Abstract

Melanoma is one of the most aggressive tumors and is accompanied by the induction of local and systemic inflammatory responses. Combinations of chemotherapeutic agents with immunotherapy are therefore commonly used for melanoma treatment. A B16 melanoma model was used to study the tumor suppressive, immunostimulating, and hepatotoxic effects of a combination of a small double-stranded immunostimulatory RNA (isRNA) with 3'-trinucleotide overhangs and the cytotoxic drug dacarbazine compared with respective monotherapies. The drugs efficiently suppressed the tumor growth and acted synergistically. Histological and immunohistochemical examinations of tumor nodes showed that the combination of isRNA and dacarbazine significantly decreased mitotic activity and more efficiently increased apoptosis in tumor tissue as compared with either monotherapy. Regardless of the treatment regimen, signs of immune activation were observed in the spleen, including an increase in the number and diameter of lymphoid follicles and the volume density of the white pulp. Destructive changes were detected in the livers of nontreated animals with B16 melanoma. Administration of isRNA in combination with dacarbazine did not cause any additional damage to liver parenchyma, while stimulating regenerative processes in hepatic tissue of tumor-bearing animals.

中文翻译：

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在鼠黑素瘤模型中，免疫刺激RNA与达卡巴嗪联用对肿瘤的抑制，免疫刺激和肝毒性作用

摘要

黑色素瘤是最具侵袭性的肿瘤之一，并伴有局部和全身性炎症反应。因此，化学治疗剂与免疫疗法的组合通常用于黑色素瘤治疗。使用B16黑色素瘤模型来研究小双链免疫刺激RNA（isRNA）与3'-三核苷酸悬突和细胞毒性药物达卡巴嗪的组合对肿瘤的抑制，免疫刺激和肝毒性作用，并与各自的单一疗法进行比较。这些药物有效地抑制了肿瘤的生长并发挥了协同作用。肿瘤淋巴结的组织学和免疫组织化学检查显示，与任一单一疗法相比，isRNA和达卡巴嗪的组合显着降低了有丝分裂活性，并更有效地增加了肿瘤组织中的细胞凋亡。不论治疗方案如何，在脾脏中均观察到免疫活化的迹象，包括淋巴滤泡的数量和直径增加以及白髓的体积密度增加。在未经治疗的B16黑色素瘤动物的肝脏中检测到破坏性变化。将isRNA与达卡巴嗪合用不会刺激肝实质，同时会刺激荷瘤动物肝组织的再生过程。