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)

The introduction of new drugs may offer significant hope for improvement in the treatment of breast cancer. They include new cytotoxic agents such as Taxanes, Topoisomerase inhibitor, MDR modulator, new hormone such as 3rd generation nonsteroidal aromatase inhibitor, pure antiestrogen for patients with refractory metastatic breast cancer and new bisphosphonates for those who have metastases to bone. Therefore, some reports evaluating such new drugs were reviewed. Japanese studies revealed response rate of Taxanes in the treatment of metastatic breast cancer as follows; Six out of 22 (27%) with 1 CR for 24 hours infusion, 21 out of 52 (34%) with 2 CR for 3 hours infusion of paclitaxel respectively, 21 out of 31 (41%) with 2 CR for 1 hour infusion, and 32 out of 72 (44%) with 5 CR for 1 hour infusion of Docetaxel, In addition, the MTD of the combination was reached at dose level with 60 mg/sqm of Docetaxel and 400 mg/sqm of cyclophosphamide. As regards hormone therapy, thirty four out of 176 (19%) with 5 CR were observed in phase II study of Fadrozol but results from the phase II study of 3rd generation aromatase inhibitor is not yet accomplished in Japan. However, any european reports did not show a difference in response rate in patients with tamoxifen refractory breast cancer between newer aromatase inhibitor and megasterol, and a good choice of hormones in the treatment of metastatic breast cancer appears to be difficult.
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PMID:[New drugs in metastatic breast cancer--1997]. 935 Feb 35

Much remains to be learned about drug resistance in the biology of RCC and its metastases. We measured MDR-1/P-glycoprotein expression in 19 tumor samples from patients with metastatic RCC by RNase protection and quantitative PCR assays. The median level of the 16 tumor metastases was 4.9 (range: 0.10 to 156.2) relative to the level of 10 assigned to a reference cell line, SW620, which has been characterized as expressing a minimum level of MDR-1. Since these levels were lower than expected for RCC, we asked whether the metastases possessed a phenotype different from primary RCC and examined MDR-1 expression in 5 paired cell lines derived from primary and metastatic RCC. In 8/10 lines, MDR-1 expression was >10. Relative to the level in the primary line, MDR-1 expression was decreased (3 to 50-fold) in 3 metastatic lines, was increased in 1, and unchanged in 1. MRP mRNA expression was lower in the metastatic lines while EGFR expression was variable. IC50 values for 6 compounds (including 4 standard agents and one new Phase 1 agent) were determined for the paired lines. Rhodamine and calcein efflux assays were performed as measures of P-glycoprotein and MRP function. Rhodamine efflux correlated with MDR-1 mRNA expression (r = 0.87) and with the IC50s (r = 0.60) for paclitaxel in the paired cell lines. In contrast, calcein efflux did not correlate with MRP expression. Lastly, MDR-1 expression correlated with cytokeratin 8 (CK8) protein levels, a measure of cellular differentiation. In sum, these data suggest renal cell carcinoma (RCC) metastases have altered MDR-1 expression potentially due to altered differentiation relative to the primary tumor. Thus, the drug resistance phenotype of primary RCC tumors may not reflect that of their metastases.
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PMID:Intrinsic drug resistance in primary and metastatic renal cell carcinoma. 1037 90

The prognosis of patients with tumors expressing P-glycoprotein (P-gp), the MDR1 gene product, is generally poor. It is assumed that this is due to decreased tumor responsiveness that results from decreased drug accumulation. We observed that treatment of animals bearing MDR1-transfected leukemic cells with P-gp substrates (i.e., drugs that are transported by P-gp) significantly worsened host survival compared to treatment with vehicle or non-P-gp substrates. This effect was seen with cancer chemotherapeutic agents (paclitaxel and vincristine) and with the MDR modulator, trans-flupenthixol. To determine the mechanism(s) underlying this observation, we studied alterations in pharmacokinetics, pharmacodynamics, and metastasis. We found that the drug-induced acceleration of disease was associated with increased metastases. P-gp(+) cells treated with P-gp substrates demonstrated several pro-metastatic features, including membrane ruffling and invasion through a hepatocyte monolayer. These results suggest that the treatment of MDR tumors with P-gp substrates may produce changes in malignant behavior that could adversely affect therapeutic outcomes.
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PMID:Treatment of multidrug resistant (MDR1) murine leukemia with P-glycoprotein substrates accelerates the course of the disease. 1058 Nov 84

