Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased P-glycoprotein expression has been shown to be the molecular cause of multidrug resistance in tumor cell lines. Sensitive immunohistochemical and molecular biologic techniques have been developed to detect P-glycoprotein/mdr1 mRNA expression in clinical samples of tumors. We have reviewed the tools now available for assessment of P-glycoprotein expression in the clinic, the current evidence for a relevant role of the protein in mediation of resistance to chemotherapy, and one strategy used to overcome therapeutic failures due to multidrug resistance. It is now recognized that low levels of increased P-glycoprotein/mdr1 mRNA can occur at diagnosis and during the course of treatment in some cases of acute myelogenous leukemia, non-Hodgkin's lymphoma, multiple myeloma, breast carcinoma, rhabdomyosarcoma and undifferentiated sarcoma of children, neuroblastoma, and retinoblastoma, and these relatively low levels of mdr1 overexpression appear to be associated with poor prognosis. In contrast, it has not been established whether a multidrug resistance mechanism is the rate-limiting factor in response to chemotherapy in carcinomas that arise from tissues normally expressing increased P-glycoprotein. Clinical trials have been initiated to determine whether pharmacologic chemosensitization improves the outcome of chemotherapy-treated malignancies. Preliminary results suggest that chemosensitizers can modulate the effects of increased P-glycoprotein in low-expressing tumors for which effective multiagent chemotherapy is available. Further research is needed for more potent chemosensitizers or combinations of agents that can be used more effectively. The successful circumvention of chemotherapy failure by chemosensitizers will ultimately establish the clinical relevance of the P-glycoprotein efflux mechanism.
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PMID:Multidrug resistance. Clinical opportunities in diagnosis and circumvention. 791 5

The occurrence of multidrug resistance (MDR) is one of the main obstacles in the successful chemotherapeutic treatment of cancer. MDR cell lines are resistant to the so-called naturally occurring anti-cancer drugs, such as anthracyclines, Vinca alkaloids and epipodophyllotoxins, but are not cross-resistant to alkylating agents, antimetabolites and cisplatin. So far, three separate forms of MDR have been characterized in more detail: classical MDR, non-Pgp MDR and atypical MDR. Although all three MDR phenotypes have much in common with respect to cross-resistance patterns, the underlying mechanisms certainly differ. Atypical MDR is associated with quantitative and qualitative alterations in topoisomerase II alpha, a nuclear enzyme that actively participates in the lethal action of cytotoxic drugs. Atypical MDR cells do not overexpress P-glycoprotein, and are unaltered in their ability to accumulate drugs. In this review we will focus on classical and non-Pgp MDR. The molecular mechanism of classical and non-Pgp MDR is transcriptional activation of membrane-bound transport proteins. These transport proteins belong to the ATP-binding cassette (ABC) superfamily of transport systems. The classical MDR phenotype is characterized by a reduced ability to accumulate drugs, due to activity of an energy-dependent uni-directional, membrane-bound, drug-efflux pump with broad substrate specificity. The classical MDR drug pump is composed of a transmembrane glycoprotein (P-glyco-protein-Pgp) with a molecular weight of 170 kD, and is, in man, encoded by the so-called multidrug resistance (MDR1) gene. Typically, non-Pgp MDR has no P-gly-coprotein expression, yet has about the same cross-resistance pattern as classical MDR. This non-Pgp MDR phenotype is caused by overexpression of the multidrug resistance-associated protein (MRP) gene, which encodes a 190 kD membrane-bound glycoprotein (MRP). MRP probably works by direct extrusion of cytotoxic drugs from the cell and/or by mediating sequestration of the drugs into intracellular compartments, both leading to a reduction in effective intracellular drug concentrations. For the classical MDR phenotype, evidence is accumulating that it plays a role indeed, in clinical drug resistance, especially in some hematological malignancies (acute myeloid leukemia, multiple myeloma and non-Hodgkin's lymphoma) and solid tumors (soft tissue sarcomas and neuroblastoma). The association of MRP with clinical drug resistance has not been elaborated, yet, and studies on MRP expression in human cancer have just begun. We found that overexpression of MRP, as determined by RNase protection assay as well as by immunohistochemistry, occurs in several human cancers, among which are cancer of the lung, esophagus, breast and ovary, and leukemias. Further studies are indicated to establish whether elevated MRP expression at diagnosis is an unfavorable prognostic factor for clinical outcome of chemotherapy.
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PMID:Molecular mechanisms of multidrug resistance in cancer chemotherapy. 888 Aug 78

High-dose chemotherapy with haematopoietic stem cell rescue has proven to be an effective treatment in relapsed lymphoma and neuroblastoma. This treatment approach should be considered also in selected patients with leukaemia, multiple myeloma, breast cancer, ovarian cancer and testicular cancer. Relative contraindications include progression of the disease on appropriate conventional treatment, poor performance status, active infection as well as serious renal, pulmonary, liver and cardiac dysfunction. Increasing age should also be taken into consideration when autologous stem cell transplantation is planned. Every effort should be made to eliminate malignant cells that can be present in the stem cell containing population, which will be infused to the patient following myeloablative treatment.
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PMID:Autologous stem cell transplantation in the treatment of cancer. 893 7

