title: Analysis of genetically engineered oncolytic herpes simplex viruses in human prostate cancer organotypic cultures.
abstract: Oncolytic herpes simplex viruses type 1 (oHSVs) such as G47Delta and G207 are genetically engineered for selective replication competence in cancer cells. Several factors can influence the overall effectiveness of oHSV tropism, including HSV-1 receptor expression, extracellular matrix milieu and cellular permissiveness. We have taken advantage of human prostate organ cultures derived from radical prostatectomies to investigate oHSV tropism. In this study, we show that both G47Delta and G207 specifically replicate in epithelial cells of the prostatic glands but not in the surrounding stroma. In contrast, both the epithelial and stromal cell compartments were readily infected by wild-type HSV-1. Analysis of oHSV replication in prostate surgical specimens 3 days post infection showed that G47Delta generated approximately 30-fold more viral progeny than did G207. This correlated with the enhanced expression of G47Delta-derived glycoprotein gB protein levels as compared with G207. In benign prostate tissues, G207 and G47Delta titers were notably reduced, whereas strain F titers were maintained at similar levels compared with prostate cancer specimens. Overall, our results show that these oncolytic herpes vectors show both target specificity and replication competence in human prostate cancer specimens and point to the utility of using human prostate organ cultures in assessing oHSV tropism and cellular specificity.
authors.affiliation: Department of Neurosurgery, Brain Tumor Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. bpasser@partners.org
authors.forename: B J
authors.initials: BJ
authors.lastname: Passer
authors.forename: C-l
authors.initials: CL
authors.lastname: Wu
authors.forename: S
authors.initials: S
authors.lastname: Wu
authors.forename: S D
authors.initials: SD
authors.lastname: Rabkin
authors.forename: R L
authors.initials: RL
authors.lastname: Martuza
mesh_terms: D000818:Animals; D005818:Genetic Engineering; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D008297:Male; D042361:Mammary Glands, Human / Q000821:virology; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics*; D009924:Organ Culture Techniques; D011471:Prostatic Neoplasms / Q000235:genetics / Q000628:therapy
references.citation: Proc Natl Acad Sci U S A. 2001 May 22;98(11):6396-401
references.pmid: 11353831
references.citation: Arch Pathol Lab Med. 2006 Aug;130(8):1193-5
references.pmid: 16879022
references.citation: Nat Rev Microbiol. 2008 Jul;6(7):529-40
references.pmid: 18552863
references.citation: J Virol. 1997 Aug;71(8):6049-54
references.pmid: 9223497
references.citation: J Clin Invest. 1997 Feb 15;99(4):618-27
references.pmid: 9045863
references.citation: J Exp Med. 2005 Apr 18;201(8):1257-68
references.pmid: 15824085
references.citation: Neoplasia. 2001 Sep-Oct;3(5):451-6
references.pmid: 11687957
references.citation: Urology. 2000 Jul;56(1):160-6
references.pmid: 10869659
references.citation: FASEB J. 2008 Jun;22(6):1839-48
references.pmid: 18234972
references.citation: Rev Med Virol. 2000 Sep-Oct;10(5):305-19
references.pmid: 11015742
references.citation: Dev Biol. 2004 Mar 15;267(2):387-98
references.pmid: 15013801
references.citation: J Virol. 1998 Sep;72(9):7005-11
references.pmid: 9696792
references.citation: Gene Ther. 2000 May;7(10):867-74
references.pmid: 10845725
references.citation: J Virol. 2000 Apr;74(8):3832-41
references.pmid: 10729157
references.citation: Urology. 2001 Oct;58(4):619-24
references.pmid: 11597556
references.citation: Cancer Res. 1993 Nov 1;53(21):5199-207
references.pmid: 7693334
references.citation: J Virol. 2008 Jan;82(2):999-1010
references.pmid: 17977977
references.citation: Mol Ther. 2007 Jan;15(1):103-13
references.pmid: 17164781
references.citation: Hum Gene Ther. 1999 Sep 1;10(13):2237-43
references.pmid: 10498254
references.citation: Hum Gene Ther. 2000 Dec 10;11(18):2465-72
references.pmid: 11119418
references.citation: Gene Ther. 1999 Oct;6(10):1751-8
references.pmid: 10516725
references.citation: Cancer Res. 2005 Feb 15;65(4):1532-40
references.pmid: 15735042
references.citation: Cancer Gene Ther. 2006 Mar;13(3):253-65
references.pmid: 16179929
references.citation: Nat Med. 1995 Sep;1(9):938-43
references.pmid: 7585221
references.citation: Cancer Res. 2000 Oct 15;60(20):5714-22
references.pmid: 11059765
references.citation: J Virol. 2007 Apr;81(7):3455-64
references.pmid: 17229694
references.citation: J Virol. 1998 Sep;72(9):7064-74
references.pmid: 9696799
references.citation: Hum Gene Ther. 2001 May 20;12(8):999-1010
references.pmid: 11387063