Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multidrug-resistant (MDR) variants of a human osteosarcoma cell line (U-2 OS) have been recently obtained by continuous exposure to doxorubicin (DX). The growth and phenotypic characteristics of these cell lines have been demonstrated to be related to the level of expression of P-glycoprotein. In this work, the morphological changes associated with MDR have been evaluated by quantitative image analysis and transmission electron microscopy. Resistant cells present morphological changes with respect to sensitive cells at both cytoplasmic and nuclear level. Some of these changes appear to be related to the degree of resistance but not to the direct presence of DX, since deprived cells maintain some modified characters, while others are partly lost. These findings suggest that DX exposure affects cell metabolism causing progressive changes of the cell morphotype.
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PMID:Multidrug-resistance (MDR) phenotype of human osteosarcoma cells evaluated by quantitative morphological and electron microscopy analyses. 872 Apr 40

Multifactorial resistance is the main mechanism of chemotherapy failure in cancers. Multidrug resistance (MDR) is related to the expression of a 170 kDa membrane glycoprotein, the so-called P-glycoprotein (P-gp). This protein is able to extrude drugs of various structures and mechanisms out of the cytoplasm. P-gp is a pronostic value in hemopathy as well as in child sarcoma, osteosarcoma and neuroblastoma. Modulator agents of different generations are capable of inhibiting P-gp. MDR modulation is obtained in hemopathies and is associated with an eradication of the P-gp (+) cell clones. In solid tumors, clinical trials using verapamil or cyclosporin are not so convincing. It is likely that other mechanisms of resistance are responsible for tumor progression, such as the MRP system, glutathion and topoisomerases. A better knowledge of multifactorial resistance and drug synthesis counteracting these resistance mechanisms will allow to elaborate new therapeutic basis for cancer therapy.
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PMID:[MDR (Multiple Drug Resistant) type of resistance to chemotherapy in clinical practice]. 886 40

Cancer survival among children and adolescents has improved markedly due to evolution of multimodal treatment that incorporates combination chemotherapy, radiation therapy and/or surgery. However, 20-30% of children with malignancies will succumb to their disease or complications associated with their disease or treatment. A major limiting factor to improvement in survival among these patients is the occurrence of intrinsic and/or acquired resistance to our treatment interventions, chemotherapy and radiotherapy. Among these mechanisms, multidrug resistance, the focus of this review, is a well-documented phenomenon whose biochemistry, pharmacology and molecular biology has been extensively studied. A role for multidrug resistance in chemoresistance and therapeutic failure in childhood malignancies is suggested by the observation of clinical resistance to treatment regimes containing agents that are known substrates of multidrug resistance mechanisms. With the current results from studies in rhabdomyosarcoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, leukemia and retinoblastoma, the role of multidrug resistance is still unclear. Earlier studies attempted to define a role for P-glycoprotein-mediated multidrug resistance; however, a limited number of reports suggest that the multidrug-associated resistance protein may play an active role in neuroblastoma. Further studies will be necessary using standardized and uniform approaches for the analyses of these mechanisms. Clinical trials directed toward reversal of multidrug resistance are premature since the exact role of P-glycoprotein is controversial in pediatric malignancies, the role of other mechanisms of multidrug resistance must be assessed and selective inhibitors of multidrug resistance have yet to be developed.
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PMID:Multidrug resistance in pediatric oncology. 888 Mar 94

