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Investigational New Drugs

, Volume 29, Issue 6, pp 1321–1327 | Cite as

Cellular uptake and cytoplasm / DNA distribution of cisplatin and oxaliplatin and their liposomal formulation in human colorectal cancer cell HCT116

  • Thititip Tippayamontri
  • Rami Kotb
  • Benoit Paquette
  • Léon Sanche
PRECLINICAL STUDIES

Summary

Liposomal formulations of cisplatin and oxaliplatin (Lipoplatin™ and Lipoxal™, respectively) were recently proposed to reduce systemic toxicity, while optimizing the anti-cancer effectiveness of these compounds. As the anti-neoplastic or radio-sensitizing activity of these drugs is attributed to their binding to DNA, we assessed the impact of the liposomal formulations on the time course of accumulation of these platinum compounds in the human colorectal cancer HCT116 cell lines and their distribution between cytoplasm and DNA. Their cytotoxicity was determined by colony formation assay. Intracellular platinum and platinum bound to DNA was measured by inductively coupled plasma mass spectrometry. Although, as a chemotherapeutic agent, cisplatin was as efficient as oxaliplatin after exposure for a short time, oxaliplatin and Lipoxal™ became more active than cisplatin against HCT116 cells after 24 h incubation. Lipoxal™ displayed a higher accumulation in the cytoplasm of HCT116 cells compared to free oxaliplatin, consistent with its proposed mechanism of fusion with the cell membrane. The distribution cytoplasm/DNA of free cisplatin and Lipoplatin™ were similar. Conversely, Lipoxal™ had a significantly different cytoplasm/DNA distribution from oxaliplatin: more than 95% of oxaliplatin transported by the liposome was trapped in the cytoplasm, even after 48 h incubation. Our study indicates that Lipoxal™ can largely improve the cellular uptake of oxaliplatin, but this was not followed by a similar increase in the DNA bound fraction.

Keywords

Liposome Cisplatin Oxaliplatin Lipoplatin™ and Lipoxal™ Colorectal cancer 

Notes

Acknowledgments

Canadian Institutes of Health Research (grant # MOP 81356). Léon Sanche, Benoit Paquette and Rami Kotb are members of the Centre de recherche Clinique-Étienne Lebel supported by the Fonds de la Recherche en Santé du Québec. Sanofi-Aventis Canada has offered a partial unrestricted grant to support this project.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Thititip Tippayamontri
    • 1
  • Rami Kotb
    • 2
  • Benoit Paquette
    • 1
  • Léon Sanche
    • 1
  1. 1.Department of Nuclear Medicine and Radiobiology, Center of Radiotherapy Research, Faculty of Medicine and Health SciencesUniversité de SherbrookeSherbrookeCanada
  2. 2.Department of MedicineCentre Hospitalier Universitaire de SherbrookeSherbrookeCanada

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