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Effective Treatment of Advanced Colorectal Cancer by Rapamycin and 5-FU/Oxaliplatin Monitored by TIMP-1

  • 2009 SSAT Poster Presentation
  • Published:
Journal of Gastrointestinal Surgery Aims and scope

Abstract

Aim

The mTOR-inhibitor rapamycin has shown antitumor activity in various tumors. Bedside observations have suggested that rapamycin may be effective as a treatment for colorectal carcinomatosis.

Methods

We established an orthotopic syngenic model by transplanting CT26 peritoneal tumors in Balb/C mice and an orthotopic xenograft model by transplanting SW620 peritoneal tumors in nu/nu mice. Expression levels of tissue inhibitor of matrix-metalloproteinases 1 (TIMP-1) in the tumor and serum was determined by enzyme-linked immunosorbent assay.

Results

Rapamycin significantly suppressed growth of syngenic and xenografted peritoneal tumors. The effect was similar with intraperitoneal or oral rapamycin administration. Tumor suppression was further enhanced when rapamycin was combined with 5-fluorouracil and/or oxaliplatin. The combination treatment showed no acute toxicity. TIMP-1 serum levels correlated well (CC = 0.75; P < 0.01) with rapamycin treatment.

Conclusions

Rapamycin suppressed advanced stage colorectal cancer, even with oral administration. Combining rapamycin with current chemotherapy regimens significantly increased antitumor efficacy without apparent toxicity. The treatment efficacy correlated with serum TIMP-1 levels, suggesting its potential as a surrogate marker in future clinical trials.

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Acknowledgment

We would like to thank Cynthia Fuhrer (University of Bern) for her help with immunohistochemistry.

Grant support

This work was supported by the 3R Research Foundation Switzerland (no 94/04); Swiss National Foundation (SNF 3100A0-104023); Oncosuisse (OCS 01431-08-2003) (SAV).

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Authors and Affiliations

  1. Department of Visceral and Transplantation Surgery and Department of Clinical Research, Inselspital, University Hospital Bern and University of Bern, CH-3010, Bern, Switzerland

    Markus Wagner, Vincent Roh, Michael Strehlen, Alexander Laemmle, Deborah Stroka, Bernhard Egger, Markus Trochsler, Daniel Candinas & Stephan A. Vorburger

  2. Department of Surgical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA

    Kelly K. Hunt

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  1. Markus Wagner
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Correspondence to Stephan A. Vorburger.

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Wagner, M., Roh, V., Strehlen, M. et al. Effective Treatment of Advanced Colorectal Cancer by Rapamycin and 5-FU/Oxaliplatin Monitored by TIMP-1. J Gastrointest Surg 13, 1781–1790 (2009). https://doi.org/10.1007/s11605-009-0948-x

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  • DOI: https://doi.org/10.1007/s11605-009-0948-x

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