P-glycoprotein expression in soft-tissue sarcomas

Nakanishi, Hirofumi; Myoui, Akira; Ochi, Takahiro; Aozasa, Katsuyuki

doi:10.1007/bf01438312

Cited by 24 publications

(15 citation statements)

References 18 publications

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“…Komdeur and colleagues found that MRP1 and lung resistance-related protein expression by immunohistochemistry was significantly higher in grades 2 and 3 STS, when compared with grade 1 (12) whereas Oda and colleagues detected a significant correlation between P-gp expression and the largest tumors (!5 cm) or high AJCC-staged tumors (13). In similar vein, Nakanishi and colleagues also documented that tumors expressing P-gp had a less favorable prognosis among high-or intermediate-grade STS in a series of 55 cases, some of which were treated with adjuvant chemotherapy (28). In synovial sarcoma, P-gp, and to a lesser extent MRP1, were not prognostic factors in a series of 54 cases (29).…”

Section: Discussionmentioning

confidence: 87%

“…The most plausible mechanism underlying the poor prognosis of ABCC1/MRP1 is related to its ability to remove diverse xenobiotics from the cell, including anticancer drugs. Besides this, some authors have found that MDR expression, at protein and/or RNA level, correlated with high grade (12,13,28) or stage III/IV (13) in STS. This is something that is not possible to test in our series, because only highest grade (G3 according FNLCC) and stage III were included.…”

Section: Discussionmentioning

confidence: 92%

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MRP1 Overexpression Determines Poor Prognosis in Prospectively Treated Patients with Localized High-Risk Soft Tissue Sarcoma of Limbs and Trunk Wall: An ISG/GEIS Study

Martin‐Broto

Gutiérrez

Ramos

et al. 2014

Molecular Cancer Therapeutics

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Patients with localized high-risk soft tissue sarcomas (STS) of the limbs and trunk wall still have a considerable metastatic recurrence rate of more than 50%, in spite of adjuvant chemotherapy. This drugceiling effect of chemotherapy in sarcoma setting could be explained, at least partially, by multidrug resistance (MDR) mechanisms. The aim of this study was to ascertain whether mRNA and protein expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and GSTA1 (glutathione S-transferase pi) was prognostic in localized high-risk STS. Immunohistochemistry and reverse transcriptase-PCR studies were performed from biopsies at the time of diagnosis. Patients of this series were prospectively enrolled into a phase III trial that compared three versus five cycles of epirubicin plus ifosfamide. The series of 102 patients found 41 events of recurrence and 37 of death with a median follow-up of 68 months. In univariate analysis, variables with a statistically significant relationship with relapse-free survival (RFS) were: MRP1 expression (5-year RFS rate of 23% in positive cases and 63% in negative cases, P ¼ 0.029), histology (5-year RFS rate of 74% in undifferentiated pleomorphic sarcoma and 43% in synovial sarcoma, P ¼ 0.028), and ABCC1 expression (5-year RFS rate of 33% in overexpression and 65% in downregulation, P ¼ 0.012). Combined ABCC1/MRP1 was the only independent prognostic factor for both RFS (HR ¼ 2.704, P ¼ 0.005) and overall survival (HR ¼ 2.208, P ¼ 0.029). ABCC1/MRP1 expression shows robust prognostic relevance in patients with localized high-risk STS treated with anthracycline-based chemotherapy, which is the standard front line treatment in STS. This finding deserves attention as it points to a new targetable protein in STS.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 92%

MRP1 Overexpression Determines Poor Prognosis in Prospectively Treated Patients with Localized High-Risk Soft Tissue Sarcoma of Limbs and Trunk Wall: An ISG/GEIS Study

Martin‐Broto

Gutiérrez

Ramos

et al. 2014

Molecular Cancer Therapeutics

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“…Various mechanisms are involved in clinical drug resistance, but best studied is overexpression of MDR proteins, which leads to decreased intracellular accumulation of cytotoxic drugs. Score\group I II III IV I II III IV I II III IV 0 2 3 7 1 2 5 10 1 1 3 16 4 1 0 0 1 0 0 0 0 0 0 0 0 0 2 1 1 1 1 1 0 1 0 0 1 2 0 3 1 1 5 2 0 0 3 2 3 1 1 1 4 2 1 10 3 3 1 10 4 2 1 MDR protein expression has been studied in various primary paediatric solid tumours (3,17,18,20,(30)(31)(32)(33)(34)(35). De Cremoux et al investigated the clinical significance of mRNA expression level of MDR-associated genes in 29 advanced neuroblastoma samples and showed that P-gp and MRP1 mRNA overexpression was present in 74 and 30% of cases, respectively (31).…”

Section: Discussionmentioning

confidence: 99%

Expression of multidrug resistance-associated proteins in paediatric soft tissue sarcomas before and after chemotherapy

et al. 2012

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Abstract. Expression of multidrug resistance (MDR) proteins is thought to significantly contribute to the different biological/ clinical behaviour of soft tissue sarcomas (STS) of various histological types and clinicopathological stages, as they are responsible for active efflux of cytotoxic drugs from tumour cells. We investigated the expression of 3 MDR proteins, i.e., permeability glycoprotein 1 (P-gp), multidrug resistance-associated protein 1 (MRP1) and multidrug resistance 3 (MDR3), in 43 STS specimens from newly-diagnosed paediatric patients, 31 with rhabdomyosarcoma (RMS) and 12 with non-RMS STS. To assess the influence of chemotherapy on STS drug resistance, the number of MDR-associated protein-positive cells was determined in 15 patients on both primary lesions before chemotherapy and on residual tumour after chemotherapy. At least one of the MDR-associated proteins tested was detected in 84% of primary untreated STS specimens. In these specimens, MRP1 was detected in a high percentage (70%) of the cases, followed by MDR3 in 58% and P-gp in 44%. Many specimens showed co-expression of two different MDR proteins. Interestingly, MDR3 was significantly associated with the presence of PAX3/ PAX7-FKHR transcripts in RMS (p<0.05). Moreover, expression of MRP1 and MDR3 was significantly more frequent in group III and IV tumours as compared with those of groups I and II (p<0.01). After chemotherapy MRP1, MDR3 and, to a lesser extent, P-gp expression was found to be increased in most of the samples. The frequent expression of these MDR-associated proteins in primary tumour cells before chemotherapy and the increase of their levels after chemotherapy, suggest that these proteins play a pivotal role in conferring drug resistance and in producing therapy-induced differentiation on STS.

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“…Synovial sarcoma RT-PCR Poor prognosis (7) , high proliferative rate (8) PAX3-FKHR Alveolar RMS RT-PCR Poor prognosis (2) Tumor-suppressor genes p53 and MDM2 coexpression Mixed STS IHC Poor prognosis (9) Dedifferentiated LS IHC Dedifferentiation (10) p53 Mixed STS IHC Poor prognosis (11) Mixed STS Mutation Poor prognosis (12) Leiomyosarcoma IHC, mutation Poor prognosis in deep tumor (13) Synovial sarcoma IHC Poor prognosis (14) Myxoid/round cell LS IHC Poor prognosis (15) Myxoid/round cell LS IHC, mutation High histological grade, poor prognosis (16) ES/PNET IHC Poor prognosis (17) DFSP Mutation Malignant transformation to fibrosarcoma (18) MDM2 mRNA Mixed STS qRT-PCR Poor prognosis (19) p16 INK4a Leiomyosarcoma IHC Poor prognosis (20) p14 ARF Myxoid/round cell LS IHC Poor prognosis (16) RB Dedifferentiated LS IHC, LOH, mutation Dedifferentiation (21) DAP kinase, p53 Leiomyosarcoma MSP, mutation High histological grade, poor prognosis (22) RASSF1A Mixed STS MSP Poor prognosis, frequent in leiomyosarcoma (23) Cell cycle regulators CHFR MPNST IHC Poor prognosis (24) p21 WAF1 Myxofibrosarcoma IHC High histological grade, poor prognosis (25) Growth factors and receptors EGFR Mixed STS IHC Poor prognosis (26) HGF/MET coexpression Synovial sarcoma IHC Poor prognosis (27) Multidrug resistance P-glycoprotein Mixed STS IHC Poor prognosis (28) Mixed STS IHC Poor response to chemotherapy (29) Mixed STS IHC Large tumor size, high stage (30) MDR1/MRP1, coexpression…”

Section: Ss18-ssx1mentioning

confidence: 99%

“…Several investigators have demonstrated that overexpression of P-gp is associated with poor prognosis in several kinds of STS, (28) as well as with poor pathological response to chemotherapy. (29) Coexpression of MDR1 and MRP1 mRNA was significantly correlated with tumor grade in STS.…”

Section: Multidrug Resistancementioning

confidence: 99%

Recent advances in the molecular pathology of soft tissue sarcoma: Implications for diagnosis, patient prognosis, and molecular target therapy in the future

Oda

Tsuneyoshi

2009

Cancer Science

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In the present paper, recent advances in the molecular pathology of soft tissue sarcomas (STS) and the implications for their prognostic value are reviewed, and the potential targets of molecular therapy are discussed. According to the molecular genetic aspect, STS are divided into two groups: chromosome translocation-associated sarcomas and sarcomas without specific translocation. In the former group, specific fusion transcripts, such as SS18-SSX, EWS-FLI1, and PAX3-FKHR, could be detected in synovial sarcoma, Ewing's sarcoma and primitive neuroectodermal tumor, and alveolar rhabdomyosarcoma, respectively. The direct or indirect interactions between these fusion transcripts and cell cycle regulators have been elucidated by several investigators. Therefore, these fusion transcripts are promising candidates as molecular targets. As evaluated in carcinomas, alterations of several tumor-suppressor genes and adhesion molecules and overexpression of growth factors and their receptors have been extensively assessed in STS. In mixed-type STS, epidermal growth factor receptor overexpression was associated with decreased overall survival, suggesting the beneficial role of epidermal growth factor receptor inhibitors in STS. In malignant rhabdoid tumor and epithelioid sarcoma, frequent alteration of the SMARCB1/INI1 tumor-suppressor gene and the loss of its protein have been demonstrated, indicating that this molecule could be an effective target of these sarcomas. In sarcomas with epithelioid differentiation, such as synovial sarcoma and epithelioid sarcoma, overexpression of dysadherin, which downregulates E-cadherin expression, was a poor prognostic factor. In conclusion, further studies are necessary to search for effective and specific molecules for the inhibition of tumor growth in each type of STS, especially in sarcomas without specific translocation. (Cancer Sci 2009; 100: 200-208) S oft tissue sarcomas are relatively rare malignant neoplasms compared with carcinomas and other neoplasms, and they constitute less than 1% of all cancers. STS are composed of many histological subtypes, such as pleomorphic undifferentiated sarcoma or malignant fibrous histiocytoma, leiomayosarcoma, and liposarcoma. In addition to their wide variety of subtypes, it is often difficult to make an accurate histological diagnosis because certain kinds of STS share similar morphological features. However, it is important to make a definitive diagnosis so that adequate therapy can be administered in each case. Recently, several reciprocal chromosomal translocations and fusion transcripts have been proven to be characteristic of particular histological types (Table 1; Fig. 1). The detection of these fusion transcripts is useful for the differential diagnosis of histologically peculiar cases.In relapsed cases of STS complete remission is difficult, despite the conventional multidisciplinary therapy. Therefore, novel therapies such as molecular target therapy are required, especially in relapsed cases. Several investigators have analyzed tumor-...

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P-glycoprotein expression in soft-tissue sarcomas

Cited by 24 publications

References 18 publications

MRP1 Overexpression Determines Poor Prognosis in Prospectively Treated Patients with Localized High-Risk Soft Tissue Sarcoma of Limbs and Trunk Wall: An ISG/GEIS Study

MRP1 Overexpression Determines Poor Prognosis in Prospectively Treated Patients with Localized High-Risk Soft Tissue Sarcoma of Limbs and Trunk Wall: An ISG/GEIS Study

Expression of multidrug resistance-associated proteins in paediatric soft tissue sarcomas before and after chemotherapy

Recent advances in the molecular pathology of soft tissue sarcoma: Implications for diagnosis, patient prognosis, and molecular target therapy in the future

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