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Biomedical subjects

G Schulz

Publications and source records attributed to G Schulz.

At least 19 recordsLinked to original sources
PubMed1992

Acyclic analogues of lipid A: synthesis and biological activities.

The synthesis of a series of novel acyclic analogues of lipid A, the lipophilic terminal of lipopolysaccharide (LPS), is reported. In these compounds, the reducing glucose unit of lipid A has been replaced by an acyclic analogue unit (abbreviated as AAU) consisting of a spacer (of varying length), an (R)-3-hydroxytetradecanamido moiety (of varying configuration at the carbon of attachment), and a CO2H group. The AAU has been attached to the anomeric carbon of the nonreducing glucose unit of lipid A, either through glycosidic linkage or through an acyl linkage. Further, amide isosteres of these acyclic analogues have been prepared using suitably protected 2,3-diamino-2,3-dideoxyglucose instead of 2-amino-2-deoxyglucose. All the compounds were well characterized and were tested for their ability to induce TNF-alpha in mouse bone marrow-derived macrophages, to enhance nonspecific resistance to infection in mice and to induce endotoxic shock in mice. The results showed a dramatic dependence, for the first time, on the length of the spacer and on the configuration of the carbon bearing the amido group in the AAU part of the analogues.

Adjuvants, Immunologic↗
PubMed1992

Sequential in vivo treatment with two recombinant human hematopoietic growth factors (interleukin-3 and granulocyte-macrophage colony-stimulating factor) as a new therapeutic modality to stimulate hematopoiesis: results of a phase I study.

In a phase I study, the sequentially administered combination of recombinant human interleukin-3 (rhIL-3) and rhGM-CSF was compared with treatment with rhIL-3 alone in 15 patients with advanced tumors but normal hematopoiesis. Patients were initially treated with rhIL-3 for 15 days. After a treatment-free interval, the patients received a second 5-day cycle of rhIL-3 at an identical dosage, immediately followed by a 10-day course of rhGM-CSF, to assess the toxicity and biologic effects of this sequential rhIL-3/rhGM-CSF combination. rhIL-3 doses tested were 125, and 250 micrograms/m2, whereas rhGM-CSF was administered at a daily dosage of 250 micrograms/m2. Both cytokines were administered by subcutaneous (SC) bolus injection. rhIL-3/rhGM-CSF treatment was more effective than rhIL-3 but equally effective to each other in increasing peripheral leukocyte counts, especially neutrophilic and eosinophilic granulocyte counts. In contrast, both modes of cytokine therapy raised the platelet counts to the same degree. rhIL-3/GM-CSF treatment was more effective than rhIL-3 in increasing the number of circulating hematopoietic progenitor cells BFU-E and CFU-GM. High-dose rhIL-3, but not low-dose rhIL-3, was as effective as the rhIL-3/rhGM-CSF combinations in increasing the number of circulating CFU-GEMM. The increase in absolute neutrophil counts correlated with the increase in the number of circulating CFU-GM. Side effects, mainly fever, headache, flushing, and sweating, were generally mild, but in two patients the occurrence of chills, rigor, and dyspnea after initiation of GM-CSF treatment necessitated dose reduction and discontinuation, respectively. These results indicate that sequential treatment with rhIL-3 and rhGM-CSF is as effective as single-factor treatment with rhIL-3 in stimulating platelet counts, whereas the effect of combination therapy on neutrophil counts and circulating progenitor cells is superior.

Antineoplastic Agents↗
PubMed1992

Biology and pharmacology of hematopoietic growth factors.

Several glycoproteins that control blood formation have recently been characterized. Through their overlapping, synergizing, and antagonistic effects, they regulate hematopoiesis in a highly differentiated network. Large scale production of these colony stimulating factors (CSFs) has been made available by recombinant DNA technology, and a series of clinical studies in a variety of indications has been finished. In general, the subcutaneous application seems to be superior to the intravenous injection and causes less toxicity. Erythropoietin has been shown to be a highly effective treatment for anemia in patients with chronic renal failure. Granulocyte colony stimulating factor and granulocyte-macrophage colony stimulating factor are capable of ameloriating the chemotherapy induced neutropenia, and to abbreviate the time span of myeloaplasia after bone marrow transplantation. The potentials of other colony stimulating factors like Interleukin 1 and Interleukin 3, and combination regimens of several CSFs will be discussed.

