Expression of P-Glycoprotein in High-Grade Osteosarcomas in Relation to Clinical Outcome

Abstract

In patients with high-grade osteosarcoma treated with surgery and chemotherapy, the presence of increased levels of P-glycoprotein in tumor cells is associated with a significantly increased risk of adverse events and is independent of the extent of necrosis after preoperative chemotherapy.

Drug selection of MDR1-transduced hematopoietic cells ex vivo increases transgene expression and chemoresistance in reconstituted bone marrow in mice

“…Substrates of this multidrug transporter include many drugs used in clinical cancer treatment, eg Vinca alkaloids, taxanes, anthracyclines, epipodophyllotoxins, colchicine and actinomycin D. Hence, overexpression of P-gp is associated with failure of anticancer chemotherapy in various malignancies. [6][7][8] tion increased the frequency of chemoresistant colonies up to 40% over the number of unselected cells. Colchicine and daunomycin were equally efficient in increasing drug resistance ex vivo, but colchicine-preselected cells rescued lethally irradiated mice under conditions where daunomycinselected bone marrow cells failed to do so.…”

Global Protein-expression Analysis of Bone and Soft Tissue Sarcomas

“…Over the last decade, considerable efforts have been made for this purpose. Not only classic parameters such as histologic subtype, tumor location, and presence of metastatic disease at diagnosis [1], but also several molecules related to drug metabolism/ transport or tumor development have been reported to correlate with the chemosensitivity of osteosarcoma [3,15,17,23].…”

Review of the Molecular Pathogenesis of Osteosarcoma

“…Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that can degrade the ECM and facilitate cellular invasion and migration (Baldini et al, 1995). High MMP-9 expression was observed in pre-treatment OSA tumor samples and in a majority of metastatic lesions, leading to speculation that MMP-9 expression is associated with the micrometastatic behavior of OSA (Himelstein et al, 1998).…”

“…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).…”