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TNP-470 fails to block the onset of angiogenesis and early tumor establishment in an intravital minimal disease model

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Background and aims

The angiogenesis inhibitor TNP-470 (AGM-1470) has shown encouraging results in animal models of established tumors. However, results of recent clinical trials using TNP-470 have been disappointing. Since little is known about the effects of TNP-470 at the minimal disease stage, we analyzed the effects of TNP-470 on the early stages of tumor establishment.

Methods

Twenty thousand green fluorescent protein (GFP)-transfected murine CT-26 (colonic carcinoma) or Panc-02-H0 (pancreatic adenocarcinoma) cells were inoculated in dorsal skin-fold chambers in BALB/c or C57BL6 mice. Tumor area and microvessel density (MVD) were quantified by intravital microscopy (IVM). Body weight was also monitored. Effects were compared with those in a conventional model involving subcutaneous (s.c.) inoculation of 106 tumor cells, followed by measurement of tumor volume, endogenous plasma VEGF/endostatin (ELISA) and proliferation/apoptosis/microvessel density (Ki-67/TUNEL/CD-34). TNP-470 was injected s.c. over the 10-day experimental period (30 mg/kg every 2 days [n=6] to 100 mg/kg/day [n=5 dorsal skin-fold chamber model, n=4 s.c. tumor model]).

Results

At 30 mg/kg/every second day neither CT-26 nor PANC-02-H0 tumors were inhibited in neither of the two models. TNP-470 dosage was escalated in CT-26-bearing animals until an antiangiogenic effect could be observed. In the IVM model, only TNP-470 100 mg/kg/day reduced MVD (P=0.006), but failed to block the onset of angiogenesis and tumor area increase. Body weight decreased by 25% (P<0.05). In the subcutaneous tumor model, tumor growth was reduced (P=0.045) but not blocked, while vascular endothelial growth factor (VEGF)/endostatin synthesis and Ki67/TUNEL/CD-34 were not significantly affected.

Conclusion

While capable of reducing tumor growth in a conventional model, treatment with TNP-470 does not block the onset of angiogenesis and tumor establishment in a model of minimal disease. When used as a single agent TNP-470 does not control minimal tumor disease in experimental colonic carcinoma.

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Acknowledgements

This work was funded in part by the Interdisciplinary Center for Clinical Research (IZKF) Grant no. 01KS9504N2 to Michael Cross. Cell sorting was performed in the Fluorescence Technology Unit of the IZKF.

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Authors and Affiliations

  1. Department of Pediatric Surgery, University of Leipzig, 04317, Leipzig, Germany

    Grigore Cernaianu, Gabriele Scholz, Ralf-Bodo Troebs, Karin Rothe & Joachim Bennek

  2. Department of Abdominal, Transplantation and Vascular Surgery, University of Leipzig, 04317, Leipzig, Germany

    Sibylle Frank, Katrin Erbstößer, Sandy Leonhardt, Temuujin Dansranjavin, Johann Hauss & Helmut Witzigmann

  3. Interdisciplinary Center for Clinical Research, University of Leipzig, 04317, Leipzig, Germany

    Michael Cross & Zoe McIvor

  4. Institute of Pathology, University of Leipzig, 04317, Leipzig, Germany

    Andrea Tannapfel & Christian Wittekind

  5. Institute of Theoretical Surgery, University of Marburg, 35032, Marburg, Germany

    Ilhan Celik

  6. Klinik für Kinderchirurgie, Universitätsklinikum Leipzig, AöR, Oststrasse 21–25, 04317, Leipzig, Germany

    Grigore Cernaianu

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  1. Grigore Cernaianu
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Correspondence to Grigore Cernaianu.

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Cernaianu, G., Frank, S., Erbstößer, K. et al. TNP-470 fails to block the onset of angiogenesis and early tumor establishment in an intravital minimal disease model. Int J Colorectal Dis 21, 143–154 (2006). https://doi.org/10.1007/s00384-005-0751-4

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  • DOI: https://doi.org/10.1007/s00384-005-0751-4

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