Universitatmedizin Gottingen

Göttingen, Germany

Universitatmedizin Gottingen

Göttingen, Germany

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Marada V.V.V.R.,Universitatmedizin Gottingen | Florl S.,PortaCellTec Biosciences GmbH | Kuhne A.,PortaCellTec Biosciences GmbH | Muller J.,Universitatmedizin Gottingen | And 3 more authors.
Pharmacological Research | Year: 2015

The ability of an antineoplastic drug to exert its cytostatic effect depends largely on the balance between its uptake into and extrusion from the cancer cells. ATP driven efflux transporter proteins drive the export of antineoplastic drugs and play a pivotal role in the development of chemoresistance. As regards uptake transporters, comparably less is known on their impact in drug action. In the current study, we characterized the interactions of two uptake transporter proteins, expressed mainly in the liver; the organic anion transporter 2 (OAT2, encoded by the SLC22A7 gene) and the sodium taurocholate cotransporting polypeptide (NTCP, encoded by the SLC10A1 gene), stably transfected in human embryonic kidney cells, with some antineoplastic agents that are routinely being used in cancer chemotherapy. Whereas NTCP did not show any strong interactions with the cytostatics tested, we observed a very strong inhibition of OAT2 mediated [3H] cGMP uptake in the presence of bendamustine, irinotecan and paclitaxel. The Ki values of OAT2 for bendamustine, irinotecan and paclitaxel were determined to be 43.3 ± 4.33 μM, 26.4 ± 2.34 μM and 10.4 ± 0.45 μM, respectively. Incubation of bendamustine with OAT2 expressing cells increased the caspase-3 activity, and this increase was inhibited by simultaneous incubation with bendamustine and probenecid, a well-known inhibitor of OATs, suggesting that bendamustine is a substrate of OAT2. A higher accumulation of irinotecan was observed in OAT2 expressing cells compared to control pcDNA cells by HPLC analysis of cell lysates. The accumulation was diminished in the presence of cGMP, the substrate we used to functionally characterize OAT2, suggesting specificity of this uptake and the fact that OAT2 mediates uptake of irinotecan. © 2014 Elsevier Ltd. All rights reserved.


Gupta S.,Universitatmedizin Gottingen | Wulf G.,Universitatmedizin Gottingen | Henjakovic M.,Universitatmedizin Gottingen | Koepsell H.,University of Würzburg | And 2 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2012

Antineoplastic agents directed at nuclear and cytoplasmic targets in tumor cells represent the current mainstay of treatment for patients with disseminated malignant diseases. Cellular uptake of antineoplastics is a prerequisite for their efficacy. Five of six lymphoma cell lines as well as primary samples from chronic lymphocytic leukemia patients demonstrated significant expression of SLC22A1 mRNA coding for organic cation transporter 1 (OCT1). Functionally, the antineoplastic agents irinotecan, mitoxantrone, and paclitaxel inhibited the uptake of the organic cation [ 3H]1-methyl-4-pyridinium iodide into OCT1-transfected Chinese hamster ovary model cells, with K i values of 1.7, 85, and 50 μM, respectively. Correspondingly, OCT1-positive cell lines and transfectants exhibited significantly higher susceptibilities to the cytotoxic effects of irinotecan and paclitaxel compared with those of OCT1-negative controls. We hypothesize that OCT1 can contribute to the susceptibility of cancer cells to selected antineoplastic drugs. In the future, an expression analysis of the transporters and the application of transporter-specific antineoplastic agents could help to tailor cancer therapy. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics.


PubMed | Universitatmedizin Gottingen
Type: Comparative Study | Journal: The Journal of pharmacology and experimental therapeutics | Year: 2012

Antineoplastic agents directed at nuclear and cytoplasmic targets in tumor cells represent the current mainstay of treatment for patients with disseminated malignant diseases. Cellular uptake of antineoplastics is a prerequisite for their efficacy. Five of six lymphoma cell lines as well as primary samples from chronic lymphocytic leukemia patients demonstrated significant expression of SLC22A1 mRNA coding for organic cation transporter 1 (OCT1). Functionally, the antineoplastic agents irinotecan, mitoxantrone, and paclitaxel inhibited the uptake of the organic cation [(3)H]1-methyl-4-pyridinium iodide into OCT1-transfected Chinese hamster ovary model cells, with K(i) values of 1.7, 85, and 50 M, respectively. Correspondingly, OCT1-positive cell lines and transfectants exhibited significantly higher susceptibilities to the cytotoxic effects of irinotecan and paclitaxel compared with those of OCT1-negative controls. We hypothesize that OCT1 can contribute to the susceptibility of cancer cells to selected antineoplastic drugs. In the future, an expression analysis of the transporters and the application of transporter-specific antineoplastic agents could help to tailor cancer therapy.

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