ISSN:0378-584X    

DOI:10.1159/000218750

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

ISSN:0378-584X    

DOI:10.1159/000218751

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

摘要:

The selective induction of apoptosis or programmed cell death in tumor cells represents a new approach in tumor therapy. In lymphoid cells, apoptosis may follow withdrawal of crucial growth factors (death by default). Alternatively, apoptosis may be induced via cell surface molecules such as APO-1 (Fas/ CD95), a 48-kD member of the TNF/NGF- receptor superfami-ly. APO-1 is weakly expressed on resting mature T cells and on the majority of immature thymocytes, and strongly expressed on activated T cells. Triggering of APO-1 by the monoclonal antibody anti-APO-1 on its natural ligand induces apoptosis in most APO-1-positive cell lines. However, in activated T cells, sensitivity to apoptosis is not fixed and depends on the state of activation. In T cell leukemias, a distinct pattern of sensitivity is also found. Mature T cell leukemias e.g. adult T cell leukemia cells (ATL) are sensitive to anti-APO-1-induced apoptosis. In contrast, the majority of APO-1 T-ALL cells representing more immature T cell phenotypes is apoptosis resistant. This resistance is independent of the expression of the antiapoptotic protooncogene bcl-2 and is turned into sensitivity by inhibition of protein synthesis. Thus, resistance towards induction of apoptosis is actively maintained by cellular programs and can be modulated. The identification of cellular factors which determine sensitivity and resistance towards apoptosis may provide new rational approaches in tumor therapy.

ISSN:0378-584X    

DOI:10.1159/000218876

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

摘要:

Malignant gliomas are the most common intracranial primary tumours. Despite aggressive treatment strategies as surgery, radiation and chemotherapy, the vast majority of patients die about one year after diagnosis. In this article we discuss histo-pathological and moleculargenetic structures of glioma. We evaluate specific topographical areas of the brain with respect to tumour surgery and radical tumour exstirpation. Gross total resection versus debulking are compared regarding the median survival time. The importance of radiotherapy and chemotherapy subsequent to surgery will be pointed out. We conclude that to date the treatment of choice in malignant gliomas of the brain is multimodal and includes surgery (the extent of surgery is limited by functionally important areas), radiotherapy and chemotherapy. However, since the median survival time averages still about one year, in the future new treatment strategies, for example gene therapy, have to be approached.

ISSN:0378-584X    

DOI:10.1159/000218752

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

摘要:

The current treatment of acute promyelocytic leukemia (APL, also called AML3 subtype) is focused on differentiating agents such as the vitamin A derivative all-trans retinoic acid (ATRA). This agent is a novel and very promising therapy for this disease that is characterized cytogenetically by a translocation t(15;17)(q21;q22) involving the α-retinoic acid on chromosome 17 and the PML gene on chromosome 15. Clinical trials have demonstrated that ATRA followed by or combined with conventional chemotherapy may be more beneficial than chemotherapy for inducing complete remission. Unfortunately, as a single agent ATRA does not appear to be able to maintain patients in remission (median 6 months) and when relapse occurs resistance to a second induction of ATRA therapy is observed in almost all cases. Recently, our laboratory investigated whether specific features of the AML3 cells at relapse could explain the in vivo resistance observed. We have demonstrated that AML3 patient cells (from 4 patients) at relapse show high levels of CRABP, a cytosolic retinoic acid binding protein, and this protein was not detected prior to ATRA therapy. Relapse-AML3 cells (n=12) showed reduced differentiation induction when compared with ‘virgin’-AML3 cells. Results from this study suggest that CRABP could modulate ATRA cellular concentrations reaching the nucleus. This induced, ATRA hypercatabolytic state should be monitored during consolidation therapy and at relapse, to detect ATRA resistance in

ISSN:0378-584X    

DOI:10.1159/000218880

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

摘要:

Because drug resistance is a barrier to the cure of many neoplastic diseases, identification of mechanisms of resistance to different classes of anticancer drugs and development of assays to recognize individual drug-resistant tumor cells are justified. We have focused our recent efforts on cells expressing multidrug resistance due to altered (decreased) activity of DNA topoisomerase II (at-MDR). We discuss herein molecular and cellular assays that permit the detection of single cells expressing the at-MDR phenotype, and suggest that these assays may have more general applicability to cells expressing other mechanisms of multidrug resistance.

ISSN:0378-584X    

DOI:10.1159/000218881

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

摘要:

Gene therapy approaches for malignant brain tumors evolved from the need to develop new treatment modalities, increasing insights in the molecular basis of tumorigenesis and the advent of recombinant DNA technology. Immunotherapy of tumors growing in an immunologically privileged organ is a challeng ing task for researchers and clinicians. Both strategies, systemic immunization and local overexpression of cytokines in the brain tumor, have been successfully applied to experimental tumor models. The first clinical gene immunotherapy trials of malignant gliomas uses a vaccine consisting of tumor cells and fibro-blasts genetically modified to express interleukin-2. Chemotherapy of brain tumors is based on the conversion of relatively nontoxic prodrugs into cytotoxic chemotherapeutic agents by suicide genes. Cytosine deaminase from E. coli and thymidine kinase from herpes simplex virus confer lethal cytotoxicity to cells expressing either one of the suicide genes in the presence of the appropriate prodrug 5-fluorocytosine or ganciclovir. Several gene therapy trials have been approved for the treatment of malignant brain tumors with herpes simplex thymidine kinase and ganciclovir. Insights in the molecular basis of tumorigenesis stimulated therapy approaches for restoration of cell cycle gene functions and growth control in malignant tumor cells. Introduction of wild-type p53 tumor suppressor gene into tumor cells lacking the normal protein has not only been shown to revert the malignant phenotype, but also to induce apoptosis in response to DNA damaging by conventional chemotherapy and radiotherapy treatment. These findings are now being translated into clinical gene transfer trials.

ISSN:0378-584X    

DOI:10.1159/000218753

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

摘要:

Proto-oncogenes have been shown to play a critical role in cell growth and differentiation via signal transduction pathways. Oncogenes, either by enhanced gene expression or altered gene expression, can trigger cellular transformation. In this study, the role of oncogenes was defined in drug-resistant human ovarian carcinoma cells. In both multidrug resistant (actinomycin D) cells and non-multidrug-resistant (cisplatin) cells, Northern analyses demonstrated enhanced gene expression for the following oncogenes: c-fos, c-jun, H-ras, and p53. Based on these findings, strategies are discussed for the use of ribozymes, catalytic RNAs, to suppress gene expression and reverse the observed drug resistance.

ISSN:0378-584X    

DOI:10.1159/000218882

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

ISSN:0378-584X    

DOI:10.1159/000218883

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

摘要:

Histopathological parameters are insufficient predictors for the individual course of disease in bladder cancer patients. In the past decade, however, other criteria have been developed as a possible prognostic aid to a better disease management, such as expression of specific cell surface antigens, DNA content, chromosomal aberrations, cell proliferation, tumor cell-associated antigens, angiogenesis, gene rearrangements, and point mutations. Since most tumors of the bladder are carcinomas and are associated with dedifferentiation and high metastatic capability, we investigated whether reduced expression of so-called differentiation factors in combination with increased cell motility might be correlated with tumor progression.

ISSN:0378-584X    

DOI:10.1159/000218754

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger