An oncolytic viral mutant that delivers the CYP2B1 transgene and augments cyclophosphamide chemotherapy.
Herpes simplex viruses type 1 (HSV-1) with an inactivated viral ribonucleotide reductase (Hsrr, ICP6) were designed to target tumor cells with upregulated mammalian ribonucleotide reductase (mRR), an enzyme whose expression is regulated by the p16/pRB tumor suppressor pathway. A recombinant HSV-1 was generated by knock-out of Hsrr and insertion of the rat CYP2B1 transgene responsible for the bioactivation of the prodrugs, cyclophosphamide and ifosfamide. The mutant virus replicated selectively in rat and human tumor cells that express mRR. Addition of cyclophosphamide potentiated oncolytic effects against cultured tumor cells and subcutaneous tumor xenografts established in athymic mice.
Chase
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Molecular Neuro-oncology Laboratory, Massachusetts General Hospital-CNY6, Harvard Medical School, Charlestown, MA 02129, USA.
Chung
R Y
RY
Chiocca
E A
EA
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000494:pharmacology*; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics*; D004279:DNA, Viral / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007069:Ifosfamide / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics; D012264:Ribonucleotide Reductases / Q000737:chemistry / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
D018906:Antineoplastic Agents, Alkylating; D004279:DNA, Viral; D011355:Prodrugs; D011994:Recombinant Proteins; D003520:Cyclophosphamide; D019362:Cytochrome P-450 CYP2B1; D012264:Ribonucleotide Reductases; D007069:Ifosfamide