Laboratory of Induced Cellular Processes, Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.
Department of Natural Sciences, Novosibirsk National Research State University, Novosibirsk, Russia.
Pathol Oncol Res. 2022 May 27;28:1610180. doi: 10.3389/pore.2022.1610180. eCollection 2022.
A new technology based on the chronometric administration of cyclophosphamide and complex composite double-stranded DNA-based compound, which is scheduled in strict dependence on interstrand crosslinks repair timing, and named "Karanahan", has been developed. Being applied, this technology results in the eradication of tumor-initiating stem cells and full-scale apoptosis of committed tumor cells. In the present study, the efficacy of this novel approach has been estimated in the model of Lewis carcinoma. To determine the basic indicative parameters for the approach, the duration of DNA repair in tumor cells, as well as their distribution along the cell cycle, have been assessed. Injections were done into one or both tumors in femoral region of the engrafted mice in accordance with the developed regimen. Four series of experiments were carried out at different periods of time. The content of poorly differentiated CD34/TAMRA+ cells in the bone marrow and peripheral blood has been determined. Immunostaining followed by the flow cytometry was used to analyze the subpopulations of immune cells. The high antitumor efficacy of the new technology against the developed experimental Lewis carcinoma was shown. It was found that the therapy efficacy depended on the number of tumor growth sites, seasonal and annual peculiarities. In some experiments, a long-term remission has been reached in 70% of animals with a single tumor and in 60% with two tumors. In mice with two developed grafts, mobilization capabilities of both poorly differentiated hematopoietic cells of the host and tumor stem-like cells decrease significantly. Being applied, this new technology was shown to activate a specific immune response. There is an increase in the number of NK cell populations in the blood, tumor, and spleen, killer T cells and T helper cells in the tumor and spleen, CD11b+Ly-6C+ and CD11b+Ly-6G+ cells in the tumor. A population of mature dendritic cells is found in the tumor. The performed experiments indicate the efficacy of the Karanahan approach against incurable Lewis carcinoma. Thus, the discussed therapy is a new approach for treating experimental neoplasms, which has a potential as a personalized anti-tumor therapeutic approach in humans.
一种基于环磷酰胺的计时给药和复杂复合双链 DNA 化合物的新技术已经开发出来，该技术严格依赖于链间交联修复时间，并命名为“Karanahan”。该技术的应用导致肿瘤起始干细胞的根除和已分化肿瘤细胞的全面凋亡。在本研究中，该新方法的疗效已在 Lewis 癌模型中进行了评估。 为了确定该方法的基本指示参数，评估了肿瘤细胞中 DNA 修复的持续时间，以及它们在细胞周期中的分布。根据制定的方案，将注射物注入植入小鼠股骨区域的一个或两个肿瘤中。在不同的时间段进行了四组实验。测定骨髓和外周血中分化不良的 CD34/TAMRA+细胞的含量。免疫染色后进行流式细胞术分析免疫细胞亚群。 该新方法对已开发的实验性 Lewis 癌具有很高的抗肿瘤疗效。结果发现，该疗法的疗效取决于肿瘤生长部位的数量、季节性和年度特点。在一些实验中，在 70%的单肿瘤动物和 60%的双肿瘤动物中达到了长期缓解。在两个已发展的移植物的小鼠中，宿主和肿瘤干细胞样细胞的分化不良造血细胞以及动员能力显著降低。该新方法被证明可激活特异性免疫反应。血液、肿瘤和脾脏中 NK 细胞群体数量增加，肿瘤和脾脏中杀伤性 T 细胞和辅助性 T 细胞增加，肿瘤中 CD11b+Ly-6C+和 CD11b+Ly-6G+细胞增加。肿瘤中发现成熟树突状细胞群体。 进行的实验表明，Karanahan 方法对不可治愈的 Lewis 癌有效。因此，所讨论的治疗方法是治疗实验性肿瘤的新方法，具有在人类中作为个性化抗肿瘤治疗方法的潜力。
