cell line 5637, whereas the promyelocytic leukemia cell line HL60 was positive for GM-CSF binding. Time course experiments showed maximum binding of GM-CSF in granulocytes after an incubation period of 60 min and a decrease in binding after an incubation period of 2 h. In parallel, we found a maximum biological signal when granulocytes were preincubated for 90 min with GM-CSF, and a decrease after an incubation time of 120 min. Preincubation of the cells with rH. GM-CSF induced an enhancement of the production of activated oxygen species by the cells in response to PMA.

Binding Sites↗
PubMed1989

Tetanus toxin as a marker for small-cell lung cancer cell lines.

Tetanus toxin labeling of human lung cancer cell lines was investigated using direct and indirect immunofluorescence and immunohistochemical staining. Cells of characterized permanent cell lines, eight small-cell lung cancer (SCLC) cell lines of classic subtype, six SCLC cell lines of variant subtype and seven non-small-cell lung cancer (NSCLC) cell lines, were incubated with a saturating concentration of tetanus toxin. For staining, fluorescein-isothiocyanate-(FITC)-conjugated anti-(tetanus toxin) antibodies were used or a mouse monoclonal anti-(fragment C) antibody with subsequent binding of FITC-conjugated anti-(mouse Ig) antibody or peroxidase-anti-peroxidase complex. Only SCLC showed an intense fluorescence/immunoreactivity restricted to the cell membrane. Quantitative analysis of tetanus toxin labeling by flow cytometry revealed the percentage of positive cells to be between 35% and 95% in SCLC without obvious differences between the classic and variant subtypes of SCLC. In NSCLC the percentage of positive cells was lower than 10%. These results demonstrate that SCLC in contrast to NSCLC can be labeled with tetanus toxin, emphasizing the neuroendocrine properties of this tumor, and that tetanus toxin labeling may become a useful diagnostic marker for SCLC cells in cytology.

Animals↗
PubMed1989

Production of insulin-like growth factor binding proteins by small-cell lung cancer cell lines.

Conditioned serum-free media (CM) from small-cell lung cancer (SCLC) cell lines were examined for the presence of insulin-like growth-factor-binding proteins (IGF-BP). 6/9 SCLC cell lines secreted binding proteins with high affinity for IGFs. When [125I]IGF-I or [125I]IGF-II was incubated with the CMs, complexes of tracer with proteins could be demonstrated by gel filtration, by precipitation with polyethylenglycol, and after adsorption of unbound tracer with activated charcoal. Analysis of binding data according to the method of Scatchard resulted in linear plots for IGF-I and IGF-II. The dissociation constants were determined to be 0.106 nM for IGF-I and 0.209 nM for IGF-II binding. Cross-linking of [125I]IGF-I or [125I]IGF-II to the CMs followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under nonreducing conditions revealed the presence of IGF-BPs with molecular masses in the range 24-32 kDa. The binding was competitively inhibited by addition of cold IGF-I and IGF-II but not by insulin. Northern blot hybridization with an IGF-BP cDNA probe encoding a low-molecular-weight IGF-BP from a human placenta cDNA library and Western blot analysis with a corresponding polyclonal antibody showed no expression of this gene. These data demonstrate that SCLC cell lines release IGF-BPs in culture supernatants, which differ from IGF-BPs detected in liver and placenta. These IGF-BPs might be important mediators in the autocrine/paracrine growth regulation of IGFs in SCLC.

Carcinoma, Small Cell↗
PubMed1989

The disturbance of hemostasis in septic shock: role of neutrophil elastase and thrombin, effects of antithrombin III and plasma substitution.

In 42 patients with septic shock, 29 of whom underwent substitution with antithrombin III concentrate and fresh frozen plasma for coagulation disorders, the proteinase-inhibitor complexes thrombin-antithrombin III and neutrophil elastase-alpha 1 proteinase inhibitor, were elevated on admission. On admission, the elastase complex was significantly higher in the patients receiving substitution (p = 0.0039), but at the endpoint it was higher in the non-survivors (p = 0.0040). The elastase decrease was confined to the substitution group with the thrombin complex decreasing in both groups. Initially the thrombin complex correlated with prothrombin times and factor XIII, while the elastase complex correlated with creatinine, thrombocyte count and prothrombin times in the late stages. Hemostatic disturbance, thrombin generation and neutrophil elastase release were favorably influenced by substitution. Furthermore, in this uncontrolled pilot study, the survival rate was higher in the treated (16 of 29) than in the untreated (1 of 13) patients, although the treated patients initially had pronounced hemostatic disturbances.

Adolescent↗
PubMed1989

High-dose chemotherapy with autologous bone marrow support in advanced malignant melanoma.

