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Effect of reactivity on cellular accumulation and cytotoxicity of oxaliplatin analogues

  • Irina Buß
  • Ganna V. Kalayda
  • Andreas Lindauer
  • Michael R. Reithofer
  • Markus Galanski
  • Bernhard K. Keppler
  • Ulrich Jaehde
Original Paper

Abstract

The purpose of this study was to systematically investigate the relationships between reactivity, cellular accumulation, and cytotoxicity of a panel of oxaliplatin analogues with different leaving groups in human carcinoma cells. The reactivity of the complexes towards the nucleotides 2′-deoxyguanosine 5′-monophosphate and 2′-deoxyadenosine 5′-monophosphate was studied using capillary electrophoresis. Cellular accumulation and cytotoxicity were measured in an oxaliplatin-sensitive and oxaliplatin-resistant ileocecal colorectal adenocarcinoma cell line pair (HCT-8/HCT-8ox). Platinum concentrations were determined by flameless atomic absorption spectrometry. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to assess cytotoxicity. Early cellular platinum accumulation was predominantly affected by lipophilicity. A relationship between reactivity and cellular accumulation was observed for three of four platinum complexes investigated, whereas the most lipophilic oxaliplatin analogue was an exception. Increased reactivity and reduced lipophilicity were associated with high cytotoxic activity. Resistance was influenced by lipophilicity but not by reactivity. The observed relationships may help in the design of analogues with high antitumoral activity in oxaliplatin-sensitive as well as oxaliplatin-resistant cells.

Keywords

Cytotoxicity Influx Oxaliplatin Reactivity Resistance 

Abbreviations

CTR1

Copper transporter 1

5′-dAMP

2′-Deoxyadenosine 5′-monophosphate

5′-dGMP

2′-Deoxyguanosine 5′-monophosphate

DMSO

Dimethyl sulfoxide

5′-GMP

Guanosine 5′-monophosphate

hCTR1

Human copper transporter 1

MTT

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

OCT

Organic cation transporter

PBS

Phosphate-buffered saline

RF

Resistance factor

TFA

Trifluoroacetato

5′-TMP

Thymidine 5′-monophosphate

Notes

Acknowledgments

The support by the Deutsche Forschungsgemeinschaft (GRK 677/3), the Fonds zur Förderung der wissenschaftlichen Forschung (FWF), the Österreichische Forschungsförderungsgesellschaft (FFG), and the European Cooperation in Science and Technology (COST) is gratefully acknowledged.

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Copyright information

© SBIC 2012

Authors and Affiliations

  • Irina Buß
    • 1
  • Ganna V. Kalayda
    • 1
  • Andreas Lindauer
    • 1
  • Michael R. Reithofer
    • 2
  • Markus Galanski
    • 2
  • Bernhard K. Keppler
    • 2
  • Ulrich Jaehde
    • 1
  1. 1.Department of Clinical Pharmacy, Institute of PharmacyUniversity of BonnBonnGermany
  2. 2.Institute of Inorganic ChemistryUniversity of ViennaViennaAustria

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