Brain tumor oncolysis with replication-conditional herpes simplex virus type 1 expressing the prodrug-activating genes, CYP2B1 and secreted human intestinal carboxylesterase, in combination with cyclophosphamide and irinotecan.

Abstract	The treatment of malignant glioma is currently ineffective. Oncolytic viruses are being explored as a means to selectively lyse tumor cells in the brain. We have engineered a mutant herpes simplex virus type 1 with deletions in the viral UL39 and gamma(1)34.5 genes and an insertion of the two prodrug activating genes, CYP2B1 and secreted human intestinal carboxylesterase. Each of these can convert the inactive prodrugs, cyclophosphamide and irinotecan (CPT-11), into their active metabolites, respectively. This new oncolytic virus (MGH2) displays increased antitumor efficacy against human glioma cells both in vitro and in vivo when combined with cyclophosphamide and CPT-11. Importantly, cyclophosphamide, CPT-11, or the combination of cyclophosphamide and CPT-11 does not significantly affect oncolytic virus replication. Therefore, MGH2 provides effective multimodal therapy for gliomas in preclinical models when combined with these chemotherapy agents.
Authors	Edyta Tyminski, Stanley Leroy, Kinya Terada, Dianne M Finkelstein, Janice L Hyatt, Mary K Danks, Philip M Potter, Yoshinaga Saeki, E Antonio Chiocca
Journal	Cancer research (Cancer Res) Vol. 65 Issue 15 Pg. 6850-7 (Aug 01 2005) ISSN: 0008-5472 [Print] United States
PMID	16061668 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Prodrugs Irinotecan Cyclophosphamide Cytochrome P-450 CYP2B1 Carboxylesterase Camptothecin
Topics	Antineoplastic Combined Chemotherapy Protocols (pharmacokinetics, pharmacology) Biotransformation Brain Neoplasms (genetics, therapy, virology) Camptothecin (administration & dosage, analogs & derivatives, pharmacokinetics) Carboxylesterase (biosynthesis, genetics, metabolism) Cell Line, Tumor Cyclophosphamide (administration & dosage) Cytochrome P-450 CYP2B1 (biosynthesis, genetics, metabolism) Genetic Therapy (methods) Glioma (genetics, therapy, virology) Herpesvirus 1, Human (enzymology, genetics, physiology) Humans Irinotecan Prodrugs (administration & dosage, pharmacokinetics) Virus Replication

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