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Hepatic arterial infusion of irinotecan and EmboCept® S results in high tumor concentration of SN-38 in a rat model of colorectal liver metastases

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Abstract

Intraarterial chemotherapy for colorectal liver metastases (CRLM) can be applied alone or together with embolization particles. It remains unclear whether different types of embolization particles lead to higher intratumoral drug concentration. Herein, we quantified the concentrations of CPT-11 and its active metabolite SN-38 in plasma, liver and tumor tissue after hepatic arterial infusion (HAI) of irinotecan, with or without further application of embolization particles, in a rat model of CRLM. Animals underwent either systemic application of irinotecan, or HAI with or without the embolization particles Embocept® S and Tandem™. Four hours after treatment concentrations of CPT-11 and SN-38 were analyzed in plasma, tumor and liver samples by high-performance liquid chromatography. Additionally, DNA-damage and apoptosis were analyzed immunohistochemically. Tumor tissue concentrations of SN-38 were significantly increased after HAI with irinotecan and EmboCept® S compared to the other groups. The number of apoptotic cells was significantly higher after both HAI with irinotecan and EmboCept® S or Tandem™ loaded with irinotecan compared to the control group. HAI with irinotecan and EmboCept® S resulted in an increased SN-38 tumor concentration. Both HAI with irinotecan and EmboCept® S or Tandem™ loaded with irinotecan were highly effective with regard to apoptosis.

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Acknowledgements

The authors thank Birgit Jünemann who helped to establish the immunohistochemistry staining.

Funding

A Kauffels salary during the time of the study and part of the study itself has beend funded by the Else Kröner-Fresenius-Stiftung (EKFS), Bad Homburg v.d.H, Germany, due to a scholarship. The cost for HPLC-analyses in Vienna has been covered by PharmaCept GmbH, Berlin, Germany.

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Authors and Affiliations

  1. Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Robert-Koch Str. 40, 37099, Göttingen, Germany

    Anne Kauffels, Hannah Nowack, Melanie Spitzner, Thilo Sprenger, Michael Ghadimi & Jens Sperling

  2. Division of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria

    Marie Kitzmüller, Andrea Gruber & Martin Czejka

  3. Institute of Pathology, University Medical Center Goettingen, Göttingen, Germany

    Hanibal Bohnenberger

  4. PharmaCept GmbH, Berlin, Germany

    Anja Kuthning

  5. Austrian Society of Applied Pharmacokinetics, Vienna, Austria

    Martin Czejka

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  1. Anne Kauffels
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Correspondence to Anne Kauffels.

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Conflict of interest

A Kuthning works for PharmaCept GmbH, Berlin. All other authors declare no potential conflict of interest.

Ethics approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted (Niedersächsisches Landesamt für Verbraucherschutz und Lebensmittelsicherheit, ethics approval number 14/1610).

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10585_2019_9954_MOESM1_ESM.png

Supplementary Fig. 1 CPT-11 concentrations of plasma (A), liver (B) and tumor tissue (C) 4 h or 24 h after treatment of animals undergoing systemic administration of irinotecan alone (preliminary experiment). Mean ± SEM (PNG 120 KB)

10585_2019_9954_MOESM2_ESM.png

Supplementary Fig. 2 SN-38 concentrations of plasma (A), liver (B) and tumor tissue (C) 4 h or 24 h after treatment of animals undergoing systemic administration of irinotecan alone (preliminary experiment). Mean ± SEM (PNG 121 KB)

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Kauffels, A., Kitzmüller, M., Gruber, A. et al. Hepatic arterial infusion of irinotecan and EmboCept® S results in high tumor concentration of SN-38 in a rat model of colorectal liver metastases. Clin Exp Metastasis 36, 57–66 (2019). https://doi.org/10.1007/s10585-019-09954-5

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