Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the effectiveness of different methods for the detection of tumor cell contamination of collected peripheral stem cells, we performed a study on 39 chronic myelogenous leukemia (CML) patients who were consecutively treated at our department. Analyses of tumor cell contamination by fluorescence in situ hybridization (FISH), conventional cytogenetics, and polymerase chain reaction (PCR) showed marked differences in the percentage of evaluable results: Quantitative analysis of tumor cell contamination was feasible in 60 of 105 (57%) samples evaluated with the use of conventional cytogenetic analysis and in 105 of 107 (98%) samples analyzed by FISH. PCR was evaluable in all 85 samples tested (100%). Both methods were shown to be adequate overall in determining the number of BCR-ABL positive cells, although cytogenetics tended to produce slightly higher percentages. Based on these results, we conclude that FISH performed on leukapheresis products is a rapid and reliable method for assessing the quality of these products and should be used for routine evaluation of tumor cell contamination of CML stem cell products.
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PMID:Autologous transplantation of in vivo purged PBSC in CML: comparison of FISH, cytogenetics, and PCR detection of Philadelphia chromosome in leukapheresis products. 1070 Aug 58

Tumor cells are often characterized by the traithey are more resistant to apoptosis induced by e.g. cytotoxic agents than normal cells. Resistance to apoptosis induction can be a direct consequence of mutations in certain tumor-suppressor genes (p53) or of certain proto-oncogenes (Bcl-2). Therefore, new cancer therapies are under development to bypass the resistance to chemo- and radio-therapy of tumors. Apoptin acts independently of p53, is stimulated by Bcl-2 and is insensitive to BCR-ABL, which means that Apoptin can induce apoptosis in cases where present (chemo)-therapeutic agents, unfortunately, will fail. The fact that Apoptin induces apoptosis in human tumorigenic cells but not in normal diploid cells, implies that side-effects of Apoptin treatment are expected to be minor. In-vivo results with a first prototype of anti-tumor therapy based on expression of Apoptin indicate that Apoptin has low acute toxicity and is effective as an anti-tumor agent.
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PMID:Apoptin. 1081 Jun 23

A 6-year-old girl presented for a second opinion with a 1-year history of an enlarging soft tissue mass just lateral to the right areola. She had been seen by a pediatric surgeon elsewhere who reassured the parents that the lesion was benign. Ultrasound scan showed a 1.5- x 1.5-cm cystic structure adjacent to the right breast bud. Excisional biopsy results showed secretory ductal adenocarcinoma. Modified radical mastectomy with axillary node dissection was performed. All 11 nodes were negative for metastatic disease. She is now disease free 3 years after diagnosis. Estrogen-progesterone receptors were negative, as was screening for BCR 1 and 2. This is the first report of cytogenetics showing an abnormal cell line with a reciprocal translocation between 12p and 15q. Although breast cancer is extremely rare in children, a history of a painless, enlarging, firm breast mass should raise concern about possible neoplastic disease. Cystic appearance on ultrasound scan caused by the pseudocapsule around the tumor may be a marker for secretory carcinoma. Histological evaluation of all suspicious masses should be obtained. Because of the risk of local recurrence and axillary metastases, the authors recommend modified radical mastectomy with axillary node dissection for children with secretory carcinoma of the breast.
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PMID:Breast cancer in a 6-year-old child. 1081 45

The degree of tumor load reduction after therapy is an important prognostic factor for patients with CML. Conventional metaphase analysis has been considered to be the 'gold standard' for evaluating patient response to treatment but this technique normally requires bone marrow aspiration and is therefore invasive. The frequency of cytogenetic analyses can be considerably reduced if patients are also monitored by molecular methods, which can be performed on peripheral blood specimens. Of the various techniques available, most attention has been paid to RT-PCR for BCR-ABL mRNA since this is by far the most sensitive. Simple, non-quantitative RT-PCR analysis gives only limited information on patients after treatment. Quantitative RT-PCR assays have been developed to monitor the kinetics of residual BCR-ABL transcripts over time. Variables in the quantitative PCR assay may be controlled for by quantification of transcripts of a normal gene (eg ABL or glucose-6-phosphate dehydrogenase, G6PD) as an internal standard. After allogeneic stem cell transplantation, most patients become RT-PCR negative, often after a period of low level positivity that may persist for several months. Those patients destined to relapse are characterized by the reappearance and/or rising levels of BCR-ABL transcripts. In contrast, for patients treated with interferon-alpha (IFN) residual disease is rarely, if ever, eliminated. The actual level of minimal residual disease in complete cytogenetic responders to IFN correlates with the probability of relapse. New quantitative real time procedures promise to simplify the protocols that are currently in use, but standardization and the introduction of rigorous, internationally accepted controls are required to enable RT-PCR to become a robust and routine basis for therapeutic decisions.
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PMID:Detection and quantification of residual disease in chronic myelogenous leukemia. 1086 64

In the prechemotherapy era arsenic derivatives were used for treatment of chronic myelogenous leukemia, a myeloproliferative disorder characterized by the t(9;22) translocation, the Philadelphia chromosome (Ph+). In acute promyelocytic leukemia response to arsenic trioxide (As2O3) has been shown to be genetically determined by the acute promyelocytic leukemia-specific t(15;17) translocation product PML/RARalpha. Hence, we reasoned that As2O3 might have a selective inhibitory effect on proliferation of BCR-ABL-expressing cells. Here, we report that: (a) As2O3 induced apoptosis in Ph+ but not in Ph- lymphoblasts; (b) enforced expression of BCR-ABL in U937 cells dramatically increased the sensitivity to As2O3; (c) the effect of As2O3 was independent of BCR-ABL kinase activity; and (d) As2O3 reduced proliferation of chronic myelogenous leukemia blasts but not of peripheral CD34+ progenitors. In summary, these data establish As2O3 as a tumor cell-specific agent, making its clinical application in Ph+ leukemia feasible.
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PMID:BCR-ABL mediates arsenic trioxide-induced apoptosis independently of its aberrant kinase activity. 1091 48

The optimization of conventional treatment approaches, such as chemotherapy, stem cell transplantation (SCT), and supportive care, and the exploration of new approaches will hopefully further improve the outcome of adults with acute lymphoblastic leukemia (ALL). Subgroup-adjusted treatment has already greatly improved treatment outcomes in T- and mature B-cell ALL. These approaches should be further refined, for example, in T-ALL with cyclophosphamide and cytarabine, in pro-B ALL with high-dose cytarabine (HdAC), in B-precursor ALL with high-dose methotrexate (HdM) and 6-mercaptopurine (6-MP), and in mature B-ALL with HdM and HdAC. The indications for SCT will be extended to include elderly patients undergoing allogeneic mini-transplants, and tumor eradication will be improved by better conditioning regimens such as radioimmunoconjugates and methods to induce the graft-versus-leukemia (GvL) effect, such as donor leukocyte infusions (DLI) or allogeneic mini-transplants applied after autologous transplants. Molecular therapeutic approaches, for example, those directed against the fusion protein BCR-ABL with ABL-tyrosine kinase inhibitor, are on the way to creating a new avenue for the treatment of ALL. In the future, drug resistance should be exploited as a pretherapeutic test for treatment strategies, but whether multidrug resistance modulation with available drugs will be used in ALL remains open. Evaluation of the pharmacokinetics of cytostatic drugs and the pharmacogenomics of cytostatic agents in adult ALL may contribute to the development of individualized treatment strategies with higher efficacy and lower toxicity. Minimal residual disease (MRD) evaluation is attractive in adult ALL, because it can be determined in a very high percentage of patients. It has been shown to be predictive for relapse and might be of benefit for redefinition of complete remission (CR), for determination of the efficacy of single treatment elements, and for treatment tailoring during the course of disease. New treatment approaches include also several forms of immunotherapy for B- as well as T-lineage ALL; after the demonstration that such approaches are also effective in ALL, their optimal place in the treatment strategy for adult ALL can be determined.
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PMID:New approaches to acute lymphoblastic leukemia in adults: where do we go? 1104 22

