Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multidrug resistance represents a major obstacle to successful chemotherapy of metastatic disease. Elevated levels in cancer cells of the product of the multidrug resistance gene, P-glycoprotein or the multidrug transporter, have been associated with the development of simultaneous resistance to a great variety of amphiphilic cytotoxic drugs. P-glycoprotein is an integral plasma membrane protein which contains 12 putative transmembrane regions and two ATP binding sites. It confers multidrug resistance by functioning as an energy-dependent drug efflux pump. Here we describe recent studies on the biosynthesis, structure, function, and mechanism of action of P-glycoprotein which have provided insights into the complexity of this multifunctional transport system and revealed an additional chloride channel activity. The physiological role of P-glycoprotein, however, still remains to be elucidated.
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PMID:P-glycoproteins: mediators of multidrug resistance. 809 27

A bisbenzylisoquinoline alkaloid, cepharanthine, significantly enhanced vinblastine, adriamycin and etoposide sensitivities in P-glycoprotein positive renal cancer cells. However, it did not show any enhancing effect on cisplatin sensitivity. Four patients with metastatic renal cell carcinomas were treated with intraarterial chemotherapy using vinblastine and/or adriamycin in combination with cepharanthine for their metastatic lesions (3 bone and 1 contralateral kidney metastases). A partial response was observed in 1 patient with femoral bone metastasis and a minor response in 1 patient with lumbar bone metastasis, although they were also treated with interferons. No adverse effects associated with cepharanthine were seen except in one patient complaining of redness and burning sense of the skin probably due to its vaso-dilatation effect.
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PMID:[Circumvention of the multidrug-resistance in renal cancer by bisbenzylisoquinoline]. 828 74

Relationships between the incidence of metastatic spread and microvessel density, expression of proto-oncogene products, or expression of resistance-related proteins were investigated in human ovarian carcinomas by immunohistochemistry. Ovarian carcinomas with a high microvessel density showed a significantly increased formation of metastases (P = 0.005). Tumors with positive immunoreactivity of c-jun and c-myc products had a higher metastatic spread; however, these results were not statistically significant. A marginally significant correlation existed between the expression of erbB1 (EGFR) and metastatic spread (P = 0.05). No significant relationship was found between the expression of the resistance-related proteins P-glycoprotein or glutathione S-transferase-pi and the incidence of metastases. Furthermore, no correlation was detected between expression of the heat shock protein 70 and the occurrence of metastases.
Clin Exp Metastasis 1996 May
PMID:Microvessel density, expression of proto-oncogenes, resistance-related proteins and incidence of metastases in primary ovarian carcinomas. 867 74

The immunosuppressive drug cyclosporin A has been evaluated recently in phase II trials in cancer therapy as a reverter of P-glycoprotein-mediated multidrug resistance. As an immunosuppressive agent, cyclosporin A potentially can enhance tumour growth. We investigated this potency of cyclosporin A in the weakly immunogenic CC531 colon adenocarcinoma model, using the same dose that had previously been shown to intensify the antitumour activity of doxorubicin in vivo. In vitro cyclosporin A caused no growth acceleration and only in high doses was growth inhibition of CC531 cells observed. In vivo no evidence of growth enhancement was found in short-term assays but, after 4 weeks, rats treated with cyclosporin A had a significantly higher tumour load, mainly consisting of locoregional metastases. These experiments in the CC531 tumour model show that cyclosporin A, used as a reverter of multidrug resistance, may produce short-term improvement of antitumour activity but may also induce enhancement of tumour metastasis.
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PMID:Cyclosporin A enhances locoregional metastasis of the CC531 rat colon tumour. 899 36

