Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Four rhabdomyosarcoma and three neuroblastoma cell lines were characterised for the presence of P-glycoprotein and MDR-1 expression using immunohistochemistry, northern analysis, RT-PCR and in situ mRNA hybridisation. None of the rhabdomyosarcoma lines were unequivocally positive in contrast to all three neuroblastoma lines. Chemosensitivity to cytotoxic agents was determined using the MTT assay and chemosensitisation by cyclosporin and verapamil was evaluated. In a single rhabdomyosarcoma line (HX 170) there was sensitisation to etoposide using verapamil but not to other drugs or using cyclosporin A. In contrast, in all three neuroblastoma lines both cyclosporin and verapamil sensitised to vincristine and doxorubicin. No evidence of sensitisation to etoposide was apparent. The sensitisation was most marked for vincristine, using either modulator and therefore the influence of modulator scheduling was evaluated with this drug in the neuroblastoma line SK N BE. Prolonged pre-exposure to modulator did not appear necessary and maximum sensitisation was apparent where either cyclosporin or verapamil was added 1-3 h prior to and post vincristine. Continuity of exposure was important and even a break of 30 min appeared to reduce sensitisation. These data confirm the potential for chemosensitisation in MDR-1 positive neuroblastoma cell lines and provide some basis for rational schedule design in clinical practice. Because of the probability that vincristine resistance is predominantly related to MDR-1 and less multifactorial than for other drugs such as doxorubicin or etoposide, this agent should be considered for inclusion in any clinical evaluation of MDR reversal strategies.
 ...
PMID:Multidrug resistance modulation in rhabdomyosarcoma and neuroblastoma cell lines. 953 41

The MDM2 protein is known to be overexpressed in some sarcomas including rhabdomyosarcoma. However, the extent to which the MDM2 protein influences sensitivity to chemotherapeutic drugs is unclear. We have analysed this further using stable transfection of the mdm2 gene into 4 well-characterised human paediatric rhabdomyosarcoma cell lines. Transfection with the mdm2 gene resulted in increased levels of the MDM2 protein in all the cell lines. In 2 of the lines, SCMC and RD, the mdm2 gene caused between 2-fold and 61-fold increase in resistance to vincristine, etoposide and doxorubicin but not to cisplatin. In these lines there was an increase in expression of the mdr-1 gene which encodes P-glycoprotein, but not the mrp1 gene which encodes the multidrug resistance protein (MRP). The resistance was reversible using the MDR modulator PSC833, confirming the presence of P-glycoprotein. We conclude that MDM2 overexpression may be a mechanism by which multidrug resistance is regulated in some rhabdomyosarcomas.
 ...
PMID:High levels of the MDM2 oncogene in paediatric rhabdomyosarcoma cell lines may confer multidrug resistance. 1174 97

Overexpression of multidrug resistance-1 (MDR-1), and multidrug resistance-associated protein (MRP) genes has been linked with resistance to chemotherapy in vitro and in vivo. Their role in chemotherapy resistance in pediatric rhabdomyosarcoma is unclear. The study was undertaken to analyze the expression of MDR-1 and MRP genes in the embryonal and the alveolar subtypes of rhabdomyosarcoma and to elucidate its clinical relevance. Twenty-three rhabdomyosarcoma samples were analyzed for the expression of MDR-1 and MRP genes using a semi-quantitative competitive RT-PCR assay. MRP gene expression was associated with a reduction in survival (p=0.02). The overall survival of patients with tumors positive or negative for MRP expression were 50% (95% confidence interval, 30-70%) and 93% (95% confidence interval, 76-100%) respectively. In contrast, the expression of MDR-1 gene was not predictive of survival. These findings suggest that MRP expression could be a prognostic factor in patients with rhabdomyosarcoma.
 ...
PMID:Expression of multidrug resistance-1 and multidrug resistance-associated protein genes in pediatric rhabdomyosarcoma. 1465 23

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.
 ...
PMID:Effects of standard chemotherapy on tumor growth and regulation of multidrug resistance genes and proteins in childhood rhabdomyosarcoma. 1721 91