Abstract
hrR3 is an oncolytic herpes simplex virus 1 (HSV-1) mutant that replicates preferentially in tumors compared with normal tissues. Portal venous administration of hrR3 in mice bearing diffuse colorectal carcinoma liver metastases significantly reduces tumor burden and prolongs animal survival. In this study, we compared survival benefit and biodistribution of hrR3 following intravenous (i.v.) administration versus intraperitoneal (i.p.) administration in immunocompetent mice bearing colon carcinoma peritoneal metastases. Mice bearing peritoneal metastases received 1 × 108 plaque-forming units hrR3 or mock-infected media every other day for three doses and were randomized to have the viruses administered by either an i.p. or i.v. route. Biodistribution was assessed by PCR amplification of HSV-1-specific sequences from tumor and normal tissues including the small bowel, liver, spleen, kidney, lung, heart and brain. LD50 for i.p. administration was compared with the LD50 for i.v. administration. In subsequent experiments, animals were monitored for survival. The frequency of HSV-1 detection in peritoneal tumors was similar in mice randomized to either i.p. or i.v. administration. However, i.p. administration resulted in a more restricted systemic biodistribution, with a reduced frequency of virus detected in the kidney, lung and heart. The LD50 associated with i.p. administration was higher than that with i.v. administration. Tumor burden was more effectively reduced with i.p. compared with i.v. administration. Median survival following i.p. administration was approximately twice that observed with i.v. administration. I.p. administration of an HSV-1 oncolytic mutant is associated with a more restricted biodistribution, less toxicity and greater efficacy against peritoneal metastases compared with i.v. administration.
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Abbreviations
- HSV-1:
-
herpes simplex virus 1
- i.p.:
-
intraperitoneal
- i.v.:
-
intravenous
- MOI:
-
multiplicity of infection
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Acknowledgements
This study was supported by the grants 2R01CA76183 (KKT); 5T32CA009535 (JDD); Massachusetts General Hospital Tucker Gosnell Gastrointestinal Cancer Center (KKT, BCF) and Fund for Medical Discovery Fellowship (BCF); and Deutsche Forschungsgemeinschaft (YK).
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Kulu, Y., Dorfman, J., Kuruppu, D. et al. Comparison of intravenous versus intraperitoneal administration of oncolytic herpes simplex virus 1 for peritoneal carcinomatosis in mice. Cancer Gene Ther 16, 291–297 (2009). https://doi.org/10.1038/cgt.2008.83
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DOI: https://doi.org/10.1038/cgt.2008.83
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