Solitary stroma-invading tumor cells expressing the ATP-binding cassette transporter P-glycoprotein have been reported to be associated with a significantly higher incidence of vessel invasion and lymph node metastases. In contrast to P-gp-mediated multidrug resistance (MDR) which has become well characterized over the last decade, little is known about further morphological and functional alterations in drug-resistant tumor cells. Binding of malignant cells to components of the extracellular matrix mediated by beta 1 integrins has been suggested to play a substantial role in the metastatic cascade. We studied alterations of beta 1 integrin expression and in vitro adhesiveness to extracellular matrix proteins of the human renal carcinoma line Caki-1 in comparison to the vinblastine resistant sublines Caki-1/V1 and Caki-1/V10 (cultured in the presence of 1 ng/ml and 10 ng/ml vinblastine, respectively). Both VLA-1 and VLA-2 receptors were acquired by the Caki-1/V10 subline, whereas untreated and Caki-1/VI cells lacked surface expression of these antigens. VLA-6 was found to be decreased in the vinblastine-resistant sublines. Attachment of drug-resistant Caki-1/V1 and Caki-1/V10 cells to collagen type I was significantly increased when compared to parental cells (p < or = 0.005). Significant differences in the attachment to type IV collagen were observed between Caki-1/V10 and untreated cells (p < or = 0.045). Both Caki-1/V1 and Caki-1/ V10 cells exhibited increased adhesion to fibronectin when compared to cells of the untreated line (p < or = 0.04). Whether an aberrant expression of beta 1 integrin receptors in resistant cells in combination with altered tumor cell adhesiveness is caused by MDR induction or whether it is an epiphenomenon of cytotoxic stress is unknown. Future studies will be needed to characterize the clinical relevance of MDR-associated changes in tumor cells.
Invasion Metastasis 1996
PMID:Exposure to vinblastine modulates beta 1 integrin expression and in vitro binding to extracellular matrix molecules in a human renal carcinoma cell line. 903 Feb 41

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

Our purpose was to study the role of the expression of P-glycoprotein (Pgp) and glutathione S transferase-pi (GST-pi) in predicting the response to chemotherapy, relapse-free interval, and survival of patients with synovial sarcoma (SS). Thirty-seven cases of primary SS, without regional lymph node or distant metastases, were studied. There were 17 females and 20 males, ranging in age from 7 to 81 years (median, 31 years) with tumors located in the lower extremity (n = 24) upper extremity (n = 5) and trunchus (n = 8). The cases were retrospectively studied without knowledge of clinical course to compare the immunohistochemical expression of Pgp and GST-pi, flow cytometry parameters (ploidy and % of cells in S+G2 phases), and PCNA and Ki-67 labeling of primary tumors before any therapy, with that observed in local recurrences and metastases after chemotherapy. The relationship of the aforementioned parameters with clinicopathological features (gender, age, and histo-blood group of the patients, size, location, histological subtype. TNM stage, and clinical response to chemotherapy of the tumors) was also evaluated. Results revealed that Pgp and GST-pi were expressed in 29.7% and 40.5% of the cases, respectively. In 48.6% of the tumors there was expression of a least one of the drug resistance markers. The markers were coexpressed in 25.0% of the tumors. The prevalence of Pgp expression was lower, but not significantly, in stage I-II (17.6%) than in stage III (40.0%) tumors, and also in cases without clinical progression (16.7%), than in cases with (36.0%). No such differences were observed for GST-pi expression. Pgp and GST-pi expressions were significantly associated with biphasic SS and were particularly noticeable in solid/glandular areas of biphasic SS. The expression of the drug resistance markers was not significantly associated with gender, age, and histo-blood group of the patients, dimension, location, and proliferative activity of the tumors; it was also not significantly related to relapse-free interval and survival of the patients. The expression of Pgp and GST-pi was not significantly associated either to response to chemotherapy or influenced by chemotherapy. We conclude that Pgp and GST-pi expressions are not good predictors response to of the chemotherapy in patients with localized SS. Other drug resistance mechanisms may be active in SS.
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PMID:Synovial sarcoma: immunohistochemical expression of P-glycoprotein and glutathione S transferase-pi and clinical drug resistance. 911 70

99mTc-Tetrofosmin (TF) is a lipophilic diphosphine compound routinely used for myocardial scintigraphy. Extracardiac utilization has occurred in evaluation of patients with malignant neoplasms and in parathyroid adenomas. Although its uptake mechanisms are not completely understood, they appear similar to those of 99mTc Setamibi (MIBI). The importance of flow and the metabolic status of cells with an intracellular uptake depending on mitochondria and the Na+/K+ pump have been hypothesized. It has also been demonstrated that Tetrofosmin shares with MIBI the property of being a substrate for P-glycoprotein (P-gp), a multidrug resistance transporter. In this review the possible clinical role in breast cancer is analysed. First experiences suggest that scintimammography with TF is useful in patients with indeterminate Mammography and to obtain complementary data to avoid surgery and/or biopsy. TF is a reliable tracer for diagnosis of primary cancer, of local recurrence of axillary lymph node metastases. Preliminary data stimulate a possible role in functional imaging of chemoresistance and in differential diagnosis of distant metastases with main reference to the evaluation of single hot lesions at bone scan.
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PMID:Diagnostic and prognostic role of 99mTc-Tetrofosmin in breast cancer. 927 32

