This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, Q. Articles by DiGiovanni, J. Search for Related Content PubMed PubMed Citation Articles by Wu, Q. Articles by DiGiovanni, J.

Therapeutic Effect of Rapamycin on Gallbladder Cancer in a Transgenic Mouse Model

¹ Department of Carcinogenesis, Science Park-Research Division, University of Texas M. D. Anderson Cancer Center, Smithville, Texas; Departments of ² Biostatistics and Applied Math, ³ Pathology, and ⁴ GI Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: John DiGiovanni, Department of Carcinogenesis, Science Park-Research Division, University of Texas M. D. Anderson Cancer Center, 1808 Park Road 1C, P.O. Box 389, Smithville, TX 78957. Phone: 512-237-9414; Fax: 512-237-2522; E-mail: jdigiovanni{at}sprd1.mdacc.tmc.edu.

The macrolide fungicide rapamycin has shown significant antiproliferative action toward a variety of tumor types. In this study, we used BK5.erbB2 transgenic mice as an animal model to examine the therapeutic effect of rapamycin as a potential treatment for gallbladder cancer. Homozygous BK5.erbB2 mice overexpressing the wild-type rat erbB2 gene in basal epithelial cells of the gallbladder have an 70% incidence of gallbladder adenocarcinoma by 2 to 3 months of age. Groups of mice (2–3 months of age) were treated with rapamycin by i.p. injection (once daily for 14 days) and then sacrificed 24 h after the last treatment. Rapamycin significantly reduced the incidence and severity of gallbladder carcinoma in BK5.erbB2 mice in a dose-dependent manner. Tumors responsive to treatment exhibited a higher number of apoptotic cells. Furthermore, rapamycin treatment led to decreased levels of phosphorylated p70 S6 kinase (Thr³⁸⁹) in gallbladder tissue as assessed by both Western blot and immunofluorescence analyses. Finally, immunofluorescence staining revealed elevated phosphorylated Akt (Ser⁴⁷³) and phosphorylated mammalian target of rapamycin (mTOR; Ser²⁴⁴⁸) in human gallbladder cancer compared with normal gallbladder tissue. Based on our results using a novel genetically engineered mouse model and the fact that the Akt/mTOR pathway is activated in human gallbladder cancer, rapamycin and related drugs may be effective therapeutic agents for the treatment of human gallbladder cancer. [Cancer Res 2007;67(8):3794–800]

This article has been cited by other articles:

				P. A. OLIVEIRA, R. ARANTES-RODRIGUES, C. SOUSA-DINIZ, A. COLACO, L. LOURENCO, L. FELIPE. DE LA CRUZ P., V. M. DA SILVA, J. AFONSO, C. LOPES, and L. SANTOS The Effects of Sirolimus on Urothelial Lesions Chemically Induced in ICR Mice by BBN Anticancer Res, August 1, 2009; 29(8): 3221 - 3226. [Abstract] [Full Text] [PDF]

				H. Alvarez, A. Corvalan, J. C. Roa, P. Argani, F. Murillo, J. Edwards, R. Beaty, G. Feldmann, S.-M. Hong, M. Mullendore, et al. Serial Analysis of Gene Expression Identifies Connective Tissue Growth Factor Expression as a Prognostic Biomarker in Gallbladder Cancer Clin. Cancer Res., May 1, 2008; 14(9): 2631 - 2638. [Abstract] [Full Text] [PDF]