ISSN:1042-8194    

DOI:10.3109/10428199309086991

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

ISSN:1042-8194    

DOI:10.3109/10428199309086992

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

At least three categories of genes are envisaged to be involved in the natural history of B-CLL. First, the genes that are responsible for the transforming event(s) in the (presently unknown) target cell; second, the gene(s) that help the progressive accumulation of malignant cells and finally the gene(s) that cause the progression toward a more aggressive lymphoma. The possibility that the clonal expansion of B-CLL is due to a prolonged life-span of monoclonal B cells rather than to an acceleration of their proliferative activity may now be reinterpreted by taking into account some recent findings on the expression of Bcl-2 gene in B-CLL cells. The Bcl-2 gene product regulates programmed cell death and a number of experiments suggest that Bcl-2 is involved in the selection and maintenance of long-lived memory B cells rescuing them from apoptotic death and leading to their accumulation in the GO phase of the cell cycle. Variant chromosomal translocations have been detected in a small fraction (5-10%) of B-CLL, involving Bcl-2 and the Ig light chain gene. Despite the low percentage of Bcl-2 rearrangements the expression of mRNA and protein is appreciable in most samples of fresh B-CLL cells in an amount comparable to that observed in Karpas 422 cells, which contain a t(14;lS). Southern blot analysis of 16 B-CLL cases with high expression of Bcl-2 failed to reveal both gene amplification and rearrangement, thereby suggesting that the level of Bcl-2 expression in B-CLL does not reflect a rearrangement of Bcl-2 gene, which appears to be a rare event in CLL cells. In addition, the half life of Bcl-2 mRNA is not prolonged in CLL cells. The expression of Bcl-2 mRNA can be modulated in B-CLL cells by using B cell activators and cytokines. In the transition from a resting to a cycling phase, Bcl-2 expression is downregulated indicating that proliferation and Bcl-2 expression are inversely related in malignant B-CLL cells from peripheral blood as observed for normal B lymphocytes derived from secondary follicles. By culturing B-CLL cells in the presence of an antisense phosphorothioate oligodeoxynucleotide complementary to the translation-initiation site of Bcl-2 gene, DNA fragmentation, characteristic of apoptosis, can be seen in a proportion of cases. These data lead to the plausible hypothesis that the high Bcl-2 expression in B-CLL cells might confer on them a survival advantage favouring their relentless accumulation, perhaps by inhibition of apoptosis.

ISSN:1042-8194    

DOI:10.3109/10428199309086993

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Bone marrow transplantation (BMT) is performed as curative therapy for acute lymphoblastic leukemia (ALL). In most patients, BMT is performed at the time of remission which implies that the number of leukemic cells is less than 5% of all hematopoietic cells, namely, 0 to 10″leukemia cells in the body. Thus, some patients may well undergo BMT despite the fact that no leukemic cells are left in the body. In this respect, more accurate diagnosis of complete remission status would be to the patients' benefit. To detect minimal residual disease (MRD) not found by light-microscopy, further strategies are required after achieving hematological remission. Cytogenetic methods, Southern blot analysis and conventional immunological techniques can all provide accurate diagnosis, however, the sensitivity of these techniques for the detection of MRD is just as low as that of the light microscopy. Recently, polymerase chain reaction (PCR) has become available for the detection of low levels of chimeric bcr-abl transcripts in Philadelphia chromosome positive (Ph1) ALL patients. With this assay, investigators have reported MRD in patients after chemotherapy or BMT. Most patients who achieve hematological remission after conventional chemotherapy still have bcr-abl transcript detectable by PCR, confirming the general concept that this particular leukemia needs BMT in order to cure the disease. Some patients who had MRD prior to BMT continued disease free survival>1 year after BMT with a negative PCR result and in these patients, MRD seems to have been eradicated by the BMT procedure. Most patients with MRD still detectable after BMT, relapsed shortly after their first positive PCR result, indicating that PCR is a sensitive early marker of hematological relapse. Thus, PCR used for the detection of MRD seems useful for a more accurate assessment of remission status before and after BMT.