The Bone Marrow Transplantation Program in Belarus was founded in 1992, and in 1993, a Bone Marrow Transplantation Centre was created in Minsk. From February 1994 to April 1996, 19 allogeneic bone marrow, 16 autologous bone marrow and 10 autologous peripheral blood stem cell transplantations were performed. Reasons for transplantation included chronic myeloid leukemia, multiple myeloma, severe aplastic anemia, acute myeloid leukemia, acute lymphoblastic leukemia, progressive myelofibrosis, Hodgkin's disease, non-Hodgkin's lymphoma, and neuroblastoma. Among the patients were two liquidators involved in the Chernobyl cleanup activity, both of whom underwent allogeneic bone marrow transplantation. A variety of ablative preparative regimens were used, and blood progenitor cells were mobilized by treatment with Cytoxan and granulocyte colony-stimulating factor. Therapy-related deaths resulted from graft-versus-host disease, septic shock, veno-occlusive disease bleeding and intestinal pulmonary fibrosis. Because the transplantation procedures were carried out on people who continued to be exposed to low-level irradiation, the post-transplantation period included a conservative strategy for prevention of graft-versus-host disease. There was nothing unusual about the post-transplantation period, although uncertainty about the continuing radiation dose should be taken into account when interpreting these data.
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PMID:The Chernobyl governmental program: two years of experience at the Belarusian Bone Marrow Transplant Centre. 936 16

To investigate neuron-specific antigens, hybridoma cells were produced between mouse spleen cells immunized with human neuroblastoma cells (IMR-32) and mouse myeloma cells. 247 hybridoma clones were harvested and one of them was further cultured for recloning. Eventually, one hybridoma clone was obtained and its antibody was designated N-A8. The characteristics of this antibody were determined by immunostaining and flow cytometry. First, the antibody recognized the surface antigens of IMR-32 cells. Second, unexpectedly, N-A8 was reactive not only with human neuroblastoma cell lines but also with human lung cancer cell lines. As analyzed by immunoprecipitation method and SDS-PAGE, the molecular size of the antigen recognized by N-A8 was 210 kDa. The antigen was then purified by affinity chromatography and identified as neural adhesion molecule L1 by amino acid sequence analysis. By the present investigation, it was clearly demonstrated that L1 is expressed in human lung cancer cells.
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PMID:Expression of neural cell adhesion molecule L1 in human lung cancer cell lines. 943 55

The incidence of documented infections after autologous peripheral blood progenitor cells transplantation (PBPCT) was retrospectively evaluated in 86 consecutive patients (47 males 39 females; median age 36 years, range, 18-63) treated in our institution; 83 patients had refractory hematological malignancies (40 non-Hodgkin's lymphoma, 19 Hodgkin's disease, 17 multiple myeloma, 7 acute myeloblastic leukemia) and 3 had solid tumors (1 rabdomyosarcoma, 1 neuroblastoma, 1 osteosarcoma). All patients developed fever after transplantation lasting a median of 2 days (range 1-17); 20 instances of documented sepsis developed in 17 patients (19.7%). Gram positive microorganisms were implicated in all but 4 cases. There were no fatalities directly due to infections and no correlation was found between the risk of infection and reaching PMN > 0, 1 x 10(9)/L, PMN > 0.5 x 10(9)/L. In addition no specific risk factors related to age, disease, conditioning regimen, use of central venous catheter (CVC), type of transplant, and isolation measures were identified.
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PMID:Incidence of sepsis after peripheral blood progenitor cells transplantation: analysis of 86 consecutive hemato oncological patients. 966 90

High-dose therapy with autografting of peripheral blood stem cells (PBSCs) has become an accepted treatment modality. However, gene-marking studies in patients with acute myeloid leukemia and neuroblastoma have revealed that malignant cells reinfused along with leukapheresis products (LPs) contribute to relapse. Thus, a reduction in the number of malignant cells in autografts is desirable. We analyzed the percentage of malignant cells and the number of CD34+ PBSCs in LPs mobilized by granulocyte colony-stimulating factor (G-CSF) alone (LP-S) compared with high-dose cyclophosphamide plus G-CSF (LP-CY) in patients with multiple myeloma (MM). A quantitative polymerase chain reaction assay involving CDR3-specific primers based on the method of limiting dilutions was used to determine the tumor loads of LPs. Sixteen LPs from eight patients with MM were analyzed intraindividually in matched pairs. The percentage of malignant cells was lower in LP-CY (p = 0.017; median 0.0067 vs. 0.009%), whereas the number of CD34+ cells was higher (p = 0.012; median 0.3 vs. 0.095%). The calculated number of malignant cells per CD34+ cell was significantly lower in LP-CY as well (p = 0.017). We conclude that mobilization by cyclophosphamide plus G-CSF leads to a lower number of malignant cells per CD34+ cell in LPs compared with G-CSF alone.
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PMID:Leukapheresis products in multiple myeloma: lower tumor load after mobilization with cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) compared with G-CSF alone. 972 32

