Selectivity of an oncolytic herpes simplex virus for cells expressing the DF3/MUC1 antigen.
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(1)34.5 to drive replication of a Herpes simplex virus 1 (HSV-1) mutant (DF3gamma34.5) preferentially in DF3/MUC1-positive cells. HSV-1 gamma(1)34.5 functions to dephosphorylate elongation initiation factor 2alpha, which is an important step for robust HSV-1 replication. After DF3gamma34.5 infection of cells, elongation initiation factor 2alpha phosphatase activity and viral replication were observed preferentially in DF3/MUC1-positive cells but not in DF3/MUC1-negative cells. Regulation of gamma(1)34.5 function results in preferential replication in cancer cells that express DF3/MUC1, restricted biodistribution in vivo, and less toxicity as assessed by LD(50). Preferential replication of DF3gamma34.5 was observed in DF3/MUC1-positive liver tumors after intravascular perfusion of human liver specimens. DF3gamma34.5 was effective against carcinoma xenografts in nude mice. Regulation of gamma(1)34.5 by the DF3/MUC1 promoter is a promising strategy for development of HSV-1 mutants for viral oncolysis.
Kasuya
Hideki
H
Division of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Pawlik
Timothy M
TM
Mullen
John T
JT
Donahue
James M
JM
Nakamura
Hideo
H
Chandrasekhar
Soundararajalu
S
Kawasaki
Hiroshi
H
Choi
Enid
E
Tanabe
Kenneth K
KK
D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics*; D002522:Chlorocebus aethiops; D015316:Genetic Therapy / Q000379:methods; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism / Q000628:therapy / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018396:Mucin-1 / Q000096:biosynthesis / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000628:therapy / Q000821:virology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014018:Tissue Distribution; D014709:Vero Cells; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D000951:Antigens, Neoplasm; D018396:Mucin-1; C019363:eIF-2 phosphatase; D010749:Phosphoprotein Phosphatases