Toxicology and Biodistribution Studies for MGH2.1, an Oncolytic Virus that Expresses Two Prodrug-activating Genes, in Combination with Prodrugs

Kazue Kasai; Hiroshi Nakashima; Fang Liu; Samantha Kerr; Jiang Wang; Mitch Phelps; Philip M Potter; William B Goins; Soledad A Fernandez; E Antonio Chiocca

doi:10.1038/mtna.2013.38

Molecular Therapy: Nucleic Acids (Jan 2013)

Toxicology and Biodistribution Studies for MGH2.1, an Oncolytic Virus that Expresses Two Prodrug-activating Genes, in Combination with Prodrugs

Kazue Kasai,
Hiroshi Nakashima,
Fang Liu,
Samantha Kerr,
Jiang Wang,
Mitch Phelps,
Philip M Potter,
William B Goins,
Soledad A Fernandez,
E Antonio Chiocca

Affiliations

Kazue Kasai: Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital/Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
Hiroshi Nakashima: Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital/Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
Fang Liu: Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital/Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
Samantha Kerr: Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital/Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
Jiang Wang: Pharmacology Core, James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
Mitch Phelps: Pharmacology Core, James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
Philip M Potter: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
William B Goins: Department of Microbiology & Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Soledad A Fernandez: Department of Biostatistics, The Ohio State University, Columbus, Ohio, USA
E Antonio Chiocca: Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital/Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA

DOI: https://doi.org/10.1038/mtna.2013.38
Journal volume & issue: Vol. 2, no. C

Abstract

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MGH2.1 is a herpes simplex virus type 1 (HSV1) oncolytic virus that expresses two prodrug-activating transgenes: the cyclophosphamide (CPA)-activating cytochrome P4502B1 (CYP2B1) and the CPT11-activating secreted human intestinal carboxylesterase (shiCE). Toxicology and biodistribution of MGH2.1 in the presence/absence of prodrugs was evaluated in mice. MGH2.1 ± prodrugs was cytotoxic to human glioma cells, but not to normal cells. Pharmacokinetically, intracranial MGH2.1 did not significantly alter the metabolism of intraperitoneally (i.p.) administered prodrugs in mouse plasma, brain, or liver. MGH2.1 did not induce an acute inflammatory reaction. MGH2.1 DNA was detected in brains of mice inoculated with 108 pfus for up to 60 days. However, only one animal showed evidence of viral gene expression at this time. Expression of virally encoded genes was restricted to brain. Intracranial inoculation of MGH2.1 did not induce lethality at 108 pfus in the absence of prodrugs and at 106 pfus in the presence of prodrugs. This study provides safety and toxicology data justifying a possible clinical trial of intratumoral injection of MGH2.1 with peripheral administration of CPA and/or CPT11 prodrugs in humans with malignant gliomas.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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