We report an aggressively behaving malignant trichogenic tumor arising in a trichoblastoma (TB) with widespread lymphatic and hematogenous metastases in a 55-year-old man with a concomitant B-cell chronic lymphocytic leukemia. The primary tumor had been present and unchanged for as long as 40 years before excision. Typical trichogenic TB with dystrophic calcification and even ossification was still present peripheral to the malignant transformation. The malignant neoplasm consisted of basaloid cells, spindle cells arranged in fascicles and densely packed rounded nests or "cell balls." The metastases consisted of immature basaloid cells and cell balls, and the recurrences became successively more undifferentiated. The residual TB reacted with antibodies to cytokeratin (CK) 6, 8, 14, and 17 and focally to S-100; the malignant primary tumor reacted uniformly with antibodies to vimentin and only focally with antibodies to CK and S-100. The metastatic tumor had lost epidermal CK expression but maintained expression of S-100 in paraffin-embedded tissues. Trichoblastic differentiation was confirmed in frozen tissues with antibodies to hair keratins. No expression of p53 or bcl-2 was identified, but p-glycoprotein (MDR-1 gene related) was expressed by primary and metastatic tumor cells. We believe that this neoplasm is best classified as a trichoblastic carcinoma arising in a TB in association with a B-cell chronic lymphocytic leukemia. This case illustrates that TBs have the potential for malignant transformation and aggressive behavior.
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PMID:Trichoblastic carcinoma ("malignant trichoblastoma") with lymphatic and hematogenous metastases. 1087 73

serum against SBC-3/DOX cells to a similar extent compared with parental SBC-3 cells. Pretreatment of human effector cells with various cytokines induced further enhancement of the KM966-dependent ADCC against SBC-3/DOX cells. Intravenous injection of SBC-3 or SBC-3/DOX cells into natural killer (NK) cell-depleted severe combined immunodeficient (SCID) mice developed metastases in multiple organs (liver, kidneys and lymph nodes). Interestingly, SBC-3/DOX cells produced metastases more rapidly than SBC-3 cells, suggesting more aggressive phenotype of SBC-3/DOX cells than their parental cells in vivo. Systemic treatment with KM966, given on days 2 and 7, drastically inhibited the formation of multiple-organ metastases produced by both SBC-3 and SBC-3/DOX cells, indicating that KM966 can eradicate metastasis by SCLC cells irrespective of MDR phenotype. These findings suggest that the mouse-human chimeric KM966 targets the GM2 antigen, and might be useful for the immunological circumvention of multiple-organ metastases of refractory SCLC.
Clin Exp Metastasis 2000
PMID:Immunological circumvention of multiple organ metastases of multidrug resistant human small cell lung cancer cells by mouse-human chimeric anti-ganglioside GM2 antibody KM966. 1146 66

Radiotherapy is the modality of choice for the treatment of nasopharyngeal carcinoma (NPC). However, systemic chemotherapy has recently been found to play an increasing role in the treatment of advanced or metastatic disease. The status of drug resistance gene expression that has crucial impact on chemotherapy has not been fully addressed for patients with NPC. In this study, we examined the expression of multidrug resistance 1 (MDR-1) and glutathione-S-transferase-Pi (GST-Pi) in primary, recurrent, and metastatic NPC using results of immunohistochemical examinations. The results were correlated with the expression of Epstein-Barr virus (EBV) latent protein, latent membrane protein 1 (LMP1), and clinicopathologic features, including stage, histopathologic types, and survival rates. MDR-1 protein expression was detected in 18 (12.6%) of 143 patients with primary NPC, 14 (32.6%) of 43 with recurrent NPC, and O (0%) of 20 with metastatic NPC, whereas 83 (58%) of 143 patients with primary NPC, 30 (69.8%) of 43 with recurrent NPC, and 13 (65%) of 20 with metastatic NPC expressed GST-Pi. EBV-LMP1 was expressed in 59 (41.3%) of 143 patients with primary NPC, 23 (53.5%) of 43 with recurrent NPC, and 9 (45%) of 20 with metastatic NPC. Simultaneous expression of MDR1 and GST-Pi was observed in 13 (72.2%) of 18 patients with primary NPC and 12 (85.7%) of 14 with recurrent NPC. The expression of LMP1 was detected in only 6 of the 13 patients with primary NPC and 6 of the 12 with recurrent NPC. We concluded that the expression of GST-Pi was more frequent in NPC tumor tissues than the expression of MDR-1. The expression of MDR-1 correlated with clinicopathologic features of primary NPC, including the histopathologic types and survival rates, but not with disease stage. The expression of GST-Pi did not correlate with clinicopathologic features. The expression of MDR-1 and GST-Pi did not correlate with expression of EBV-LMP1 for patients with NPC.
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PMID:Expression of multidrug resistance 1 and glutathione-S-transferase-Pi protein in nasopharyngeal carcinoma. 1172 64

Growth of human tumor cells as three-dimensional (3D) multicellular spheroids modifies their invasive properties. Here we study the differences in the biological features of MCF-7, a human breast cancer cell line, and its multidrug resistant variant (MDR-MCF-7) cultured as spheroids or as monolayers. Three-dimensional culture decreased the proliferative rate of both cell lines, reduced the drug sensitivity of MCF-7 cells and did not affect the resistance of MDR-MCF-7 cells. Transmission electron microscopic studies and intercellular junctions labeling showed that MCF-7 spheroids had a junctional system involving E-cadherin, tight-junctions and desmosomes. In MDR-MCF-7 cell spheroids, cell cohesion was mostly due to membrane interdigitations. MDR-MCF-7 cells, but not their parental counterpart, displayed a higher invasive potential when cultured as spheroids, as shown in the Boyden chamber assay. 3D-induced invasiveness was correlated with serine protease and plasminogen activator (PA) secretion. MCF-7 cells did not show any tendency to invade, whatever the mode of culture. These results show that 3D-cultures as spheroids distinctively altered structural features of parental and MDR-MCF-7 cells. In MCF-7 cells, 3D-culture increased cell-cell contacts and drug resistance; in MDR-MCF-7 cells, it induced invasive properties.
Clin Exp Metastasis 2002
PMID:Distinctive alterations of invasiveness, drug resistance and cell-cell organization in 3D-cultures of MCF-7, a human breast cancer cell line, and its multidrug resistant variant. 1196 80

Miltefosine is a phospholipid analog that exhibits antineoplastic activity against breast cancer metastases, but its mechanism of action remains uncertain. The aim of this study was to investigate the transport mechanism for the removal of miltefosine and [99mTc]-hexakis-2-methoxyisobutyl isonitrile (99mTc-MIBI) from multidrug-resistant cells. The P-glycoprotein pump function, cell viability, and 99mTc-MIBI and 2-[18F]fluoro-2-deoxy-D-glucose (18FDG) uptakes were measured in NIH 3T3 (3T3) and NIH 3T3MDR1 G185 (3T3MDR1) mouse fibroblasts and human lymphoid B JY cells. Miltefosine treatment increased the permeability and fluidity of these tumor cells in a concentration-dependent manner. The multidrug-sensitive cells were 3-4 times more sensitive to miltefosine than the multidrug-resistant ones. The extent of 99mTc-MIBI accumulation in the P-glycoprotein-expressing cells increased in the presence of miltefosine, whereas the rhodamine123 and daunorubicin uptakes of the cells did not change significantly. In the 3T3MDR1 cells verapamil reinstated the rhodamine123 and daunorubicin accumulation, but not the 99mTc-MIBI uptake. Cyclosporin A reinstated the uptakes of 99mTc-MIBI, daunorubicin and rhodamine123 by the 3T3MDR1 cells. In a concentration-dependent manner miltefosine decreased the extents of 99mTc-MIBI, rhodamine123, daunorubicin and 18FDG accumulation in the JY and 3T3 cells. Our findings indicate a common transport mechanism for 99mTc-MIBI and miltefosine, which is distinct from that for rhodamine123 and daunorubicin in MDR cells.
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PMID:Effects of miltefosine on membrane permeability and accumulation of [99mTc]-hexakis-2-methoxyisobutyl isonitrile, 2-[18F]fluoro-2-deoxy-D-glucose, daunorubucin and rhodamine123 in multidrug-resistant and sensitive cells. 1578 39

