gms | German Medical Science

27. Deutscher Krebskongress

Deutsche Krebsgesellschaft e. V.

22. - 26.03.2006, Berlin

Enzastaurin: Correlations of Chemosensitivity and Gene Expression in Human Solid Tumors

Meeting Abstract

  • corresponding author presenting/speaker Ulrike Eismann - Allgemeines Krankenhaus St. Georg, Hamburg, Deutschland
  • Olaf Oberschmidt - Allgemeines Krankenhaus St. Georg, Hamburg
  • Michael Ehnert - Allgemeines Krankenhaus St. Georg, Hamburg
  • Jochen Fleeth - Allgemeines Krankenhaus St. Georg, Hamburg
  • Frank Erich Lüdtke - Allgemeines Krankenhaus St. Georg, Hamburg
  • Sakine Struck - Allgemeines Krankenhaus St. Georg, Hamburg
  • Lena Schulz - Allgemeines Krankenhaus St. Georg, Hamburg
  • Johannes Blatter - Eli Lilly & Co, Indianapolis
  • Michael M. Lahn - Eli Lilly & Co, Indianapolis
  • Doreen Ma - Eli Lilly & Co, Indianapolis
  • Axel-Rainer Hanauske - Allgemeines Krankenhaus St. Georg, Hamburg

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocPO442

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dkk2006/06dkk552.shtml

Veröffentlicht: 20. März 2006

© 2006 Eismann et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

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Background: Enzastaurin is a potent and selective inhibitor for the beta-isoform of the protein kinase C (PKC-beta). The enzyme is implicated in processes that control tumor cell growth and survival. It is activated by several growth factors, eg VEGF. Enzastaurin blocks the enzyme`s ATP-binding site and signal transmission is abrogated.

The purpose of the present study was to correlate gene expression with in vitro chemosensitivity of freshly explanted human tumor specimens. Such correlations in tumors taken directly from patients will help to rationally design subsequent clinical trials.

Methods: Soft-agar cloning experiments were performed using single cell suspensions derived from freshly biopsied tumor cells (solid tumors, pleural effusions, or ascites). Cells were exposed for 1 h or continuously (21 days) to various concentrations of Enzastaurin and clonogenic tumor growth was evaluated after three weeks of cultivation. Small portions of the same tumor specimens were shock-frozen immediately after removal. Subsequently, total RNA was isolated and reversely transcribed to cDNA followed by real-time multiplex PCR experiments based on Taqman technology. Results from gene expression experiments were normalized against beta-actin transcripts.

Results: The gene expression of PKC-beta1, PKC-beta2, IL8RA, IL8RB, IL8, GSK3-beta, and TGF-beta was studied in 56 samples. Transcript quantities were correlated with the in vitro chemosensitivity pattern of Enzastaurin based on continuous and 1h-exposure experiments. In Enzastaurin-sensitive samples, high levels of IL8 and low levels of GSK3-beta transcripts were observed. Using a 1h-exposure, differences in gene expression between Enzastaurin-sensitive and Enzastaurin-resistant specimens were statistically significant with p=0.007 for IL8 (median: 2300 vs. 505; n=51) and p=0.011 for GSK3-β (median: 1.5 vs. 8.6; n=51). A statistically significant difference between Enzastaurin-sensitive and Enzastaurin-resistant specimens was also observed for IL8 mRNA expression after continuous drug exposure (p=0.044; median: 1137 vs. 530; n=56). No correlations were noted for PKC-β1, PKC-β2, IL8RA, IL8RB, and TGF-β.

Conclusions: Our results indicate that Enzastaurin-sensitive tumors can be identified by low expression of GSK3-beta and high expression of IL8. These findings will help direct further clinical development of this compound.

Supported in part by Eli Lilly & Company