Growth factor-dependent hematopoietic cell lines expressing the BCR/ABL oncoprotein of the Ph chromosome show growth factor-independent proliferation and resistance to apoptosis. Apoptosis resistance of BCR/ABL-expressing cells may depend on enhanced expression of anti-apoptotic proteins as well as reduced expression and/or inactivation of pro-apoptotic proteins. Compared to myeloid precursor 32Dcl3 cells expressing wild type BCR/ABL, cells expressing a BCR/ABL mutant lacking amino acids 176-426 in the BCR domain (p185 delta BCR) are susceptible to apoptosis induced by interleukin-3 (IL-3) deprivation. These cells exhibited the hypophosphorylated apoptotic BAD and markedly reduced levels of Bcl-2. Upon ectopic expression of Bcl-2, these cells showed no changes in BAD phosphorylation, but they became apoptosis-resistant and proliferated in the absence of IL-3, albeit more slowly than cells expressing wild type BCR/ABL. Moreover, the p185 delta BCR/Bcl-2 double transfectants were leukemogenic when injected into immunodeficient mice, but Bcl-2 expression did not restore the leukemia-inducing effects of p185 delta BCR to the levels of wild type BCR/ABL. Leukemic cells recovered from the spleen of mice injected with p185 delta BCR/Bcl-2 cells did not show rearrangements in the Bcl-2 genomic locus, but they exhibited enhanced proliferation in culture and induced a rapidly fatal disease process when inoculated in secondary recipient mice. Together, these data support the importance of anti-apoptotic pathways for BCR/ABL-dependent leukemogenesis and suggest that Bcl-2 expression promotes secondary changes leading to a more aggressive tumor phenotype. (Blood. 2000;96:3915-3921)
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PMID:Bcl-2 expression restores the leukemogenic potential of a BCR/ABL mutant defective in transformation. 1109 78

Dermatofibrosarcoma protuberans (DP) is a skin tumor of intermediate malignancy characterized by high recurrence rates, for which surgical excision is the main therapy. All DP cases carry a specific t(17;22) translocation, resulting in a COL1A1/PDGFB rearrangement. The subsequently deregulated production of PDGFB generates autocrine stimulation of PDGFrbeta, leading to malignant transformation. Using NIH-3T3 cells transformed by the COL1A1/PDGFB rearrangement (5A cell line), we explored the possibility of blocking the PDGFB autocrine loop, both in vitro and in vivo, using STI571, an inhibitor of the PDGF receptor and of ABL kinase activity. The presence of small amounts of serum in the culture medium was required for the in vitro growth and morphological transformation of 5A cells. In the presence of STI571, the growth rate was reduced and the associated transformed phenotype changed to a flattened one. This effect could be reversed on removal of the inhibitor. The growth rate of tumors induced by 5A cells in nude mice was reduced by STI571 administration. Interestingly, this effect was also evident on pre-existing tumors, but no tumor eradication was observed. This is consistent with the reversible effects of the inhibitor observed in vitro but differs from the eradication effect of STI571 on BCR-ABL-induced tumors. Our data indicate that STI571 might be a candidate compound for the pharmacological treatment of DP and demonstrate that the same compound may act in different ways (cytotoxic vs. cytostatic), according to the specificity of the inhibited tyrosine kinase, namely, ABL or PDGFrbeta.
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PMID:Growth-inhibitory effect of STI571 on cells transformed by the COL1A1/PDGFB rearrangement. 1129 Oct 71