The prognosis of rhabdomyosarcoma (RMS) in advanced stages is still sobering. Therapy is limited due to local tumor recurrence, development of metastases and multidrug resistance. The aim of this study was to investigate the development of multidrug resistance in cell lines and in xenografts of alveolar and embryonal RMS treated according to the German Soft Tissue Sarcoma Study (CWS). Alveolar and embryonal RMS cell lines were treated with Vincristine, Topotecan, Carboplatin, Actinomycin D, or Ifosfamide. Expression levels of resistance-associated genes were assessed using Real time-PCR. Nude mice (NMRI nu/nu, n = 10 per group) underwent xenotransplantation of human embryonal or alveolar RMS. Animals were treated with standard chemotherapeutic drugs Vincristine, Topotecan, Carboplatin, Actinomycin D, or Ifosfamide according to treatment schedules of the CWS-study. Tumor sizes were measured and relative tumor volumes were calculated. Animals were sacrificed after 20 days and standard histology, Real-time-PCR for MDR1-, MRP-, LRP- and MDM2-gene as well as immunohistochemistry for MDR1-, LRP-, and MRP-protein were performed. In the cell lines, an up-regulation of MDR-1 gene was found in alveolar rhabdomyosarcoma. In embryonal rhabdomyosarcoma, an up-regulation of LRP and MRP was found. Standard chemotherapy of alveolar rhabdomyosarcoma resulted in a significant reduction of tumor growth (P < 0.05) in all groups. In embryonal rhabdomyosarcoma strongest effects were found after treatment with Ifosfamide, Vincristine and Carboplatin (P < 0.05). RT-PCR revealed a MDR1-dependent mechanism in alveolar rhabdomyosarcoma. In embryonal rhabdomyosarcoma, MDR1 occurred to a lower degree. Immunohistochemistry revealed correlating expression levels of multidrug resistance-associated proteins. The use of established chemotherapy on human RMS in vivo had strong effects on xenografts compared to their controls. In all cases, there was only a reduction of tumor growth, but not a complete eradication of the tumors. Chemotherapy seemed to upregulate the expression of resistance-associated genes in vitro and in vivo. The mechanism of multidrug resistance depends on the tumor subtype. Therefore, further investigations will be required to evaluate multidrug resistance in patients and to investigate new modalities for a reversal of multidrug resistance.
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PMID:Effects of standard chemotherapy on tumor growth and regulation of multidrug resistance genes and proteins in childhood rhabdomyosarcoma. 1721 91

The onset of chemo- and/or radio-resistance in tumour cells is one of the main causes of failure of integrated treatment protocols combining intra-arterial administration of platinum derivatives and radiotherapy, and is associated with recurrent disease and/or distant metastases. In the present study, the expression of a series of markers of chemo- and/or radio-resistance was investigated in 21 patients with advanced squamous cell carcinoma of the head and neck treated with combined intra-arterial carboplatin and radiotherapy. The results were correlated with local response to treatment, recurrence and overall and disease-free survival. In non-responders or in patients presenting recurrence, caspase 8 was significantly (p 0.05) under-expressed while p-Gp (p 0.035) and MDR-3 (p 0.049) were significantly over-expressed. Tumours with unfavourable outcome more frequently over-expressed two or more anti-apoptotic factors (p-53, BCL-2, BCL-x) (p 0.01). Patients with shorter overall survival, significantly overexpressed p53 (p 0.04), LRP (p 0.038) and a larger number of trans-membrane transport proteins compared with those who survived more than one year (p 0.013). Finally, patients with the shortest disease-free survival presented over-expression of p53 (p 0.027) and BCL-x (p 0.023). Further studies are necessary to confirm the possibility, in a future perspective, of using a panel of markers of chemo- and radio-resistance to identify those patients potentially sensitive to the treatment and to avoid patients at high risk of resistance from being submitted to ineffective and toxic treatment protocols.
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PMID:Markers of chemoradiation resistance in patients with locally advanced head and neck squamous cell carcinoma, treated by intra-arterial carboplatin and concurrent radiation. 1795 47


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