gms | German Medical Science

27. Deutscher Krebskongress

Deutsche Krebsgesellschaft e. V.

22. - 26.03.2006, Berlin

Combination of mTOR inhibitor and radiotherapy – a new strategy in multimodal therapy of malignant tumors

Meeting Abstract

  • corresponding author presenting/speaker Philipp Manegold - Chirurgische Klinik und Poliklinik, Universitätsklinikum München-Grosshadern, München, Deutschland
  • Carmen Paringer - Chirurgische Klinik und Poliklinik, Universitätsklinikum München-Grosshadern, München
  • Ulrike Kulka - Klinik und Poliklinik für Strahlentherapie und Radioonkologie, Universitätsklinikum München-Grosshadern, München
  • Ralf Wilkowski - Klinik und Poliklinik für Strahlentherapie und Radioonkologie, Universitätsklinikum München-Grosshadern, München
  • Karl-Walter Jauch - Chirurgische Klinik und Poliklinik, Universitätsklinikum München-Grosshadern, München
  • Markus Guba - Chirurgische Klinik und Poliklinik, Universitätsklinikum München-Grosshadern, München
  • Christiane J. Bruns - Chirurgische Klinik und Poliklinik, Universitätsklinikum München-Grosshadern, München

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocPO198

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dkk2006/06dkk308.shtml

Veröffentlicht: 20. März 2006

© 2006 Manegold 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

Text

Background: Upregulation of VEGF dependent tumor angiogenesis via the PI3K/Akt-mTOR-p70s6k pathway may be responsible for radiotherapy resistance of malignant tumors. We have recently shown that the mTOR inhibitor rapamycin inhibits VEGF driven tumor angiogenesis and can induce tumor specific thrombosis in the tumor vasculature.Thus, the combined use of the mTOR inhibitor RAD001 and radiotherapy might help to overcome radiotherapy resistance and might therefore exert additive/synergistic effects on tumor growth.

Methods: In vitro cell proliferation of murine colon carcinoma CT-26, fibrosarcoma BFS-1, human pancreatic carcinoma L3.6pl, and HUVEC were assessed after single doses of 0.25-2Gy with or without RAD001 0.01-20ng/ml. Phosphorylation of p70s6k was assessed by western blotting. In vivo CT-26 and BFS-1 cells were implanted subcutaneously on the back of syngen mice. Human L3.6pl cells were implanted orthotopically in the pancreas of nude mice. Fractionated radiotherapy of 5x2Gy was initiated 14 days after tumor cell implantation. RAD001 (1.5mg/kg/d) was administered until the end of experiments beginning two days before radiotherapy or after the last fraction of radiotherapy.

Results: Single dose of 2Gy radiation reduces cell proliferation in vitro by 21% in L3.6pl, 5% in BFS-1, 61% in CT-26, and 70% in HUVEC. RAD001 at a concentration of 10ng/ml reduces cell proliferation by 12% in L3.6pl, 33% in BFS-1, 81% in CT-26, and 83% in HUVEC. Combination of suboptimal RAD001 concentration of 0.01ng/ml and 0.25Gy low dose radiation results in significant reduction by 56% in proliferation of HUVEC. In subcutaneous and orthotopic tumors we observed under combination of RAD001 introduced two days before fractionated radiotherapy a significant reduction in tumor volumes compared to controls (L3.6pl 326mm3 vs. 1144mm3; BFS-1 742mm3 vs. 1573mm3; CT-26 210 vs. 636mm3; p<0.05 vs. control). These effects were superior to respective monotherapies of fractionated radiotherapy or RAD001, and superior to the combination of RAD001 given after the last fraction of radiotherapy.

Conclusion: Combination of mTOR inhibitor and fractionated radiotherapy results in an improved control of malignant tumors compared to respective monotherapies. Therefore we propse combination of mTOR inhibitor and radiotherapy should be enrolled in clinical studies as a multimodal therapy of malignant tumors.