Particulate mediators of the bystander effect linked to suicide and interferon-β transgene expression in melanoma cells.,Gene Therapy

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Particulate mediators of the bystander effect linked to suicide and interferon-β transgene expression in melanoma cells.
Gene Therapy ( IF 4.6 ) Pub Date : 2020-03-03 , DOI: 10.1038/s41434-020-0136-x
Lucrecia Agnetti ₁ , Chiara Fondello ₁ , María Florencia Arbe ₁ , Gerardo C Glikin ₁ , Liliana M E Finocchiaro ₁

Affiliation

In the context of comparative oncology, melanoma cells derived from companion animal tumors are good models for optimizing and predicting their in vivo response to therapeutic strategies. Here, we report that human, canine, and feline melanoma cells driven to death by bleomycin, interferon-β gene, or herpes simplex virus thymidine kinase/ganciclovir suicide gene (SG) treatment significantly increased their internal granularity. This fact correlated with the release of a heterogeneous collection of nano- and micro-sized granules as revealed by transmission electron microscopy. While killing lipofected cells, the expressed transgenes and their derived products were incorporated into these granules that were isolated by differential centrifugation. These particulate factors (PFs) were able to transfer, in a dose- and time-dependent manner, appreciable levels of therapeutic genes, related proteins, and drugs. Thus, when recipient cells of SG-carrying PFs were exposed to ganciclovir, this prodrug was efficiently activated, eliminating them. These PFs kept the functionality of their cargo, even after being subjected to adverse conditions, such as the presence of DNase, freezing, or heating. Since our in vitro system did not include any of the immune mechanisms that could provide additional antitumor activity, the chemo-gene treatments amplified by these delivery bags of therapeutic agents offer a great clinical potential.

中文翻译：

旁观者效应的微粒介质与黑色素瘤细胞中的自杀和干扰素-β 转基因表达有关。

在比较肿瘤学的背景下，源自伴侣动物肿瘤的黑色素瘤细胞是优化和预测其对治疗策略的体内反应的良好模型。在这里，我们报告了被博来霉素、干扰素-β 基因或单纯疱疹病毒胸苷激酶/更昔洛韦自杀基因 (SG) 治疗致死的人类、犬和猫黑色素瘤细胞显着增加了它们的内部粒度。这一事实与透射电子显微镜所揭示的纳米和微米尺寸颗粒的异质集合的释放相关。在杀死脂质感染细胞的同时，将表达的转基因及其衍生产物掺入这些通过差速离心分离的颗粒中。这些颗粒因子 (PFs) 能够以剂量和时间依赖的方式转移，可观水平的治疗基因、相关蛋白质和药物。因此，当携带 SG 的 PF 的受体细胞暴露于更昔洛韦时，该前药被有效激活，消除了它们。即使在受到不利条件（例如 DNase、冷冻或加热）的影响之后，这些 PF 仍能保持其货物的功能。由于我们的体外系统不包括任何可以提供额外抗肿瘤活性的免疫机制，由这些治疗剂递送袋放大的化学基因治疗提供了巨大的临床潜力。即使在受到不利条件（例如 DNase 的存在、冷冻或加热）之后。由于我们的体外系统不包括任何可以提供额外抗肿瘤活性的免疫机制，由这些治疗剂递送袋放大的化学基因治疗提供了巨大的临床潜力。即使在受到不利条件（例如 DNase 的存在、冷冻或加热）之后。由于我们的体外系统不包括任何可以提供额外抗肿瘤活性的免疫机制，由这些治疗剂递送袋放大的化学基因治疗提供了巨大的临床潜力。

更新日期：2020-04-24

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