Animals↗
PubMed1992

Treatment of de novo acute myelogenous leukemia with recombinant granulocyte macrophage-colony-stimulating factor in combination with standard induction chemotherapy: effect of granulocyte macrophage-colony-stimulating factor on white blood cell counts.

GM-CSF is a major regulator of myelopoiesis. Recombinant human GM-CSF (250 micrograms/m2 per day i.v.) was used prior to chemotherapy ("3 + 7" scheme) to recruit leukemic blasts in vivo (de novo AML patients, n = 20) into the chemotherapy sensitive phases of the cell cycle. The stimulatory effect of GM-CSF on peripheral blood AML blasts was associated with a rapid redistribution of leukemic blood cells and with an increase in "S-phase positive" cells. Standard induction chemotherapy ("3 + 7") following GM-CSF induced complete aplasia in 19/20 patients. In the same patients, rhGM-CSF (given after chemotherapy) was found to shorten the time of complete aplasia compared to historical controls whereas post-chemotherapy- and follow-up data suggest no significant differences for CCR and survival. Together, our studies show that GM-CSF can safely be administered to AML patients in combination with induction chemotherapy to recruit leukemic cells into the cell cycle.

Adult↗
PubMed1992

Interleukin-3 and granulocyte-macrophage colony-stimulating factor in combination: clinical implication.

The multilineage hematopoietic effects of IL-3 appear to be most important for its clinical use comprising especially leucocyte and platelet responses. This was demonstrated to be dose dependent characterising doses of 250 to 500 micrograms/m2/day subcutaneously as hematopoietic effective and well tolerable. Since preclinical data suggest synergism between IL-3 and GM-CSF hematopoietic effects of their sequential administration were evaluated in 15 patients with preserved hematopoietic function. An enhanced stimulation of megakaryopoiesis combined with more pronounced stimulation of granulopoiesis than IL-3 alone could be demonstrated. The cytokine combination of IL-3 and GM-CSF was thus used during chemotherapy induced myelosuppression. Data indicates beyond the known amelioration of myelosuppression by GM-CSF additional chances to enhance platelet recovery which can be of important clinical impact.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

The influence of testosterone substitution on bone mineral density in patients with Klinefelter's syndrome.

The aim of this study was to clarify the extent of bone mineral deficiency in patients with Klinefelter's syndrome on the premise that testosterone substitution could prevent this deficiency. Bone mineral density was measured by single-photon absorptiometry in 42 patients with Klinefelter's syndrome, (21 patients without therapy, 10 with testosterone substitution before the age of 20 and 11 patients with testosterone substitution beginning after the age of 20). We found significantly lower bone mineral density in patients without therapy and in patients when the therapy began later compared to normal individuals. Patients with early therapy showed a high proportion of normal values of bone mineral density. We found a positive correlation between bone mineral density and plasma testosterone and a negative correlation between plasma testosterone and age for patients without therapy. These findings suggest that low testosterone levels before or during puberty cause inadequate bone development and low bone mineral density in Klinefelter's syndrome. Only early testosterone substitution may prevent bone mineral deficiency. Later substitution no longer affects bone mineral density.

Adult↗
PubMed1992

Analysis of a novel linkage unit of O-linked carbohydrates from the crystalline surface layer glycoprotein of Clostridium thermohydrosulfuricum S102-70.

The surface layer glycoprotein of Clostridium thermohydrosulfuricum S102-70 was shown to contain a new type of glycan chain. Different from all known eubacterial glycoproteins, the saccharide moiety consists only of six sugar residues without any repeat sequences. Proteolytic digestion of purified S-layer glycoprotein resulted in isolation of several glycopeptide fractions. These are composed of the same hexasaccharide portion but are linked to oligopeptides of different length. One of them contains only a single amino acid. As concluded from chemical analyses and proton and carbon nuclear magnetic resonance spectroscopy of this preparation, the hexasaccharide moiety is linked via a novel O-glycosidic linkage. This is a beta-D-glucose residue linked to the phenolic hydroxyl group of tyrosine in intact S-layer glycoprotein.

Bacterial Outer Membrane Proteins↗
PubMed1992

Sequential administration of interleukin-3 and granulocyte-macrophage colony-stimulating factor following standard-dose combination chemotherapy with etoposide, ifosfamide, and cisplatin.

