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[Cancer Research 64, 2561-2567, April 1, 2004]
© 2004 American Association for Cancer Research

Regular Articles

Selectivity of an Oncolytic Herpes Simplex Virus for Cells Expressing the DF3/MUC1 Antigen

Hideki Kasuya, Timothy M. Pawlik, John T. Mullen, James M. Donahue, Hideo Nakamura, Soundararajalu Chandrasekhar, Hiroshi Kawasaki, Enid Choi and Kenneth K. Tanabe

Division of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

Replication-conditional viruses destroy tumors in a process referred to as viral oncolysis. An important prerequisite for this cancer therapy strategy is use of viruses that replicate preferentially in neoplastic cells. In this study the DF3/MUC1 promoter/enhancer sequence is used to regulate expression of {gamma}134.5 to drive replication of a Herpes simplex virus 1 (HSV-1) mutant (DF3{gamma}34.5) preferentially in DF3/MUC1-positive cells. HSV-1 {gamma}134.5 functions to dephosphorylate elongation initiation factor 2{alpha}, which is an important step for robust HSV-1 replication. After DF3{gamma}34.5 infection of cells, elongation initiation factor 2{alpha} phosphatase activity and viral replication were observed preferentially in DF3/MUC1-positive cells but not in DF3/MUC1-negative cells. Regulation of {gamma}134.5 function results in preferential replication in cancer cells that express DF3/MUC1, restricted biodistribution in vivo, and less toxicity as assessed by LD50. Preferential replication of DF3{gamma}34.5 was observed in DF3/MUC1-positive liver tumors after intravascular perfusion of human liver specimens. DF3{gamma}34.5 was effective against carcinoma xenografts in nude mice. Regulation of {gamma}134.5 by the DF3/MUC1 promoter is a promising strategy for development of HSV-1 mutants for viral oncolysis.




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
Copyright © 2004 by the American Association for Cancer Research.