Eight patients with advanced malignant melanoma were treated with high-dose melphalan (80-90 mg/m2) and BCNU (600-800 mg/m2). In all patients autologous bone marrow preservation was performed prior to therapy. Bone marrow was stored for 48 h in a refrigerator at 10 degrees C and reinfused 48 h post-therapy. Three patients had a complete response (CR), 1 a partial response and 4 patients no response. Two patients with CR died 4 and 5 months after therapy. One had an interstitial pneumonitis and 1 patient died from unknown cause. The third patient had a relapse 12 months after therapy. Major side effects were severe nausea/vomiting and a mild mucositis. Two patients suffered from BCNU-related encephalopathy. All patients had a full hematologic reconstitution after 6 weeks. High-dose chemotherapy with autologous bone marrow support achieves a high response rate. Long-term disease-free survival, however, was not seen with this approach.

Adult↗
PubMed1989

Expression of p64c-myc and neuroendocrine properties define three subclasses of small cell lung cancer.

Twelve human small cell lung cancer (SCLC) cell lines and 6 non-SCLC cell lines were analysed with respect to expression of the c-myc, c-myb, and c-raf1 protooncogenes at the protein level. Analysis of p64c-myc protein expression in 12 SCLC cell lines resulted in the observation that it is present at high levels not only in cells with low, but also in those with moderate neuroendocrine differentiation. Neuroendocrine differentiation was based on parameters such as growth rate, colony formation, L-Dopa decarboxylase (DDC) activity, bombesin, and neurotensin described before. Surprisingly, in two cell lines with low neuroendocrine differentiation but without c-myc protein expression (SCLC-86M1 and NCI-H526) p75c-myb expression was observed which may therefore be able to substitute for the p64c-myc protein. Analysis of p74c-raf1 expression did not result in correlation with any growth or differentiation parameter since it was expressed at low levels in 11 out of 12 cases. We conclude that SCLC in vitro can be classified in three rather than two previously defined subclasses. In addition to the classic subclass with slow growth, high neuroendocrine differentiation, and absent or very low p64c-myc expression and the variant subclass with fast growth, absent to very low neuroendocrine differentiation, and high p64c-myc expression, we suggest a third subclass designated as transitional with moderate growth, moderate neuroendocrine differentiation, and high p64c-myc expression. Data on a small number of non-SCLC cell lines tested showed that high levels of p64c-myc correlate with high in vitro growth rates. This indicates that high p64c-myc levels may be associated with high proliferative activity, and lack of differentiation in lung cancer in general. The p74c-raf1 protein was found in all non-SCLC cell lines. Whether this classification of SCLC cell lines is applicable to SCLC in vivo remains to be determined.

Biomarkers, Tumor↗
PubMed1989

Experience of a German multicenter study group with ifosfamide in small cell lung cancer.

In three German multicenter randomized trials, which included 718 patients, the activity of ifosfamide in small cell lung cancer (SCLC) was tested. In study 1, IE (ifosfamide, 1.5 g/m2, days 1 through 5; etoposide, 120 mg/m2, days 3 through 5) alternating with CAV (cyclophosphamide, 600 mg/m2, days 1 and 2; doxorubicin, 50 mg/m2, day 1; vincristine, 2 mg, day 1) was compared with a response-oriented treatment with IE therapy up to maximum response and subsequently an immediate switch to CAV. After chemotherapy, patients with limited disease received chest irradiation with 45 Gy. Prophylactic cranial irradiation (30 Gy) was given to all patients who achieved complete response (CR). A total of 324 patients were evaluable. Total response rate (CR + partial response [PR]) was 75% v 78% for the two treatment groups; the CR rate was 29% for both groups. Survival was nearly identical in both arms, with a median survival of 10.0 months for all patients, 12.0 months for those with limited disease (LD), and 7.5 months for those with extensive disease (ED). The 2-year survival rate was 11%. In study 2, IE was compared with PE (cisplatin, 90 mg/m2, day 1; etoposide, 150 mg/m2, days 3 through 5). A total of 141 patients were evaluable. Total response (CR + PR) rate was 65% for PE and 68% for IE; the CR rate for PE was 32% v 20% for IE. Survival favored PE with a median survival of 11.6 months v 9.4 months for all patients, 14.8 months v 11.0 months for LD, and 8.9 months v 7.5 months for ED. Two-year survival rates were 12% v 9% for all patients, 23% v 10% for those with LD, and 5% v 9% for those with ED. From these trials, we conclude that IE is an active and well-tolerated regimen for SCLC, and that PE may be superior to IE in limited-stage disease. Taking these results into account, we modified our chemotherapy protocols in study 3 and compared IAV (ifosfamide, 2 g/m2, days 1 to 5; doxorubicin, 25 mg/m2, days 1 and 2; vincristine, 2 mg, day 1) alternating with either PE or JE (carboplatin, 300 mg/m2, day 1; etoposide, 120 mg/m2, days 1 to 3). Interim results of 253 evaluable patients are as follows: CR + PR rate after 4 cycles was 68%; the CR rate was 28%; median survival was 11.6 months for all patients, 14.8 months for LD, and 10.2 months for ED.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1989

Granulocyte-related bioincompatibility of hemodialysis: inhibition of oxidative metabolism, degranulation reaction, enzyme release and leukocyte sequestration in the lung.

Hemodialysis (HD) induced contact of granulocytes with cuprophan and modified cuprophan, i.e. hemophan, membranes leads to over-stimulation of their oxidative metabolism. This is shown by the fact that after starting HD the peripheral granulocytes are less stimulable to chemiluminescence (CL) and peroxide production (cytochrome C reduction). Such alterations are likely to be connected with a granular staining loss, enzyme release and sequestration of granulocytes in the lung, which coincides with reported clinical features like dyspnoea and drop in arterial oxygen pressure. HD with polysulfone membranes causes a degranulation reaction too, but does not produce granulocyte inhibition and pulmonary sequestration of leukocytes, clearly indicating that these phenomena strongly depend on the different dialyzer membranes.

Biocompatible Materials↗
PubMed1988

Prognostic value of pretreatment carcinoembryonic antigen, neuron-specific enolase, and creatine kinase-BB levels in sera of patients with small cell lung cancer.

Carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and the BB isoenzyme of creatine kinase (CK-BB) were evaluated before therapy in the sera of 195 patients with histologically confirmed small cell lung cancer (SCLC) in a prospective multicenter trial. Forty-four percent (84 of 193) of all patients had CEA levels higher than 5 ng/ml, 66% (111 of 168) had NSE levels higher than 12.5 ng/ml, and 32% (40 of 123) had CK-BB levels higher than 10 ng/ml. Clear pathologic levels were less frequently observed. Significantly higher pretreatment titers for CEA, NSE, and CK-BB were found in patients with bone marrow and/or liver metastases. The most elevated marker levels were observed in the group of nonresponding patients with bone marrow and/or liver metastases. Only a slight correlation between the pretreatment CEA level and survival time could be observed. Patients with pathologic NSE (greater than or equal to 30 ng/ml) levels and, in particular, those with pathologic CK-BB (greater than or equal to 25 ng/ml) levels had a significantly shorter median survival than those with normal or elevated levels. In addition, a positive linear correlation between pretreatment NSE and CK-BB (n = 116, r = 0.54) levels was found, but CEA levels did not correlate with other marker levels. From these data it is concluded that pretreatment CEA, NSE, and CK-BB levels are helpful in the clinical management of a subset of patients with SCLC, i.e., those with bone marrow and/or liver metastases.

Biomarkers, Tumor↗
PubMed1988

Epidermal growth factor receptor expression in human lung cancer cell lines.

Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines were studied for epidermal growth factor (EGF) receptor expression. All NSCLC cell lines tested (eight of eight) had specific EGF binding sites, whereas only five of 11 SCLC cell lines bound EGF. NSCLC and SCLC cell lines expressed the same type of high affinity EGF binding sites with a Kd of 0.5 to 4.5 nM; however, NSCLC cells bound significantly more EGF than SCLC cell lines. The amount of binding sites in NSCLC cells ranged between 71 and 1,000 fmol/mg of protein and in SCLC cells, between 26 and 143 fmol/mg of protein. The two SCLC cell lines with EGF binding values within the range of NSCLC belonged to the variant subtype of SCLC. By means of an anti-erbB serum and indirect radioimmunoprecipitation, a strong Mr approximately 170,000 protein band could be detected in the NSCLC cell lines. This protein corresponds to the EGF receptor molecule. Its identity was proven by competition with excess erbB antigen for the antibody during the radioimmunoprecipitation. Furthermore, this Mr 170,000 protein exhibited protein kinase activity as evidenced by in vitro autophosphorylation. The radioactivity incorporated into the Mr 170,000 band in radioimmunoprecipitation and protein kinase assays was 10 to 100 times lower in these SCLC cell lines which were positive in the EGF binding assay compared to the NSCLC cell lines. We conclude that NSCLC in contrast to SCLC expresses high levels of EGF receptors which may be used to facilitate the differential diagnosis in some cases of lung cancer. These data suggest that EGF may play a role in growth and differentiation of NSCLC.

Carcinoma, Small Cell↗