Multimodality therapy with a replication-conditional herpes simplex virus 1 mutant that expresses yeast cytosine deaminase for intratumoral conversion of 5-fluorocytosine to 5-fluorouracil.
Infection of tumor cells by herpes simplex virus 1 (HSV-1) results in cell destruction and production of progeny virion in a process referred to as viral oncolysis. In this study, an HSV-1 mutant (HSV1yCD) was engineered such that the viral ribonucleotide reductase gene is disrupted by sequences encoding yeast cytosine deaminase, which efficiently metabolizes the prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU). HSV1yCD-infected cells convert 5-FC to 5-FU, which enhances cytotoxicity without significantly reducing viral replication and oncolysis. Oncolysis by a replicating HSV-1 mutant combined with therapeutic transgene delivery represents a new paradigm; HSV1yCD-infected cells are destroyed by viral replication, and uninfected cells are subjected to bystander killing from both progeny virion and extracellular diffusion of 5-FU. In contrast, HSV1yCD-mediated bioactivation of another prodrug, ganciclovir, impairs viral replication. HSV1yCD administered into the portal venous system replicates preferentially in liver metastases rather than normal liver. The anti-neoplastic activity of HSV1yCD combined with systemic 5-FC administration is greater than that achieved with HSV-1 replication alone. Combination oncolysis and prodrug bioactivation leads to significant prolongation of survival in mice with diffuse liver metastases.
Nakamura
H
H
Division of Surgical Oncology and Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Mullen
J T
JT
Chandrasekhar
S
S
Pawlik
T M
TM
Yoon
S S
SS
Tanabe
K K
KK
D000818:Animals; D002522:Chlorocebus aethiops; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase; D005437:Flucytosine / Q000378:metabolism* / Q000494:pharmacology; D005472:Fluorouracil / Q000378:metabolism*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D019073:HT29 Cells; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy; D009700:Nucleoside Deaminases / Q000235:genetics / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D016019:Survival Analysis; D014709:Vero Cells; D014779:Virus Replication
D011355:Prodrugs; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil