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R Becher

Publications and source records attributed to R Becher.

At least 73 records · Page 4Linked to original sources
PubMed1991

Biclonal analysis of busulfan-induced sister chromatid exchange in blast crisis of Philadelphia chromosome-positive chronic myeloid leukemia.

The frequency of induced sister chromatid exchange (SCE) as a sensitive parameter for chemotherapy resistance was studied after in vitro treatment with busulfan in four cases of myeloid blast crisis of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Prerequisite was a chromosomally biclonal condition with cells characterized by numerical and/or structural clonal evolution [e.g., +8, +17, +19, or i(17q)] and those only Ph+, which allowed a direct comparison of both clones. We found almost identical mean SCE frequencies in cells with and without clonal evolution after in vitro treatment with 1, 3, and 5 micrograms busulfan. The distribution of the SCE frequency within chromosome groups also remained similar in all cases. Because the SCE assay has proven a very sensitive tool for detection of resistance to chemotherapy with alkylating agents, we conclude that the clonal evolution of CML blast crisis is not associated with a significant degree of chemotherapy resistance. Other aspects, e.g., the lack of normal bone marrow cells necessary for reconstitution of hematopoiesis, may play a more important role in the poor results of chemotherapy in myeloid CML blast crisis.

Blast Crisis↗
PubMed1991

Translocation (8;21) in acute nonlymphocytic leukemia delineated by chromosomal in situ suppression hybridization.

In situ suppression hybridization with recombinant bacteriophage DNA libraries for chromosomes 8 and 21 was performed in two cases of acute nonlymphocytic leukemia, type FAB M2. In both cases, cytogenetic analysis by conventional G-banding revealed t(8;21)(q22;q22). In situ suppression hybridization was able to prove the reciprocal nature of the translocation in both cases by identifying the terminal end of chromosome 21 translocated to the derivative chromosome 8q-.

Chromosome Aberrations↗
PubMed1991

Interferon alfa-2b in acute- and chronic-phase chronic myelogenous leukaemia: initial response and long-term results in 54 patients.

Fifty-four patients with Ph1-positive chronic myelogenous leukaemia (CML) (48 with chronic-phase and six acute-phase disease) were treated with interferon alfa-2b subcutaneously (s.c.). The starting dose was 4 million units (MU)/m2 body surface area daily. It was reduced in parallel with serially determined leucocyte counts, and minimal effective doses were given as maintenance after achieving remission. Haematological remissions were induced in 22 of the 48 patients (46%) with chronic-phase disease. Thirteen patients (27%) revealed partial haematological remission and another 13 no response to treatment. No complete remission could be induced, although minor or partial cytogenetic responses were seen in 16 patients (33%). Moreover, a bcr-abl reduction was detected on Southern blot analysis in two patients. In chronic-phase disease, results of treatment were influenced by elapsed time after diagnosis, extent of previous treatment and interferon dosage. No beneficial effects of interferon were detected in the six patients with acute-phase disease. Principal acute side effects were fever and flu-like symptoms at the beginning of the therapy, which usually subsided within 3-7 days. Chronic side effects, especially weakness and neuropathy, were less frequent but more severe and necessitated discontinuation of treatment in 10 patients. In summary, interferon alfa-2b seems to be an effective treatment in early chronic-phase CML. Long-term effects on the course of the disease, however, must be determined.

Adolescent↗
PubMed1991

Phase II study of vinorelbine by oral route (in a hard gelatine capsule) for metastatic breast cancer patients. A trial of the phase I/II study group of the Association for Medical Oncology of the German Cancer Society.

17 patients with advanced low-risk breast carcinoma not previously pretreated by cytostatic agents were treated by Vinorelbine (VIN), 5'-Nor-anhydro-vinblastine, a new semisynthetic compound of the vinca alkaloid series. A dose of 130 mg per week was administered in a hard gelatine formulation for at least eight weeks. Out of 15 evaluable patients, no complete or partial remission was observed. However, there were 9 patients (60%) achieving no change and tumor stabilization, respectively, lasting for a median of 3.0 months. Main toxicities were leukopenia (17.7%, WHO grade 3-4), nausea and vomiting (17.7%, WHO grade 3-4), and acute diarrhea (70.6%, WHO grade 1-4). Thus, further trials with the oral medication used for this study are not recommended.

