Systemic therapy of experimental breast cancer metastases by mutant vesicular stomatitis virus in immune-competent mice
Systemic therapy of experimental breast cancer metastases by mutant vesicular stomatitis virus in immune-competent mice
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DOI：
10.1038/sj.cgt.7700794
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发表时间：
2005-04-01
影响因子：
6.4
通讯作者：
Woo, SLC
中科院分区：
文献类型：
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作者：
Ebert, O;Harbaran, S;Woo, SLC
鉴于转移性乳腺癌的现有治疗方式的有限成功，需要开发替代和补充策略。溶瘤性水泡性口炎病毒（VSV）是一种很有前途的新型肿瘤治疗药物。本研究的目的是评估静脉注射含有基质（M）蛋白基因中M51 R突变的重组VSV作为治疗实验性乳腺癌转移小鼠的有效和安全的治疗剂的潜力。重组VSV（M51 R）-LacZ的产生和表征在体外对人类和小鼠乳腺癌细胞。通过静脉注射同基因4 T1细胞在免疫活性Balb/c小鼠中建立乳腺癌转移。通过尾静脉将载体输注到荷瘤动物中，并通过冷冻肺切片的X-gal染色评估肺乳腺癌病变的生产性感染。为了评价潜在的全身毒性，分析了主要器官的组织学和血清化学。为了评估有效性，跟踪缓冲液或载体处理的荷瘤小鼠的存活率，并通过Kaplan-Meier方法和对数秩检验分析结果。我们发现VSV（M51 R）-LacZ有效地复制和裂解人乳腺癌细胞，但在体外4 T1细胞中部分减弱。我们还证明，其最大耐受剂量静脉输注后，在正常Balb/c小鼠升高了至少100倍以上的亲本VSV载体含有野生型M基因。当将VSV（M51 R）-LacZ重复静脉注射到携带同系4 T1肿瘤的小鼠中时，该病毒能够感染肺部的多个乳腺癌病变而没有明显的毒性，这导致动物存活的显著延长（P =. 003）。总之，全身施用M突变VSV在治疗免疫活性小鼠的实验性乳腺癌转移中是有效且安全的，这表明这种方法的进一步开发可能具有在患者中临床应用的潜力。
In view of the limited success of available treatment modalities for metastatic breast cancer, alternative and complementary strategies need to be developed. Oncolytic vesicular stomatitis virus (VSV) is a promising novel therapeutic agent for the treatment of cancer. The aim of this study was to evaluate the potential of recombinant VSV containing the M51R mutation in the matrix ( M) protein gene administered intravenously as an effective and safe therapeutic agent for treating mice with experimental breast cancer metastases. Recombinant VSV( M51R)-LacZ was generated and characterized in vitro on human and murine breast cancer cells. Breast cancer metastases were established in immune-competent Balb/c mice by intravenous injection of syngeneic 4T1 cells. The vector was infused into the tumor-bearing animals via the tail vein, and productive infection of pulmonary breast cancer lesions was assessed by X-gal stainings of frozen lung sections. To evaluate potential systemic toxicity, histology of major organs and serum chemistries were analyzed. To assess effectiveness, buffer- or vector-treated tumor-bearing mice were followed for survival and the results were analyzed by the Kaplan-Meier method and the log-rank test. We found that VSV( M51R)-LacZ efficiently replicated and lysed human breast cancer cells but was partially attenuated in 4T1 cells in vitro. We also demonstrated that its maximum tolerated dose after intravenous infusion in normal Balb/c mice was elevated by at least 100-fold over that of the parental VSV vector containing the wild-type M gene. When VSV( M51R)-LacZ was repeatedly injected intravenously into mice bearing syngeneic 4T1 tumors, the virus was able to infect multiple breast cancer lesions in the lungs without apparent toxicities, which led to significant prolongation of animal survival ( P =. 003). In conclusion, systemic administration of M mutant VSV is both effective and safe in the treatment of experimental breast cancer metastases in immune-competent mice, suggesting that further development of this approach may have potential for clinical application in patients.