ISSN:1042-8194    

DOI:10.3109/10428199309086994

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Deletions of 9p21-22, that frequently include theα-,β-andω-IFN gene cluster, are common in malignant diseases such as acute lymphocytic leukemia, malignant melanoma and malignant glioma. There is also evidence to support the role of a gene(s) on chromosome 9p21 in predisposition for familial malignant melanoma.Although initial studies implicated that the IFN genes could serve as tumor suppressor genes, there is now data, mainly based on estimations of minimum region of overlap for the deletions, indicating that the relevant tumor suppressor gene is located centromeric of theα-,β-,ω-IFN gene cluster.

ISSN:1042-8194    

DOI:10.3109/10428199309086995

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Themycproto-oncogenes encode nuclear DNA-binding phosphoproteins which regulate cell proliferation and differentiation. The c-mycgene is implicated in hematopoietic malignancies on the basis of its frequent deregulation in naturally occumng leukemias and lymphomas. Recent evidence suggests that also the N-mycand L-mycgenes may have a role in normal and malignant hematopoiesis. N-mycand to a certain degree L-myccan substitute for c-mycin transformation assaysin vitvo, and their overexpression can block the differentiation of leukemia cell lines. Immunoglobulin heavy chain enhancer (IgH)-driven overexpression of N-mycor L-mycgenes cause lymphatic and myeloid tumors, respectively, in transgenic mice. Furthermore, the L-mycand N-mycgenes are expressed in several human leukemias and leukemia cell lines, L-mycpredominantly in myeloid and N-mycboth in myeloid and in some lymphoid leukemias. All N/L-mycpositive leukemias and leukemia cell lines coexpress the c-mycgene, thus exemplifying a lack of negative cross-regulation between the differentmycgenes in leukemia cells. Taken together, these data suggest that L-mycand N-mycmay participate in the growth regulation of hematopoietic cells.

ISSN:1042-8194    

DOI:10.3109/10428199309086996

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

The redox cycling of anthracyclines promotes the formation of free radicals which are believed to play a central role in their cardiotoxicity. A number of observations indicate that the mechanism of the antineoplastic effect of anthracyclines is independent of their cardiotoxic effect and that it may be possible to prevent toxicity without interfering with therapeutic effect. Iron plays an important role in anthracycline toxicity by promoting the conversion of superoxide into highly toxic hydroxyl radicals through the Haber-Weiss reaction. Conversely, iron deprivation by its high-affinity binding to iron chelating compounds may inhibit anthracycline toxicity by interfering with free radical formation. ICRF-187, a bispiperazonedione which is hydrolyzed intracellularly into a bidentate chelator resembling EDTA, is able to decrease adriamycin-induced free hydroxyl radical formation and to prevent the development of clinical cardiac toxicity in patients receiving long-term anthracycline therapy. Our studies in rat heart cell cultures have shown that iron overload aggravates anthracycline toxicity and that this interaction can be prevented by prior iron chelating treatment. Since iron overload caused by multiple blood transfusions and bone marrow failure is a common condition in patients requiring anthracycline therapy, these observations may have significant clinical implications to the prevention of anthracycline cardiotoxicity.

