Selective killing of Smad4-negative tumor cells via a designed repressor strategy.

Molecular Pharmacology
Vidula Dixit, Rudy L Juliano

Abstract

Smad4 is a key tumor suppressor that is frequently deleted or inactive in pancreatic and colon tumors. In this report, we describe an approach for attaining selective killing of Smad4-deficient tumor cells. Using a vector system involving a designed repressor with zinc finger binding domains and the herpes simplex virus thymidine kinase (HSV-TK) "suicide gene," we demonstrate Smad4-responsive regulation of HSV-TK expression and consequent altered susceptibility to the prodrug ganciclovir (GCV). In pancreatic tumor cell lines stably transfected with the vector system, a robust differential of HSV-TK expression and GCV toxicity was attained depending on the presence or absence of cotransfected Smad4. In matched colon tumor cell lines lacking Smad4 or expressing physiological levels of Smad4, an adenoviral version of the vector system attained a significant degree of preferential killing of Smad4-negative tumor cells in response to GCV. These findings demonstrate the possibility of achieving selective killing of pancreatic and colon cells depending on their Smad4 status.

References

Apr 16, 1998·Proceedings of the National Academy of Sciences of the United States of America·S ZhouB Vogelstein
Apr 22, 1999·Immunology Today·J LloberasA Celada
Apr 3, 2002·Trends in Molecular Medicine·David P Lane, Sonia Lain
Aug 17, 2002·The Journal of Pharmacology and Experimental Therapeutics·Dong XuR L Juliano
May 8, 2004·Trends in Biochemical Sciences·Peter ten Dijke, Caroline S Hill
Jul 6, 2004·European Journal of Biochemistry·Gerald ThielMathias Hohl
Aug 3, 2004·Nature Medicine·Bert Vogelstein, Kenneth W Kinzler
Aug 26, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Roland L ChuErwin G Van Meir
Sep 1, 2004·The Lancet Oncology·Mary J MacKenzie
Sep 2, 2004·Molecular Pharmacology·Pilar BlancafortCarlos F Barbas
Jan 18, 2005·Cell·Karen H Vousden, Carol Prives
Mar 5, 2005·Anti-cancer Drugs·Gabi U DachsGillian M Tozer
Jun 18, 2005·Cancer Gene Therapy·Chengwen LiRichard Jude Samulski
Jun 22, 2005·The Journal of Cell Biology·Rudy L JulianoDong Xu
Aug 17, 2005·Current Gene Therapy·Hamid Sadeghi, Mary M Hitt
Mar 22, 2006·Best Practice & Research. Clinical Gastroenterology·Madhumita Bhattacharyya, Nick R Lemoine
Mar 25, 2006·Future Oncology·Daniel T ReinDavid T Curiel
May 16, 2006·Journal of Gastroenterology·Tetsuji TakayamaYoshiro Niitsu
Jul 11, 2006·Molecular Therapy : the Journal of the American Society of Gene Therapy·Zhijian WuR Jude Samulski
Dec 16, 2006·Current Gene Therapy·Silke Schepelmann, Caroline J Springer

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