PURPOSE: To combine the benefits of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on neutrophil recovery and recombinant human interleukin-3 (rhIL-3) on platelet recovery, we applied standard-dose chemotherapy with the combined administration of IL-3 and GM-CSF to investigate their efficacy and toxicity. PATIENTS AND METHODS: Thirty-six patients with advanced malignancies were treated with etoposide (VP16) 500 mg/m2, ifosfamide 4 g/m2, and cisplatin 50 mg/m2 (VIP), followed by the sequential administration of IL-3 (days 1 to 5 subcutaneously [SC]) and GM-CSF (day 6 to 15 SC). Control patients received GM-CSF alone or were treated without hematopoietic growth factors. RESULTS: Subcutaneous IL-3 and GM-CSF treatment was well tolerated; low-grade fever (World Health Organization grade 1 to 2) was the only consistent clinical symptom. Neutrophil recovery documented that the duration of neutropenia less than 0.1 x 10(9)/L or less than 0.5 x 10(9)/L was identical in GM-CSF as well as IL-3 and GM-CSF-treated patients, but was shortened significantly when compared with patients who were treated without cytokines. Overall platelet recovery was not different significantly in the three treatment groups. The biologic activity of IL-3 in this cytokine combination was reflected in a variety of effects, which included an increase in basophil and eosinophil counts and the induction of circulating hematopoietic progenitor cells. CONCLUSION: We conclude that after conventional-dose VIP chemotherapy, a shortened treatment course of IL-3 (5 days) sequentially followed by GM-CSF (10 days) combines the benefits of prolonged single GM-CSF treatment on WBC count recovery in all patients and an accelerated platelet recovery only in some intensively pretreated patients.

Adult↗
PubMed1991

Interleukin-3. Biologic effects and clinical impact.

Human interleukin-3 (IL-3) is expressed in yeast and has a specific activity of 5 x 10(7) U/mg of protein. It exerts functional and proliferative effects on multiple hematopoietic cell lineages including the neutrophil, eosinophil, basophil, monocytic, and thrombopoietic cell lines. IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) share common binding capacities on hematopoietic cells. Each of these agents has entered clinical trials. The clinical experiences with IL-3 alone and in combination with GM-CSF in a Phase I/II trial are summarized in this report.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Recombinant human interleukin-3 in patients with hematopoietic failure.

Nine patients with bone marrow failure and prolonged severe cytopenias were treated with recombinant human interleukin-3 (rhIL-3) at doses ranging from 30 micrograms/m2 to 500 micrograms/m2. rhIL-3 was administered in a subcutaneous bolus injection daily for 15 days. Platelet counts increased by a mean of 6-fold (range: 1.3- to 14.3-fold) in five out of eight evaluable patients. Reticulocyte counts increased 2.9-fold in three patients, and neutrophil counts increased by a mean of 3.1-fold in all eight patients. Platelet transfusions could be discontinued after treatment with rhIL-3 in two out of three evaluable transfusion-dependent patients. Only mild side effects, mainly fever and headache, were observed. These results indicate that rhIL-3 functions as a multilineage hematopoietic growth factor in vivo in patients with secondary bone marrow failure.

Adult↗
PubMed1991

Electrophoretic karyotype of cellulolytic Penicillium janthinellum strains.

The genome of the cellulolytic fungus Penicillium janthinellum BIOURGE was resolved completely by rotating field electrophoresis. The gel pattern revealed 8-10 different chromosomes. On the basis of data for yeast chromosome size standards from Schizosaccharomyces pombe and Saccharomyces cerevisiae, chromosome sizes in the range from 2.0 to 8 mb were estimated. By Southern hybridization with heterologous probes, the chromosomal locations of rDNA, the elongation factor EF1, actin and ubiquitin have all been mapped. In addition, first results with heterologous and homologous probes for cellulolytic genes from Trichoderma reesei and P. janthinellum are presented. In contrast to the other probes, signals obtained with cellulase genes are clearly distributed over several chromosomes.

Blotting, Southern↗
PubMed1991

Common infections in the history of cancer patients and controls.

The association between the frequency of manifest infectious diseases and cancer risk was investigated in a case-control study at Heidelberg, FRG. A total of 255 cases with carcinomas of the stomach, colon, rectum, breast, and ovary, as well as 255 population controls and 230 hospital controls were interviewed using a standard questionnaire. Controls were matched to the cases for age, sex, and region of residence at the time of the interview. A history of common colds or gastroenteric influenza prior to the interview was found to be associated with a decreased cancer risk. Thus the odds ratios for "three or more common colds per year (on average)" versus "no common cold within the last 5 years prior to the interview" were 0.18 (95% CI = 0.05-0.69) and 0.23 (95% CI = 0.06-0.89) relative to population controls and hospital controls, respectively. There was no apparent relationship between childhood infections or other diseases reported in the earlier history, and cancer risk. While the findings are supported by previous studies and fit well into the results of other fields of cancer research, a conclusive interpretation and biological explanation cannot yet be given.

