Involvement of drug transporters in the synergistic action of FOLFOX combination chemotherapy

Abstract

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In conclusion, we propose as one mechanism for FOLFOX synergism the 5-FU mediated suppression of ATP7B, the over-expression of glutathione exporters such as MRP2/ABCC2 and the decrease of glutathione levels by oxalate.

Cellular Pharmacokinetic/Pharmacodynamic Relationship of Platinum Cytostatics in Head and Neck Squamous Cell Carcinoma Evaluated by Liquid Chromatography Coupled to Tandem Mass Spectrometry

“…In particular, HNO210 with the highest expression of SLC22A2 (encoding OCT2) concurrently demonstrated profound accumulation of both cisplatin and oxaliplatin, underlining recent findings demonstrating OCT2 to be a major determinant of the uptake and cytotoxicity of these drugs (Burger et al, 2010). HNO210 also had the highest expression of ABCC2 (encoding MRP2) that is involved in the efflux of Pt drugs, thus lowering intracellular Pt concentrations and mediating drug resistance (Taniguchi et al, 1996;Cui et al, 1999;Guminski et al, 2006 (Theile et al, 2009). This might be related to MRP2-mediated deprivation of GSH levels increasing Pt drug efficacy (Theile et al, 2009).…”

“…Polymerase chain reaction amplification was carried out in 20 l of reaction volume containing 5 l of 1:10 diluted cDNA by using the SYBR Green format with the Absolute QPCR SYBR Green Mix (Abgene, Hamburg, Germany). Primer sequences were published previously (Theile et al, 2009(Theile et al, , 2011. The following genes were quantified: ABCC2 (encoding for MRP2), SLC22A1 (encoding for OCT1), SLC22A2 (encoding for OCT2), SLC31A1 (encoding for human copper transporter 1), ATP7A, and ATP7B.…”

Determination of Pt–DNA adducts and the sub-cellular distribution of Pt in human cancer cell lines and the leukocytes of cancer patients, following mono- or combination treatments, by inductively-coupled plasma mass spectrometry

“…The partitioning assay affords opportunity to establish whether the reported synergy from combining oxaliplatin, 5-FU and folinic acid in the FOLFOX regimen could be related to changes in Pt distribution in the cell or adduct formation. The data presented in Figure 3 combination [84]. The partitioning assay was also applied to study the effect of Se supplementation combined with oxaliplatin.…”

285 Downregulation of Organic Cation Transporters Oct1 (Slc22a1) and Oct3 (Slc22a3) in Human Hepatocellular Carcinoma and Their Prognostic Significance

“…Downregulation in HCC could be responsible for a worse or lacking response towards platin treatment. In colorectal cancer OCTs are determinants of oxaliplatin cytotoxicity [11,[25][26][27]. Moreover, SLC22A3 expression in renal cell carcinoma cell lines enhances the sensitivity towards chemotherapeutics as melphalan, irinotecan and vincristin [28].…”