Preclinical therapy of disseminated HER-2⁺ ovarian and breast carcinomas with a HER-2-retargeted oncolytic herpesvirus.
Preclinical therapy of disseminated HER-2⁺ ovarian and breast carcinomas with a HER-2-retargeted oncolytic herpesvirus.
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DOI：
10.1371/journal.ppat.1003155
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发表时间：
2013-01
期刊：
影响因子：
6.7
通讯作者：
Lollini PL
中科院分区：
文献类型：
--
作者：
Nanni P;Gatta V;Menotti L;De Giovanni C;Ianzano M;Palladini A;Grosso V;Dall'ora M;Croci S;Nicoletti G;Landuzzi L;Iezzi M;Campadelli-Fiume G;Lollini PL
溶瘤病毒的目的是特异性杀死肿瘤细胞。一个主要的挑战是体内播散性肿瘤的有效靶向。我们将单纯疱疹病毒（HSV）的嗜性重新定位于卵巢癌和乳腺癌中过表达的HER-2癌蛋白p185。HER-2重靶向的R-LM249只感染并杀死表达高水平人HER-2的肿瘤细胞。在这里，我们评估了全身口服R-LM249对女性腹膜扩散肿瘤小鼠模型的疗效。人卵巢癌SK-OV-3细胞腹腔植入免疫缺陷Rag2−/−；Il2rg - / -小鼠引起了一种进行性腹膜癌，模仿了晚期人类患者的致命状况。ig给药R-LM249强烈抑制癌变，使60%的小鼠免于腹膜扩散，肿瘤结节总重量减少95%。腹腔内转移是乳腺癌的常见结果：口服R-LM249可强烈抑制HER-2+ MDA-MB-453乳腺细胞卵巢转移的生长。脑转移也减少了。累积起来，经口服后，her -2重定向的溶瘤性HSV有效地减少了扩散到腹腔的卵巢癌和乳腺癌的生长。在人类单纯疱疹病毒（HSV）的基因组中，我们用针对乳腺癌和卵巢癌中过度表达的癌蛋白HER-2的抗体片段取代了编码受体结合糖蛋白的部分序列。重定向的HSV只感染并杀死表达高水平HER-2的人类癌细胞。早期的实验表明，在免疫缺陷小鼠中，将重靶向的HSV注射到局部肿瘤中可以抑制人类肿瘤的生长。由于肿瘤播散是癌症死亡的主要原因，我们现在使用HER-2重靶向HSV治疗免疫缺陷小鼠的播散性HER-2+卵巢癌和乳腺癌。腹腔内治疗显著抑制卵巢癌细胞的腹膜扩散（癌变和腹水形成）和卵巢癌细胞在卵巢中的转移性生长。脑转移也受到抑制。我们的研究结果表明，HER-2重定向溶瘤性HSV是一种有效的治疗转移性HER-2+癌症的药物，更普遍地说，首次证明了系统给药的重定向溶瘤性HSV的疗效。
Oncolytic viruses aim to specifically kill tumor cells. A major challenge is the effective targeting of disseminated tumors in vivo. We retargeted herpes simplex virus (HSV) tropism to HER-2 oncoprotein p185, overexpressed in ovary and breast cancers. The HER-2-retargeted R-LM249 exclusively infects and kills tumor cells expressing high levels of human HER-2. Here, we assessed the efficacy of systemically i.p. delivered R-LM249 against disseminated tumors in mouse models that recapitulate tumor spread to the peritoneum in women. The human ovarian carcinoma SK-OV-3 cells implanted intraperitoneally (i.p.) in immunodeficient Rag2−/−;Il2rg−/− mice gave rise to a progressive peritoneal carcinomatosis which mimics the fatal condition in advanced human patients. I.p. administration of R-LM249 strongly inhibited carcinomatosis, resulting in 60% of mice free from peritoneal diffusion, and 95% reduction in the total weight of neoplastic nodules. Intraperitoneal metastases are a common outcome in breast cancer: i.p. administration of R-LM249 strongly inhibited the growth of ovarian metastases of HER-2+ MDA-MB-453 breast cells. Brain metastases were also reduced. Cumulatively, upon i.p. administration the HER-2-redirected oncolytic HSV effectively reduced the growth of ovarian and breast carcinoma disseminated to the peritoneal cavity. In the genome of human herpes simplex virus (HSV) we have replaced part of the sequences encoding the receptor-binding glycoprotein with antibody fragments directed against the oncoprotein HER-2, overexpressed in human breast and ovarian cancers. The retargeted HSV only infects and kills human cancer cells expressing high levels of HER-2. Earlier experiments showed that the retargeted HSV injected inside localized tumors inhibits human tumor growth in immunodeficient mice. As tumor dissemination is the major cause of cancer mortality, we have now used the HER-2-retargeted HSV to treat disseminated HER-2+ ovarian and breast cancer in immunodeficient mice. Intraperitoneal treatments significantly inhibited the peritoneal spread (carcinomatosis and ascites formation) of ovarian cancer cells and the metastatic growth of breast cancer cells in the ovaries. Brain metastases were also inhibited. Our results showed that a HER-2-redirected oncolytic HSV is an effective therapeutic agent against metastatic HER-2+ cancers and, more generally, provide the first demonstration of the efficacy of a systemically-administered, retargeted oncolytic HSV.
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影响因子：
3.6
作者：
Gancz, Dana;Fishelson, Zvi
通讯作者：
Fishelson, Zvi
DOI：
10.1073/pnas.92.23.10516
发表时间：
1995-11-07
影响因子：
11.1
作者：
CHOU, J;CHEN, JJ;ROIZMAN, B
通讯作者：
ROIZMAN, B
影响因子：
6.4
作者：
Bergman, Ira;Griffin, Judith A.;Whitaker-Dowling, Patricia
通讯作者：
Whitaker-Dowling, Patricia
DOI：
10.1038/nrmicro1927
发表时间：
2008-07
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.4
作者：
Menotti, Laura;Cerretani, Arianna;Campadelli-Fiume, Gabriella
通讯作者：
Campadelli-Fiume, Gabriella