Adult↗
PubMed1991

Adjuvant therapy with recombinant interleukin-3 and granulocyte-macrophage colony-stimulating factor.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) are important members of the system of hematopoietic growth factors which control blood formation. Recombinant human (rh) GM-CSF stimulates proliferation and differentiation of myeloid cells and enhances effectively the regeneration of granulocytes and monocytes after chemotherapy or bone marrow transplantation. RhIL-3 acts on multipotent progenitor cells and induces an increase of leukocytes, platelets and reticulocytes after in vivo application. Combination of rhIL-3 and rhGM-CSF exerts a highly synergistic action on several hematopoietic cell lineages in monkeys and patients. Sequential application of rhIL-3 (5 days) followed by rhGM-CSF (10 days) has equivalent effects on myelopoiesis and thrombopoiesis compared with the effects of 15 days' monotherapy with rhGM-CSF on myelopoiesis and of a 15 days' treatment with IL-3 on platelet production. This combination seems to be very potent to reduce risk of neutropenia-associated infection and thrombocytopenic bleeding in patients with hematopoietic failure.

Adjuvants, Immunologic↗
PubMed1991

New therapeutic modalities for the clinical use of rhGM-CSF in patients with malignancies.

Data from several clinical trials in patients with solid tumors clearly demonstrate that recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) is able to shorten the time period of neutropenia after chemotherapy and to reduce neutropenia-related morbidity such as infections, time in hospital, etc. A placebo-controlled, double-blind multicenter trial including 81 patients with acute lymphoblastic leukemia and non-Hodgkin's lymphoma demonstrates the efficacy of rhGM-CSF to enhance engraftment (neutrophils greater than 0.5 x 10(3)/mm3) after autologous bone marrow transplantation (p less than 0.001) and to reduce the frequency of bacterial infections (34% vs. 56%). In addition, GM-CSF is able to shift the cell cycle of myeloid leukemic cells from the G0 to S phase in vitro and in vivo, which results in an increased sensitivity to cell-cycling-dependent cytostatic agents. Dose intensification of chemotherapy in patients with soft tissue sarcoma and metastatic breast cancer is possible due to adjuvant treatment with GM-CSF and results in a higher frequency of remissions. Further controlled clinical studies are warranted to support these results.

Animals↗
PubMed1991

Clinical effects of recombinant human interleukin-3.

Interleukin-3 (IL-3) is a glycoprotein belonging to the hematopoietic growth factor family that in preclinical in vitro and in vivo studies has exhibited a multilineage activity. Phase I/II trials with recombinant human IL-3 (rhIL-3) expressed in yeast are being done in patients with advanced malignancies as well as in patients with bone marrow failure states. Subcutaneous administration of rhIL-3 at dosages between 30 and 500 micrograms/m2 for 15 consecutive days has resulted in a dose-dependent increase in platelet counts as well as in a substantial increase in the number of circulating neutrophils, eosinophils, monocytes, and lymphocytes in patients with advanced malignancies but normal hematopoiesis. Erythropoiesis is less stimulated with an increase in hemoglobin concentration only in a minority of patients. In patients with secondary hematopoietic failure due to prolonged chemo-/radiotherapy or bone marrow infiltration by tumor cells, treatment with rhIL-3 leads to a clinically significant restoration of hematopoiesis, especially of thrombopoiesis and granulopoiesis. rhIL-3 has also been shown to improve neutrophil and platelet counts in patients with myelodysplastic syndromes, while improvement of hematopoiesis is rarely observed in patients with severe aplastic anemia with the presently used treatment schedules. Adverse effects of rhIL-3 are minor at the clinically used dosages and include fever, bone pain, headache, and stiffness of the neck. Transient thrombocytopenia has been observed in a few patients with myelodysplastic syndrome or aplastic anemia treated at dosages of 250-500 micrograms/m2. rhIL-3 is a multilineage hematopoietic cytokine with promising effects on platelet and neutrophil counts and special usefulness in patients with secondary hematopoietic failure.

Anemia, Aplastic↗