ISSN:1042-8194    

DOI:10.3109/10428199309086997

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Rodents given cyclosporhe (CSP) for several weeks after autologous or syngeneic bone marrow transplantation develop a syndrome that mimics allogeneic graft-versus-host disease (GVHD). Autologous GVHD has also been reported after administration of CSP in patients who have received autologous bone marrow transplantation (ABMT) with untreated marrow for lym-phoma or acute myeloid leukemia (AML). Our study was designed to determine whether CSP administration is associated with appearance of autologous GVHD in patients with AML receiving ABMT with 4-hydroperoxycyclophosphamide (4HC)-purged marrow and whether there was a dose-dependent effect of CSP on development of the syndrome. Thirty-three patients with AML (18 in first remission [CRl], 10 in CR2, and 5 in CR3) received intravenous CSP, beginning on the day of ABMT, after a preparative regimen of busulfan and cyclophosphamide and ABMT with 4HC-treated marrow. Skin biopsies were obtained weekly after ABMT or on appearance of rash and were graded for GVH changes. In the first phase of this study, groups of patients received CSP dosages of either 1 mg/kg/day (7 patients), 2.5 mg/kg/day (8 patients), or 3.75 mg/kg/day (6 patients) for 28 days. Sixteen of the 21 patients (76%) developed cutaneous histopathologic grade 2 GVHD at a median of 34 days (range, 14-49) after ABMT, and cutaneous manifestations were present at time of positive biopsy in 11 of the 16 patients. There was no apparent difference in frequency, time to onset, or duration of GVHD among the three CSP dosage groups. In the subsequent trial, 12 patients received 1.0 mg/kg/day of CSP for 35 days; 6 developed biopsy-documented GVHD at a median of 42 days (range, 18-52) after ABMT. Overall, 22 of 33 patients (67%) had positive biopsies for GVHD, compared with a historical 7% incidence of spontaneous GVHD in ABMT recipients. No patients had hepatic or gastrointestinal dysfunction attributable to GVHD or required specific therapy for GVHD. Six of the 33 patients died with ABMT-related complications; 3 had positive biopsies for cutaneous GVHD. Eleven patients (6 CR1, 4 CR2, 1 CR3) relapsed with AML at a median of 285 days (range, 115-633) after ABMT; 9 had positive biopsies. Sixteen patients (9 CRl, 3 CR2, 4 CR3) are alive without relapse at a median of 509+days (range, 96+-1176+) after ABMT; 10 had cutaneous GVHD. Randomized prospective trials will be needed to determine whether autologous GVHD is associated with alterations in relapse rate and disease-free survival after ABMT for acute leukemia and lymphoma.

ISSN:1042-8194    

DOI:10.3109/10428199309086998

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

In an attempt to obtain a synergistic effect on the hemoglobin levels in anaemic patients with myelodysplastic syndromes (MDS), granulocyte colony-stimulating factor (G-CSF) and erythropoietin (epo) were combined in a clinical phase II trial. Twenty-two patients with MDS were included in the study. G-CSF was given alone for six weeks and then in combination with epo for the following twelve weeks. Eight (38%) of 21 evaluable patients showed a significant increase in hemoglobin. One patient with a previous response and subsequent failure to epo alone improved after the addition of G-CSF. Responses were more frequent in patients with less advanced pancytopenia, lower endogenous levels of serum-epo and in those with ring sideroblasts in the bone marrow. The response frequency of 38% is higher than in any study of epo as monotherapy. Moreover, patients with ring sideroblasts, who respond poorly to epo alone, showed a response rate of 60%. Our findings suggest a synergistic in vivo effect of granulocyte-CSF and erythropoietin in patients with myelodysplastic syndromes.

ISSN:1042-8194    

DOI:10.3109/10428199309086999

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

To assess the clinical and hematopoietic effects of rhGM-CSF, a placebo-controlled double blind multicenter phase III study was undertaken in patients with non-Hodgkin's lymphoma receiving cytotoxic chemotherapy. Sixty-two patients who had granulocytopenia (<1×103/μl) after the first cycle of chemotherapy with cyclophosphamide, adriamycin, vincristine, and prednisolone were enrolled. After the second cycle of chemotherapy with the same regimen, patients randomly received either rhGM-CSF (125μg/m2/day) or placebo for 14 days (rhGM-CSF; 31 patients and placebo; 31 patients). Administration of rhGM-CSF induced a significant increase in granulocytes mainly with neutrophils, eosinophils and monocytes, but elevation of lymphocytes, latelets, and reticulocytes was not induced. Median days of granulocytes less than 1×103/μl in patients receiving rhGM-CSF were significantly shorter than in patients receiving placebo (p = O.001). Adverse reactions encountered with rhGM-CSF, and observed in 58% of the patients were never life-threatening and always rapidly reversible. They included fever, nausea and vomiting, diarrhea, skin eruption, and malaise. These results suggest that rhGM-CSF can be safely administered to prevent neutropenia after chemotherapy in patients with non-Hodgkin's lymphoma.

ISSN:1042-8194    

DOI:10.3109/10428199309087000

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor