P-glycoprotein Expression: Critical Determinant in the Response to Osteosarcoma Chemotherapy

Chan, Helen S. L.; Grogan, Thomas M.; Haddad, Ghazal; DeBoer, Gerrit; Ling, Victor

doi:10.1093/jnci/89.22.1706

Cited by 121 publications

(67 citation statements)

References 43 publications

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“…Heterogeneity for disease progression was driven in particular by two studies with opposing results. Chan et al 12 described a very impressive correlation between Pgp and clinical disease progression. Conversely, Wunder et al 7 found no such association in the largest study conducted to date, but their CIs suggest that a modest association with disease progression could not be ruled out.…”

Section: Discussionmentioning

confidence: 99%

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The association of P‐glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma

Pakos

Ioannidis

2003

Cancer

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The nm23‐H1 gene is known as a potential metastasis suppressor gene in various types of carcinomas. However, the role of nm23‐H1 in colorectal carcinoma still remains controversial and the cellular mechanisms by which its protein may modulate the metastatic phenotype are not yet known. We transfected nm23‐H1 cDNA into the human colon cancer cell line, HT‐29, to test the effects and cellular biological mechanism of nm23 protein in colon cancer. We found that nm23‐H1 strongly inhibited the liver metastasis of HT‐29 cells in nude mice and inhibited the epidermal growth factor (EGF)‐induced cell migration in vitro. Furthermore, we clarified the regulation of the myosin light chain (MLC) phosphorylation by nm23‐H1, which has been demonstrated as having potential role in cell migration. © 2003 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

“…Several studies have tried to investigate the role of Pgp in osteosarcoma, but the overall results remain controversial. [5][6][7][8][9][10][11][12][13][14][15][16][17][18] Single studies are limited unavoidably in terms of sample size, even when multicenter efforts are undertaken. However, the total accumulated data provide a considerable body of evidence.…”

mentioning

confidence: 99%

The association of P‐glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma

Pakos

Ioannidis

2003

Cancer

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“…Certainly, the protein is endogenously expressed in a variety of tumours (for a review see Goldstein, 1996). Furthermore, the expression is frequently induced or upregulated following chemotherapy particularly in breast and the gastrointestinal tract (Schneider et al, 1989;Ro et al, 1990;Chan et al, 1991Chan et al, , 1997Pirker et al, 1993;Tokunaga et al, 2001;Coley et al, 2002).…”

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confidence: 99%

The expression of P-glycoprotein does influence the distribution of novel fluorescent compounds in solid tumour models

et al. 2003

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Solid tumours display a complex drug resistance phenotype that involves inherent and acquired mechanisms. Multicellular resistance is an inherent feature of solid tumours and is known to present significant barriers to drug permeation in tumours. Given this barrier, do acquired resistance mechanisms such as P-glycoprotein (P-gp) contribute significantly to resistance? To address this question, the multicellular tumour spheroid (MCTS) model was used to examine the influence of P-gp on drug distribution in solid tissue. Tumour spheroids (TS) were generated from either drug-sensitive MCF7 WT cells or a drug-resistant, P-gp-expressing derivative MCF7 Adr . Confocal microscopy was used to measure time courses and distribution patterns of three fluorescent compounds; calcein-AM, rhodamine123 and BODIPY-taxol. These compounds were chosen because they are all substrates for P-gp-mediated transport, exhibit high fluorescence and are chemically dissimilar. For example, BODIPY-taxol and rhodamine 123 showed high accumulation and distributed extensively throughout the TS WT , whereas calcein-AM accumulation was restricted to the outermost layers. The presence of P-gp in TS Adr resulted in negligible accumulation, regardless of the compound. Moreover, the inhibition of P-gp by nicardipine restored intracellular accumulation and distribution patterns to levels observed in TS WT . The results demonstrate the effectiveness of P-gp in modulating drug distribution in solid tumour models. However, the penetration of agents throughout the tissue is strongly determined by the physico-chemical properties of the individual compounds.

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“…Although resistance to doxorubicin in human tumor cells may be caused by different mechanisms, including increased efflux, more efficient intracellular detoxification, alterations of topo-isomerase II and increased DNA repair, the most relevant mechanism of doxorubicin resistance in OSA has been demonstrated to be the ATP-binding cassette (ABC) transporters mediated drug efflux (Chou et al, 2006). In particular, high expression of ABCB1 protein (also known as MDR1 or P-glycoprotein) has bee n demonstrated to be responsible for doxorubicin resistance in human OSA cell lines and to be associated with an adverse clinical outcome in high-grade, non-metastatic OSA patients treated with conventional chemotherapy protocols (Baldini et al, 1995;Chan et al, 1997;Pakos et al, 2003;Serra et al, 2003). However, a few studies did not confirm this evidence (Gorlick et al, 1999;Schwartz et al, 2007) and have been recently discussed (Serra et al, 2007).…”

Section: Mechanisms Of the Chemotherapy Resistance By Abcb1 To Doxorumentioning

confidence: 99%

Review of the Molecular Pathogenesis of Osteosarcoma

Hao²,

Wang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

124

109

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Treating the osteosarcoma (OSA) remains a challenge. Current strategies focus on the primary tumor and have limited efficacy for metastatic OSA. A better understanding of the OSA pathogenesis may provide a rational basis for innovative treatment strategies especially for metastases. The aim of this review is to give an overview of the molecular mechanisms of OSA tumorigenesis, OSA cell proliferation, apoptosis, migration, and chemotherapy resistance, and how improved understanding might contribute to designing a better treatment target for OSA.

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P-glycoprotein Expression: Critical Determinant in the Response to Osteosarcoma Chemotherapy

Abstract: P-glycoprotein expression does correlate with treatment failure in patients with osteosarcoma. This correlation raises the possibility that inhibiting the action of P-glycoprotein as part of therapy for this disease would improve outcome.

Cited by 121 publications

References 43 publications

The association of P‐glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma

The association of P‐glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma

The expression of P-glycoprotein does influence the distribution of novel fluorescent compounds in solid tumour models

Review of the Molecular Pathogenesis of Osteosarcoma

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