Anthracyclines were introduced for the treatment of breast cancer in the 1970s and were considered the most active single agents until the recent introduction of the taxoids. Although incorporation of anthracyclines into combination regimens has been shown to improve clinical outcomes, the duration of response and survival in women with metastatic disease is still modest, and 50% of women treated with adjuvant chemotherapy eventually relapse. Intrinsic and acquired drug resistance, leading to untreatable disease, are fundamental reasons for clinical failure in breast cancer, but the clinical relevance of the various known mechanisms of drug resistance is not clear. P-glycoprotein (Pgp)-mediated multidrug resistance, the most studied form of anthracycline resistance, can be inhibited by a variety of chemicals. While in vitro studies have demonstrated the efficacy of some Pgp inhibitors, and led to the development of more clinically acceptable agents, clinical studies have not shown a consistent advantage in using Pgp inhibitors. Since Pgp is a physiologic efflux mechanism, consideration also should be given to the possible consequences of its inhibition. Studies with Pgp knock-out transgenic mice suggest that Pgp is not essential for life, but that Pgp inhibition may make some tissues, such as the brain, more vulnerable to cytotoxic drugs. Correlating overexpression of the MDR1 gene in human tumor samples with treatment failure has not proved straightforward, and further studies are needed to clarify the contribution of multidrug resistance mechanisms to clinical anthracycline resistance. Mechanisms other than drug efflux pumps, which may contribute to anthracycline resistance, include changes in topoisomerase II, the major cellular target of anthracyclines. There remains a gulf between the laboratory definitions of drug resistance, which can be elucidated in great detail, and the clinical definition, which is based on the time to treatment failure. New drugs still need to be assessed empirically in the clinic, and these results may then be correlated with laboratory findings. We cannot yet reliably predict clinical efficacy, cross-resistance, or the mechanisms responsible for treatment failure from laboratory studies.
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PMID:Anthracycline resistance: the problem and its current definition. 927 1

Tissue from primary tumors was analyzed for 118 patients with urothelial cancer who subsequently received cisplatin-based chemotherapy. Immunohistochemical staining was performed for nuclear p53 reactivity; for two proposed mediators of drug resistance, metallothionein (MT) and P-glycoprotein; and for the cell proliferation marker MIB-1. For each marker, immunoreactivity was expressed as a percentage of positively staining cells, and overall intensity of staining was graded on a scale from 0 to 3. The product of these two measurements was calculated to generate a percentage-intensity index. Clinical data were obtained independently via retrospective chart review. Chemotherapy regimens containing cisplatin (cisplatin, methotrexate, and vinblastine or methotrexate, vinblastine, doxorubicin, and cisplatin) were administered for metastatic disease (n = 64), for locally advanced disease (n = 45), or as an adjuvant treatment (n = 9). The overall response rate was 56% among 99 evaluable patients, and median survival was 12.7 months. By univariate analysis, Eastern Cooperative Oncology Group performance status (P = 0.0025), tumor grade (P = 0.03), percentage of MT staining (P = 0.01), and percentage-intensity index of MT staining (P = 0.04) were significant predictors of response to chemotherapy. The first three of these were significant in a multivariate model (P = 0.05, 0.04, and 0.04, respectively). By subgroup analysis, the percentage of MT staining predicted for response in metastatic disease (P = 0.03), but not in locally advanced disease (P = 0.28). Only performance status was significantly related to overall survival (P = 0.0001, log-rank test) in the whole cohort. Overexpression of MT in the 64 patients with metastatic disease was associated with a shorter survival (P = 0.04). Expression of p53, P-glycoprotein, and MIB-1 did not predict for survival. In conclusion, overexpression of MT is associated with a poorer outcome from chemotherapy, possibly due to cisplatin resistance.
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PMID:The prognostic role of p53, metallothionein, P-glycoprotein, and MIB-1 in muscle-invasive urothelial transitional cell carcinoma. 953 22


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