It is well accepted that the Bcr-Abl oncoprotein encoded by the Philadelphia chromosome is responsible for causing chronic myelogenous leukemia (CML). We have previously demonstrated that expression of Bcr interferes with the oncogenic effects of Bcr-Abl. To examine the effects of increased Bcr expression on Bcr-Abl oncogenic effects in a more physiological system, we tested the leukemogenic potential of a clone of K562 cells (K6 K562) containing an inducible BCR gene in NOD/scid mice. In this clone, the BCR gene was placed under the control of a tetracycline (Tet) repression system with a cytomegalovirus (CMV) promoter. Induction of exogenous Bcr protein by removal of Tet from the culture medium caused a dramatic increase in Bcr serine kinase activity, yielding predominantly phosphoserine Bcr, despite the presence of Bcr-Abl in the kinase reaction mixture. Prior to induction, the endogenous Bcr was predominantly in the phosphotyrosine form because of phosphorylation by Bcr-Abl, which we previously have shown suppresses Bcr serine/threonine kinase activity. Injection of K6 K562 cells into NOD/scid mice under conditions where BCR expression was suppressed resulted in death or terminal illness in 100% of the mice within 35 days after injection. These mice had a severe wasting syndrome characterized by atrophy of bone marrow hematopoiesis, and/or neoplasia of liver, bone marrow and spleen. Neoplastic spleens from these mice usually contained b3a2 Bcr-Abl transcripts. In contrast, induction of BCR expression at the time of injection allowed 80% survival; these healthy mice had no detectable microscopic lesions in blood forming organs. This difference in survival was significant with P<0.0001. Of interest, mice that were fed Tet for 19 days to initiate the disease syndrome and then released from the BCR transcriptional block had a significantly better survival pattern than mice exposed to Tet throughout the entire period. Moreover, 30% of these mice (three mice) survived through day 50. We conclude from these findings that BCR gene expression strongly inhibits the oncogenic effects of Bcr-Abl in NOD/scid mice, yielding healthy mice in most cases.
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PMID:BCR gene expression blocks Bcr-Abl induced pathogenicity in a mouse model. 1131 35

p210bcr/abl is detected in almost all chronic myelogenous leukemia (CML) patients and a significant number of acute lymphoblastic leukemia (ALL) cases. It is generated by a reciprocal chromosomal translocation, t(9;22) (q34;q11), and the enhanced kinase activity of the protein is believed to be implicated in the pathogenesis of the diseases. To examine its oncogenicity in vivo and to create an animal model for BCR/ABL-positive leukemias, we generated transgenic mice expressing p210bcr/abl driven by the promoter of the mouse tec gene, a cytoplasmic tyrosine kinase preferentially expressed in early hematopoietic progenitors. While the founder mice showed excessive proliferation of lymphoblasts shortly after birth and were diagnosed as ALL, the transgenic progeny reproducibly exhibited marked granulocyte hyperplasia with thrombocytosis after a long latent period, which closely resembles the clinical course of human CML. In addition, to investigate whether loss of p53 would play a role in the transition from chronic phase to blast crisis of CML, we crossmated p210bcr/abl transgenic (BCR/ABLtg/-) mice with p53 heterozygous (p53+/-) mice and generated p210bcr/abl transgenic, p53 heterozygous (BCR/ABLtg/- p53+/-) mice, in which a somatic alteration in the residual p53 allele directly abrogates p53 function. The BCR/ABLtg/- p53+/- mice exhibited rapid proliferation of blast cells and died in a short period compared with their wild-type (BCR/ABL-/- p53+/+), p53 heterozygous (BCR/ABL-/- p53+/-), and p210bcr/abl transgenic (BCR/ABLtg/- p53+/+) littermates. Interestingly, the normal p53 allele was frequently and preferentially lost in the tumor tissues, providing in vivo evidence that acquired loss of p53 contributes to the blastic transformation of p210bcr/abl-expressing hematopoietic cells. Our transgenic mice will be a useful model for investigating oncogenic properties of p210bcr/abl in vivo and will provide insights into the molecular mechanism(s) underlying the progression from chronic phase to blast crisis of CML.
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PMID:Model mice for BCR/ABL-positive leukemias. 1135 87


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