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¹ Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont; ² Department of Oncology and Neuroscience, Sections of Clinical and General Pathology, G. D'Annunzio University, Chieti, Italy; ³ Health Authority 11, Piemonte-IRRCS S. Maugeri Foundation; and ⁴ Matteo University Hospital, Pavia, Italy

Requests for reprints: Brooke T. Mossman, Department of Pathology, College of Medicine, University of Vermont College of Medicine, 89 Beaumont Avenue, HSRF 215, Burlington, VT 05405. Phone: 802-656-0382; Fax: 802-656-8892. E-mail: Brooke.Mossman{at}uvm.edu

Malignant mesothelioma is an aggressive cancer with no known cure, which has become a therapeutic challenge. Onconase is one of few chemotherapeutic agents that have been studied in patients with malignant mesothelioma that has the advantage of low toxicity and limited side effects. Here, we evaluate the effect of Onconase on killing of malignant mesothelioma cells and how the phosphatidylinositol 3-kinase/AKT (PI3-K/AKT) survival pathway influences this effect. Our results show that Onconase induces apoptosis in malignant mesothelioma cell lines and that this effect is tumor cell specific. Malignant mesothelioma cell lines with the highest AKT activation, which correlated with the presence of the SV40 large and small T antigen (SV40+), were the most resistant to the drug. Finally, a cooperative effect was observed between small molecule inhibitors of PI3-K and Onconase in the killing of malignant mesothelioma cells. Our results suggest that kinase screening of individual malignant mesotheliomas for endogenous levels of activated PI3-K/AKT may be predictive of the efficacy of Onconase and possibly other chemotherapeutic agents.

Key Words: AKT • PI3-K • chemotherapy • Onconase • survival • resistance • SV40

Grant support: NIH grant R01s ES/HL02913 (B.T. Mossman), K01 CA104159-01 (M.E. Ramos-Nino), and the Italian Association of Cancer Research (G. Vianale).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁵ Altamore DA, You H, Xiao G, et al. Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth. Oncogene. In Press 2005.

Received 9/13/04; revised 1/22/05; accepted 3/ 2/05.