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.

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.

[1]  Franck Delaunay,et al.  Effects of Chronic Jet Lag on Tumor Progression in Mice , 2004, Cancer Research.

[2]  R. Botting,et al.  Acetaminophen-induced hypothermia in mice is mediated by a prostaglandin endoperoxide synthase 1 gene-derived protein. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[3]  P. Boehmer,et al.  Reconstitution of recombination-dependent DNA synthesis in herpes simplex virus 1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[4]  M. Wierdl,et al.  Carboxylesterase-mediated sensitization of human tumor cells to CPT-11 cannot override ABCG2-mediated drug resistance. , 2003, Molecular pharmacology.

[5]  T S Deisboeck,et al.  Development of a novel non-human primate model for preclinical gene vector safety studies. Determining the effects of intracerebral HSV-1 inoculation in the common marmoset: a comparative study , 2003, Gene Therapy.

[6]  Peter McL Black,et al.  The Neurosurgeon as Local Oncologist: Cellular and Molecular Neurosurgery in Malignant Glioma Therapy , 2003, Neurosurgery.

[7]  H. Wakimoto,et al.  Effects of innate immunity on herpes simplex virus and its ability to kill tumor cells , 2003, Gene Therapy.

[8]  S. Keir,et al.  The emerging role of irinotecan (CPT‐11) in the treatment of malignant glioma in brain tumors , 2003, Cancer.

[9]  K. Hoang-Xuan,et al.  Primary brain tumours in adults , 2003, The Lancet.

[10]  I. Lehman,et al.  Origin-specific unwinding of herpes simplex virus 1 DNA by the viral UL9 and ICP8 proteins: Visualization of a specific preunwinding complex , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[11]  T. Pawlik,et al.  Prodrug bioactivation and oncolysis of diffuse liver metastases by a herpes simplex virus 1 mutant that expresses the CYP2B1 transgene , 2002, Cancer.

[12]  H. Wakimoto,et al.  The complement response against an oncolytic virus is species-specific in its activation pathways. , 2002, Molecular therapy : the journal of the American Society of Gene Therapy.

[13]  E. Chiocca.  Oncolytic viruses , 2002, Nature Reviews Cancer.

[14]  M. Wierdl,et al.  Sensitization of human tumor cells to CPT-11 via adenoviral-mediated delivery of a rabbit liver carboxylesterase. , 2001, Cancer research.

[15]  M. Wierdl,et al.  A virus-directed enzyme prodrug therapy approach to purging neuroblastoma cells from hematopoietic cells using adenovirus encoding rabbit carboxylesterase and CPT-11. , 2001, Cancer research.

[16]  O. Colvin,et al.  Intraneoplastic polymer-based delivery of cyclophosphamide for intratumoral bioconversion by a replicating oncolytic viral vector. , 2001, Cancer research.

[17]  M. Dolan,et al.  Schedule-dependent activity of temozolomide plus CPT-11 against a human central nervous system tumor-derived xenograft. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  M. Tan,et al.  Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[19]  H. Wakimoto,et al.  Complement Depletion Facilitates the Infection of Multiple Brain Tumors by an Intravascular, Replication-Conditional Herpes Simplex Virus Mutant , 2000, Journal of virology.

[20]  R. Martuza,et al.  Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial , 2000, Gene Therapy.

[21]  K. Bastow,et al.  1,3-Dihydroxyacridone derivatives as inhibitors of herpes virus replication. , 2000, Antiviral research.

[22]  S. Keir,et al.  Schedule-dependent activity of irinotecan plus BCNU against malignant glioma xenografts , 2000, Cancer Chemotherapy and Pharmacology.

[23]  X. Breakefield,et al.  Multimodal cancer treatment mediated by a replicating oncolytic virus that delivers the oxazaphosphorine/rat cytochrome P450 2B1 and ganciclovir/herpes simplex virus thymidine kinase gene therapies. , 1999, Cancer research.

[24]  D. Louis,et al.  Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses , 1999, Nature Medicine.

[25]  P. Houghton,et al.  Comparison of activation of CPT-11 by rabbit and human carboxylesterases for use in enzyme/prodrug therapy. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  M. Wierdl,et al.  Cellular localization domains of a rabbit and a human carboxylesterase: influence on irinotecan (CPT-11) metabolism by the rabbit enzyme. , 1998, Cancer research.

[27]  C. Morton,et al.  Isolation and partial characterization of a cDNA encoding a rabbit liver carboxylesterase that activates the prodrug irinotecan (CPT-11). , 1998, Cancer research.

[28]  R. Chung,et al.  An oncolytic viral mutant that delivers the CYP2B1 transgene and augments cyclophosphamide chemotherapy , 1998, Nature Biotechnology.

[29]  C. Morton,et al.  Overexpression of a rabbit liver carboxylesterase sensitizes human tumor cells to CPT-11. , 1998, Cancer research.

[30]  E. Chiocca,et al.  The effect of ganciclovir on herpes simplex virus-mediated oncolysis. , 1997, The Journal of surgical research.

[31]  I. Lehman,et al.  Herpes simplex virus DNA replication. , 1997, Annual review of biochemistry.

[32]  P. Elias,et al.  Inhibition of topoisomerase II by ICRF-193 prevents efficient replication of herpes simplex virus type 1 , 1996, Journal of virology.

[33]  J. Park,et al.  Long-term survival of rats harboring brain neoplasms treated with ganciclovir and a herpes simplex virus vector that retains an intact thymidine kinase gene. , 1994, Cancer research.