Human P-glycoprotein (Pgp) is a 170-kDa plasma membrane protein that confers multidrug resistance to otherwise sensitive cells. A mutation in Pgp, G185-->V, originally identified as a spontaneous mutation, was shown previously to alter the drug resistance profiles in cell lines that are stably transfected with the mutant MDR1 cDNA and selected with cytotoxic agents. To understand the mechanism by which the V185 mutation leads to an altered drug resistance profile, we used a transient expression system that eliminates the need for drug selection to attain high expression levels and allows for the rapid characterization of many aspects of Pgp function and biosynthesis. The mutant and wild-type proteins were expressed at similar levels after 24-48 h in human osteosarcoma (HOS) cells by infection with a recombinant vaccinia virus encoding T7 RNA polymerase and simultaneous transfection with a plasmid containing MDR1 cDNA controlled by the T7 promoter. For both mutant and wild-type proteins, photolabeling with [3H]azidopine and [125I]iodoarylazidoprazosin, drug-stimulated ATPase activity, efflux of rhodamine 123, and accumulation of radiolabeled vinblastine and colchicine were evaluated. In crude membrane preparations from HOS cells, a higher level of basal Pgp-ATPase activity was observed for the V185 variant than for the wild-type, suggesting partial uncoupling of drug-dependent ATP hydrolysis by the mutant. Several compounds, including verapamil, nicardipine, tetraphenylphosphonium, and prazosin, stimulated ATPase activities of both the wild-type and mutant similarly, whereas cyclosporin A inhibited the ATPase activity of the mutant more efficiently than that of the wild-type. This latter observation explains the enhanced potency of cyclosporin A as an inhibitor of the mutant Pgp. No differences were seen in verapamil-inhibited rhodamine 123 efflux, but the rate of accumulation was slower for colchicine and faster for vinblastine in cells expressing the mutant protein, as compared with those expressing wild-type Pgp. We conclude that the G185-->V mutation confers pleiotropic alterations on Pgp, including an altered basal ATPase activity and altered interaction with substrates and the inhibitor cyclosporin A.
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PMID:Functional characterization of a glycine 185-to-valine substitution in human P-glycoprotein by using a vaccinia-based transient expression system. 889 56

The multiple drug type of resistance to anticancer agents (MDR) is mediated by an over-expression of the MDR1 gene product, the P-glycoprotein. This is largely present at the cell surface of MDR cells, mediating the active efflux of cytotoxic molecules, but may be found also intracellularly. In this paper, using Saos-2 human osteosarcoma cells as a model, we provide further evidence of increased presence of P-glycoprotein at the plasma membrane and in the nucleus of MDR cells, where it is closely bound to the nuclear matrix. The structural changes observed in Saos-2 MDR cells, including an increase of the cell surface by the formation of blebs, and a peculiar clustering of chromatin, which are similar to those observed in other MDR cell lines, are likely to be associated with the observed overexpression of the P-glycoprotein at the cell membrane and nuclear level. These findings suggest the existence of more complex, still undetermined, mechanisms underlying the MDR phenomenon.
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PMID:Ultrastructural features and P-glycoprotein immunolocalization in Saos-2/DX580 multidrug-resistant human osteosarcoma cells. 892 31

Based on a literature review and the SSG experience, the most important prognostic factors in high-grade osteosarcoma appear to be the presence of detectable metastases at diagnosis, tumour volume, old age, sex, histologic response, and possibly tumoral P-glycoprotein expression. However, for an adolescent patient with non-metastatic extremity disease, there is no consensus regarding prognostic factors at initial presentation, and currently there is thus no established method for dividing them into high- and low risk groups for the purpose of treatment differentiation. It should also be remembered that available prognostic factors have been identified only in a retrospective manner, following aggressive treatment of all patients. Thus patients in "favourable" prognostic groups may simply be patients who have had a good effect from aggressive treatment, and how they would have done with reduced treatment remains to be shown. Obviously the best method for prognostication would be the direct demonstration of micrometastatic disease in the lungs or in peripheral blood. In the relatively near future, this may become possible with immunoscintigrapy or immunohistochemistry utilizing monoclonal antibodies [29-31]. In Ewing's sarcoma, the most powerful factors indicating poor prognosis are metastases at diagnosis, poor histologic response, large tumour size and possibly pelvic localisation. There appears to be a somewhat better international consensus regarding prognostic factors in Ewing's sarcoma than in osteosarcoma. Although several studies have implemented intensified treatment for poor prognostic groups [8, 32], the role (if any) of high-dose treatment with stem cell rescue remains to be proven. The same factors are prognostic both for the development of metastases and local recurrence, but in addition, surgical treatment as opposed to radiotherapy appears to reduce local failure rate [12, 17, 33, 34]. As in osteosarcoma, the near future offers promise regarding the detection and quantification of micrometastatses and minimal residual disease, by means of PCR techniques recognizing specific genetic changes in the Ewing family of tumors [35].
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PMID:Prognostic factors in bone sarcomas. 905 8

