Analysis of genetically engineered oncolytic herpes simplex viruses in human prostate cancer organotypic cultures.
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.
Passer
B J
BJ
Department of Neurosurgery, Brain Tumor Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. bpasser@partners.org
Wu
C-l
CL
Wu
S
S
Rabkin
S D
SD
Martuza
R L
RL
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
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