In this study we provide evidence that the protein kinase C (PKC)-straight theta isoenzyme is recruited on to the mitotic spindle in dividing murine erythroleukaemia (MEL) cells and associates specifically with centrosome and kinetochore structures. None of the other PKC isoenzymes (-alpha, -delta, -epsilon, -mu and -zeta) expressed by MEL cells shows this localization on the mitotic spindle. An identical subcellular distribution of PKC-straight theta is also observed in dividing murine P3 myeloma cells and human LAN-5 neuroblastoma cells, indicating that this PKC isoenzyme interacts with the mitotic apparatus in mammalian cells. In phorbol-ester-treated non-growing MEL cells, a rapid change in the intracellular distribution of PKC-straight theta occurs. Under these conditions, PKC-straight theta is translocated from the nuclear to the cytosolic cell compartment, an event that is accompanied by phosphorylation of the PKC-straight theta molecule and is followed by its down-regulation. The recovery of cell growth capacity results in the concomitant reappearance of PKC-straight theta. Furthermore, when MEL cells acquire the differentiated non-growing phenotype, the level of PKC-straight theta is reduced to less than 5%, suggesting that this PKC isoenzyme is no longer required. We propose that, unlike other members of the PKC family, PKC-straight theta may play a role in cell proliferation.
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PMID:Protein kinase C-theta is specifically localized on centrosomes and kinetochores in mitotic cells. 985 32

The epithet "less is more" is usually applied to the essentials of good design, but it might be equally true of autologous blood or marrow transplantation. Ever since autologous marrow transplantation was first used to reconstitute recipients of high-dose chemotherapy or radiotherapy, there has been much discussion about the relative contribution of residual tumor cells in the graft to the occurrence of subsequent relapse. It was not until the early 1990s that this risk was finally confirmed by the use of gene marking [1]. A retroviral vector was used to mark a proportion of the autologous remission bone marrow from patients with acute myeloid leukemia (AML) before marrow infusion after high-dose therapy. Two recipients relapsed and both had leukemic blasts with the marker, the neomycin-resistance gene. As the safety of autologous hematopoietic stem cell transplantation has increased, the use of high-dose therapy followed by stem cell "rescue" is becoming more widespread. The malignancies treated in this way include leukemia, lymphoma, myeloma, neuroblastoma, breast cancer, and ovarian tumors. In each of these conditions a number of important questions should be addressed: Can we identify and quantitate tumor cells in the grafts and establish their oncogenic potential? If so, how best can we remove them? Can they be removed without compromising the graft, and will such purging produce a clinically significant reduction in relapse risk? Finally, will the procedure be cost-effective?
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PMID:"Less is More": The Role of Purging in Hematopoietic Stem Cell Transplantation. 1038 58

Data from the annual survey on transplant activity 1997, collected from 457 transplant teams in 31 European countries by the European Group for Blood and Marrow Transplantation (EBMT) were used to describe current status and to assess relative and absolute changes in indication, donor type and stem cell source compared to 1991. A total of 16950 patients were reported to have a first blood or marrow transplant in 1997, a total of 18 923 procedures, including re- and double transplants were performed. Of the 16950 first transplants, 4751 (28%) were allogeneic, 12199 (72%) autologous transplants. Of the autologous transplants, 829 (7%) were bone marrow derived, 11370 (93%) from peripheral blood stem cells or combined bone marrow and peripheral blood stem cell transplants. Of the allogeneic transplants, 3311 (70%) were bone marrow, 1440 (30%) were peripheral blood stem cell transplants. In 1991, the respective figures were 2175 allogeneic (44%) and 2786 (56%) autologous transplants, more than 90% of the autologous, all allogeneic transplants bone marrow derived. Main indications in 1997 were leukemias with 5253 transplants (31%), 70% allogeneic; lymphomas with 6773 transplants (40%), 94% autologous; solid tumors with 4154 transplants (24%), 99% autologous; non-malignant disorders with 770 transplants (5 %), 85 % allogeneic. There was an absolute increase of 11971 transplants since 1991. An increase was observed in all disease categories. Marked differences were found, when the relative increase index (RII) for specific disease categories over time was analyzed. In allogeneic transplants, relatively more transplants were performed in 1997 for acute myeloid leukemia beyond 1st complete remission (RII 1.28), myelodysplastic syndromes (RII 1.58), chronic lymphocytic leukemia (RII 1.33) and non-Hodgkin's lymphoma (RII 1.58). For autologous transplant indications, a high relative increase index was observed in myelodysplastic syndromes (RII 3.77), in multiple myeloma (RII 2.12) and carcinoma of the breast (RII 6.37) with a relative decrease in leukemias (RII 0.39) and certain solid tumors such as glioma (RII 0.27) and neuroblastoma (RII 0.46). These data present the current status of blood and marrow transplantation in Europe. They show the change from bone marrow to blood as stem cell source and highlight shifts in indication. They provide a basis for patient counselling and health care planning.
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PMID:Blood and marrow transplantation activity in Europe 1997. European Group for Blood and Marrow Transplantation (EBMT). 1045 92


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