title: 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.affiliation: Molecular Neuro-oncology Laboratories, Neurosurgery Service and Biostatistics Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Edyta
authors.initials: E
authors.lastname: Tyminski
authors.forename: Stanley
authors.initials: S
authors.lastname: Leroy
authors.forename: Kinya
authors.initials: K
authors.lastname: Terada
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Finkelstein
authors.forename: Janice L
authors.initials: JL
authors.lastname: Hyatt
authors.forename: Mary K
authors.initials: MK
authors.lastname: Danks
authors.forename: Philip M
authors.initials: PM
authors.lastname: Potter
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Saeki
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000494:pharmacology; D001711:Biotransformation; D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D043182:Carboxylesterase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D005910:Glioma / Q000235:genetics / Q000628:therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D006801:Humans; D000077146:Irinotecan; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics; D014779:Virus Replication
chemical_list: D011355:Prodrugs; D000077146:Irinotecan; D003520:Cyclophosphamide; D019362:Cytochrome P-450 CYP2B1; D043182:Carboxylesterase; D002166:Camptothecin