Antitumor activity of a selectively replication competent herpes simplex virus (HSV) with enzyme prodrug therapy.
BACKGROUND
HSV1790 is an oncolytic virus generated by inserting the enzyme nitroreductase (NTR) into the virus HSV1716. NTR converts the prodrug CB1954 into an active alkylating agent.


METHODS
In vitro, 3T6 cells (non permissive to HSV) were used in order to distinguish between virus-induced cytopathic effect and cell death due to activated prodrug. In vivo, xenograft models were injected with HSV1790 (10(5)-10(9) PFU) with or without CB1954 (max 80mg/kg) and tumor volume recorded regularly. Biodistribution of HSV1790 was determined immunohistochemically and by PCR.


RESULTS
HSV1790 + CB1954 in vitro was more effective at killing tumor cells than the virus or the prodrug alone. In vivo, the combination reduced tumor volume and increased survival compared to treatment with HSV1790 or CB1954 alone. Following systemic administration of HSV1790, viral replication was detected in tumors, but not organs.


CONCLUSIONS
HSV1790 + prodrug enhances tumor cell killing in vitro and reduces tumor volume and increases survival in vivo.
Braidwood
Lynne
L
Crusade Laboratories Ltd, Dept of Neurology, Southern General Hospital, Glasgow, G51 4WF, U.K. Lbraidwood@crusadelabs.co.uk
Dunn
Paul D
PD
Hardy
Susan
S
Evans
T R Jeffry
TR
Brown
S Moira
SM
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001388:Aziridines / Q000627:therapeutic use*; D015153:Blotting, Western; D003131:Combined Modality Therapy; D005260:Female; D006561:Herpes Simplex / Q000235:genetics / Q000473:pathology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics / Q000628:therapy* / Q000821:virology; D050504:Oncolytic Viruses / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D014779:Virus Replication
D000970:Antineoplastic Agents; D001388:Aziridines; D011355:Prodrugs; C100099:tretazicar