Kulu Y, Dorfman J D, Kuruppu D, Fuchs B C, Goodwin J M, Fujii T, Kuroda T, Lanuti M, Tanabe K K
Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
Cancer Gene Ther. 2009 Apr;16(4):291-7. doi: 10.1038/cgt.2008.83. Epub 2008 Nov 7.
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 x 10(8) 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. LD(50) for i.p. administration was compared with the LD(50) 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 LD(50) 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.
hrR3是一种溶瘤单纯疱疹病毒1型（HSV-1）突变体，与正常组织相比，它在肿瘤中优先复制。在患有弥漫性结直肠癌肝转移的小鼠中门静脉注射hrR3可显著减轻肿瘤负担并延长动物生存期。在本研究中，我们比较了在患有结肠癌腹膜转移的免疫活性小鼠中，静脉内（i.v.）给药与腹腔内（i.p.）给药后hrR3的生存获益和生物分布。患有腹膜转移的小鼠每隔一天接受1×10⁸ 空斑形成单位的hrR3或模拟感染的培养基，共三剂，并随机分为通过腹腔内或静脉内途径给予病毒。通过从肿瘤和正常组织（包括小肠、肝脏、脾脏、肾脏、肺、心脏和大脑）中PCR扩增HSV-1特异性序列来评估生物分布。比较腹腔内给药的半数致死量（LD₅₀）与静脉内给药的LD₅₀。在随后的实验中，监测动物的生存情况。随机接受腹腔内或静脉内给药的小鼠中，腹膜肿瘤中HSV-1检测频率相似。然而，腹腔内给药导致全身生物分布更局限，在肾脏、肺和心脏中检测到病毒的频率降低。与静脉内给药相关的LD₅₀高于腹腔内给药。与静脉内给药相比，腹腔内给药能更有效地减轻肿瘤负担。腹腔内给药后的中位生存期约为静脉内给药的两倍。与静脉内给药相比，腹腔内给予HSV-1溶瘤突变体与更局限的生物分布、更低的毒性以及针对腹膜转移的更高疗效相关。