Aged↗
PubMed1991

Ifosfamide, methotrexate and 5-fluorouracil for pretreated advanced breast cancer.

A total of 51 fully evaluable patients with advanced and intensively pretreated breast cancer were treated with a combination chemotherapy of ifosfamide plus mesna, methotrexate and 5-fluorouracil. All patients had received at least one series of combined chemotherapy, 30 patients had received more than one combination and 41 patients had had anthracyclines before. Metastatic lesions in more than one site were found in 42 patients, and 24 patients had metastatic liver lesions. Partial remission was achieved in 10 patients (20%) and no change in 16 patients (31%). Survival was almost identical in both groups of responding patients and significantly shorter in treatment failures. Response was favorable in patients without pretreatment with anthracyclines. Two patients who received this protocol directly after progression with cyclophosphamide, methotrexate and 5-fluorouracil (CMF protocol) responded with a partial remission. Median time to progression was 7 months for partial responders and 4.5 months for patients achieving a no-change status. Median survival was 8 months for all patients. Toxicity was tolerable. Leukocytopenia and thrombocytopenia were treatment-limiting parameters. Overall, this protocol is well tolerable and effective in breast cancer patients with advanced disease and in intensively pretreated patients.

Adult↗
PubMed1991

In vivo effects of granulocyte-macrophage colony-stimulating factor and interleukin-3 on clonal and non-clonal cell populations in patients with clonal hematopoietic disorders.

Restriction fragment length polymorphisms (RFLP) of the X-chromosome genes phosphoglycerate kinase and hypoxanthine phosphoribosyl transferase were used in conjunction with cytogenetic analysis to study the clonality of hematopoiesis in four female patients with myelodysplastic syndromes, treated with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3), and in one patient with essential thrombocythemia (ET) treated with IL-3. Both conventional karyotyping and X-inactivation analysis demonstrated the persistence of a monoclonal pattern of hematopoiesis in the two patients with refractory anemia (RA) treated either with GM-CSF or with IL-3. The partial restoration of non-clonal hematopoiesis was observed in one patient with RA and an excess of blasts following treatment with a combination of GM-CSF and low dose cytosine arabinoside. In a fourth patient with RA and in the patient with ET, treatment with IL-3 resulted in the complete restoration of a non-clonal pattern of peripheral blood cells. In contrast, the bone marrow cells remained monoclonal by Southern blot analysis in the patient with RA in whom it could be tested. Non-clonal lymphocytes appear to have been released into the peripheral blood in the two latter cases and are responsible for the non-clonal RFLP pattern. These results suggest that cytokine therapy may have diverse effects on hematopoiesis, including the release of residual normal cells into the peripheral blood.

Adult↗
PubMed1990

Nonrandom chromosomal abnormalities in primary uveal melanoma.

We report on 14 cases of clonal chromosomal anomalies in patients with primary uveal melanoma. An increased dosage of chromosome 8 or of parts of the long arm of chromosome 8 (8q) were detected in eight patients (57%). The smallest multiplied area of 8q appeared to be the region 8q2.1----qter. Monosomy of chromosome 3 was seen in six patients (43%), five of which were associated with anomalies of chromosome 8. Increased dosage of parts of chromosome 8q and loss of heterozygosity of chromosome 3, or the combination of both, seemed to be nonrandom for uveal melanoma and may distinguish it genetically from cutaneous malignant melanoma. Anomalies of chromosome 6, mostly resulting in additional material of 6p or a deletion of 6q, were found in six patients (43%). These anomalies, which seem to be common features of cutaneous malignant melanoma, were considered secondary rather than primary changes in uveal melanoma, since they were present only in subclones in most cases. Loss of the Y chromosome, restricted to tumor cells, was detected in four male patients, and loss of one X chromosome was detected in a female patient.

Adult↗
PubMed1990

Effects of recombinant human interleukin-3 in patients with myelodysplastic syndromes.

In a phase I-II study, nine patients with myelodysplastic syndromes and concomitant severe transfusion-dependent cytopenias were treated with recombinant human interleukin-3 (rhIL-3) to improve hematopoietic function. Doses of rhIL-3 ranged from 250 micrograms/m2 to 500 micrograms/m2 and were given as daily subcutaneous bolus injections for 15 days. Blood leucocyte counts increased 1.3- to 3.6-fold in all nine patients, including neutrophils, eosinophils, lymphocytes, basophils, and monocytes. The mean absolute neutrophil counts increased from 1,350/microL (range, 150 to 2,420) to 2,660/microL (range, 300 to 9,380) (P less than .05) immediately after the end of rhIL-3 therapy and to a maximum count of 4,096/microL (range, 350 to 10,820) (P less than .01). Platelet responses were seen in two of four profoundly thrombocytopenic patients, resulting in discontinuation of platelet transfusion. The requirements for red blood cell transfusion temporarily improved in one patient. Stimulation of plasma cells was evident by a significant increase in serum IgM and IgA levels. Mild side effects (fever, headache, local erythema, and bone pain) were observed in some patients, while transient thrombocytopenia developed in two patients. Disease progression with an increase in blast cells was seen in one patient. These results suggest that rhIL-3 is effective in stimulating hematopoiesis of all lineages in patients with myelodysplastic syndromes and may produce at least short-term hematologic improvement.

Adult↗
PubMed1990

Synthesis of granulocyte colony-stimulating factor and its requirement for terminal divisions in chronic myelogenous leukemia.

In this paper we demonstrate that maturing neoplastic cells from patients with chronic myelogenous leukemia (CML) constitutively produce G-CSF and are also receptive for this molecule. G-CSF functions as an autocrine growth factor in stable phase CML, and thus is responsible for divisions of maturing leukemic cells leading to an expansion of the compartment of mature cells. This observation is well in line with in vivo features of CML in stable phase, i.e., the hyperplasia of the mature granulocyte compartment. In acute blastic phase of CML expression of the G-CSF gene seems to be less common and not related to autonomous blast growth.

Antigens, CD↗
PubMed1990

[Cardiac side effects of 5-fluorouracil].

In four patients (a 54-year-old man and three women aged 57, 60 and 65 years, respectively) with colorectal carcinoma and no obvious cardiac abnormality anginal symptoms and ECG changes occurred during chemotherapy with 5-fluorouracil at a dose of 400 and 600 mg/m2. The ECG changes consisted of descending ST depressions with preterminally negative T waves, terminally negative T waves, ventricular extrasystoles and sinus tachycardia with intermittent atrial fibrillation. The signs first appeared between the second and fourth day of treatment; in two patients they improved with glyceryl trinitrate. A few days after 5-fluorouracil had last been administered all ECG changes had disappeared. The causes of cardiotoxicity of the drug remain unknown.

Aged↗
PubMed1990

Isochromosome 17q in Ph1-negative leukemia: a clinical, cytogenetic, and molecular study.

We report on eight patients who were 35 to 77 years old with an isochromosome 17q as the sole structural chromosomal anomaly. Additional numerical chromosomal changes were a trisomy 8 or 17 in two cases each and a trisomy 19 in one case. Five patients had myelodysplastic syndrome (MDS) diagnosed according to the FAB nomenclature as chronic myelomonocytic leukemia (CMML) in two cases, refractory anemia with excess of blasts in transformation (RAEBt) in two cases, and refractory anemia with excess of blasts (RAEB) in one case. One patient suffered from a myeloproliferative disorder (MPS). All cases progressed to acute nonlymphocytic leukemia (ANLL) type M1, M2, or M4 in a period of 2 to 30 months after initial diagnosis, except one patient with RAEBt who died within 2 months. Two patients presented with ANLL-M2 at time of diagnosis. Treatment during the chronic phase of disease consisted of mild cytoreduction and/or substitution of platelets or red blood cells. One patient with CMML received an allogeneic bone marrow graft and relapsed after 33 months with ANLL-M1. Treatment results for overt leukemia were poor, and survival was short, lasting from 1 to 4 months. Overall survival was 1 to 37 months (median duration, 6.5 months). Molecular studies in two cases revealed neither a BCR rearrangement nor a translocation of the ABL protooncogene, as observed in Ph1-positive chronic myeloid leukemia (CML). Thus, an i(17q) anomaly seems to identify a distinct subgroup of mostly myelodysplastic and, less frequently, myeloproliferative disorders that progress rapidly to ANLL, respond poorly to chemotherapy, and are associated with short survival after transformation.

Acute Disease↗
PubMed1990

Mafosfamide induces less sister chromatid exchange in Ph-positive cells than in normal bone marrow.

The frequency of induced sister chromatid exchange (SCE) is a sensitive tool for the monitoring of DNA damage and has been shown to indicate chemotherapy resistance. Mafosfamide is presently used for the purging of bone marrow in autologous bone marrow transplantation in the treatment of acute leukemia. We studied the SCE-inducing effect of mafosfamide on leukemic cells of Philadelphia (Ph)-positive chronic myeloid leukemia (CML) as a model for leukemic cells. Corresponding data from normal bone marrow were analyzed for comparison. A positive linear correlation (r = 0.99, P = 0.0005) was found between the dose of mafosfamide and induced SCE in Ph-positive CML and normal bone marrow. The concentration of mafosfamide used was 0.1, 0.2, 0.4, and 0.8 micrograms/ml. Additionally, we analyzed five cases of CML and six cases of normal bone marrow. A significant difference in the frequency of induced SCE/metaphase was found between CML and normal bone marrow even after addition of 0.8 micrograms/ml mafosfamide. Also, spontaneous SCE was significantly lower in CML. Our data indicate a lower sensitivity of the leukemic cells to mafosfamide as shown by the induction of a lower frequency of SCE events.

Bone Marrow↗
PubMed1990

Formation of genotoxic products from N-nitrosoheptamethyleneimine (NHMI), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) by isolated rabbit lung cells.

The genotoxic potentials of N-nitrosoheptamethyleneimine (NHMI), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) were studied in fresh preparations of Clara cells and type II cells isolated by centrifugal elutriation and density gradient centrifugation, and macrophages from rabbit lung. The activation of the compounds to bacterial mutagens was assayed in the Salmonella mutagenicity test using strains of TA 100 and TA 1530 preincubated with test chemicals and cells placed in chambers with nucleopore membranes to separate cells and bacteria. Unscheduled DNA synthesis was measured by incorporation of [3H]-thymidine in the cells after exposure to the compounds. NHMI, NNK and NNN were not activated to bacterial mutagens by Clara cells, type II cells or macrophages, presumably because the reactive metabolites generated were not released into the incubation medium. However, NHMI and NNK increased unscheduled DNA synthesis in Clara cells, and the highest repair activity was found after incubation with NNK. The effect of NNN was only marginal. This indicates that NHMI and NNK are genotoxic in the rabbit lung and that the Clara cells are involved in the metabolic activation of these compounds.

Animals↗
PubMed1990

Treatment of chronic myelogenous leukemia with interferons alpha and gamma.

A 23-year-old male patient with Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML) was treated with both IFN alpha and IFN gamma. Normalization of leukocyte counts was reached after 3 months of treatment. Southern blot analysis failed to detect the neoplastic cell clone after 19 months of therapy. Cytogenetically, complete suppression of Ph positive cells in the patient's bone marrow and blood was observed after 20 months and 25 months, respectively. This response was achieved with doses of IFN alpha and IFN gamma which were considerably lower than the dosage of IFN used in single agent therapy of CML.

Adult↗
PubMed1990

Species differences in short term toxicity from inhalation exposure to bromobenzene.

Lung, liver and kidney injury were studied in mice, rats and rabbits 48 h after termination of a 4 h inhalation exposure to bromobenzene vapour (250-3400 ppm). Light and electron microscopy of lung tissue revealed injury to Clara cells and adjacent epithelium in mouse bronchioli (bromobenzene concentration 250 ppm and 1000 ppm) and to Clara cells of rat bronchi and bronchioli (1000 ppm bromobenzene) and of rabbit bronchi (2500 ppm and 3400 ppm). Histological and clinicochemical indices of liver damage were found in the same animals, whereas kidney toxicity was observed in mice (two out of ten showed tubular necrosis and elevated concentration of plasma urea) and rats (all had elevated plasma concentrations of creatinine) exposed to 1000 ppm bromobenzene. Inhalation exposure thus produced less kidney injury than expected from previous studies with equimolar doses given intraperitoneally. The mouse was the most severely affected species, followed by the rat, and lastly the rabbit. The animal susceptibility could not be ranked according to the rate of 14C-bromobenzene covalent binding in lung or liver, but it was inversely related to the rate of N-demethylation of benzphetamine (indicative of P450IIB activity) in both lung and liver microsomal preparations. Differences in a P450 mediated detoxification could therefore be of importance in species variability to bromobenzene injury.

Administration, Inhalation↗