The multidrug resistance (MDR) phenotype that is mediated by an overexpression of P-glycoprotein, has been suggested to be related also to an increased activity of protein kinase C (PKC) and to changes in phospholipid pattern. By electron microscope quantitative immunocytochemistry, we investigated whether PKC and other elements of the polyphosphoinositide signal transduction system are affected in an MDR variant of the human osteosarcoma cell line Saos-2. These cells, which are characterized by an increased expression of P-glycoprotein not only at the plasma membrane but also at the nuclear level, showed increased intranuclear amounts of phosphatidylinositol 4,5-bisphosphate and of phospholipase C beta 1, while both the amount and activity of both nuclear and cellular PKC were not modified with respect to sensitive cells. These results suggest that, in this model, the changes observed in the elements of nuclear signal transduction could be related to previously reported modifications of the MDR phenotype, but that P-glycoprotein phosphorylation is not dependent from increased PKC activity.
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PMID:Increase of nuclear phosphatidylinositol 4,5-bisphosphate and phospholipase C beta 1 is not associated to variations of protein kinase C in multidrug-resistant Saos-2 cells. 908 Apr 7

One important mechanism by which multidrug resistance is mediated is the mdr1 gene product, P-glycoprotein (Pgp). Even though chemotherapy, in the treatment of high grade central osteosarcoma (hgc-OS), has led to dramatic improvements in survival rate, a certain percentage of patients still show only a poor response to chemotherapy. To further characterize a potential connection between Pgp and chemotherapy as well as the role of Pgp in tumorigenesis of osteosarcoma, we analyzed Pgp-expression in hcg-OS. Immunohistochemistry was performed on 68 hgc-OS samples from 58 patients using the monoclonal antibody JSB-1; in addition, Pgp-expression in normal bone cells was studied in 5 human epiphyseal growth plates. 70.5% of all cases stained positive for P-glycoprotein, while 29.5% of the cases were negative. Cases investigated after chemotherapy showed a higher incidence (82.9%) of positive P-glycoprotein immunostaining than cases prior to chemotherapy (64.4%). The Pgp-expression of 34 biopsies was compared with chemotherapy, as determined at the surgical specimen. In these cases, however, no correlation could be established between P-glycoprotein expression of the biopsy and the later response to chemotherapy. 48.4% of the cases with biopsies, initially positive for Pgp, showed a good response in the surgical specimen, while only 27.2% of Pgp-positive biopsies were later classified as non-responders. In the normally growing skeleton, positive immunostaining was detected in the area of mineralization of epiphyseal growth plates. Osteoclasts, hypertrophic chondrocytes, and cuboidal osteoblasts showed Pgp-expression, while there was a lack of Pgp in the majority of osteocytes and chondrocytes in the resting and proliferating zone. These data therefore suggest that P-glycoprotein expression in hgc-OS resembles, at least in part, the phenotype of active bone cells. These results may explain why P-glycoprotein, by using immunohistochemistry, in biopsies of osteosarcomas is insufficient to predict the response to chemotherapy.
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PMID:P-glycoprotein expression in high grade central osteosarcoma and normal bone cells. An immunohistochemical study. 922 55

We examined the expression levels of P-glycoprotein (P-Gp)/the human multidrug resistance gene (MDR1) and in vivo chemosensitivity in the 7 osteosarcoma xenografts. Three of seven (43%) osteosarcoma xenografts expressed MDR1 by reverse transcriptase-polymerase chain reaction (RT-PCR). The OSS-516R xenograft selected with vincristine (VCR) from the MDR1-negative xenograft OSS-516, which was sensitive to VCR and doxorubicin (DOX), acquired cross-resistance to DOX. In the OSS-516R, RT-PCR assay showed definite MDR1 expression and immunohistochemical analysis demonstrated P-Gp-positive tumor cells. These results suggest that P-Gp/MDR1 overexpression is related to multidrug resistance in human osteosarcoma in vivo.
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PMID:Multidrug resistance mediated by overexpression of P-glycoprotein in human osteosarcoma in vivo. 945 50

We have previously reported that P-glycoprotein (Pgp)-overexpressing multidrug resistant (MDR) osteosarcoma cells were functionally more differentiated than their parent cells. The present study showed that in the parent cells, the actin filaments were sparsely distributed or were diffusely spread throughout the cytoplasm, whereas the MDR osteosarcoma cells exhibited a remarkable increase in well-organized actin stress fibers. Furthermore, dihydrocytochalasin B, a specific inhibitor of actin polymerization, dramatically disrupted this network of stress fibers, increased the intracellular accumulation of doxorubicin (DOX) and modified the resistance against DOX. These results indicate that the organization of actin filaments associated with cellular differentiation may be involved in the expression of Pgp function in the MDR osteosarcoma cells.
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PMID:Actin organization associated with the expression of multidrug resistant phenotype in osteosarcoma cells and the effect of actin depolymerization on drug resistance. 956 51


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