TY - JOUR

T1 - Chronometric Administration of Cyclophosphamide and a Double-Stranded DNA-Mix at Interstrand Crosslinks Repair Timing, Called “Karanahan” Therapy, Is Highly Efficient in a Weakly Immunogenic Lewis Carcinoma Model

AU - Ruzanova, Vera

AU - Proskurina, Anastasia

AU - Efremov, Yaroslav

AU - Kirikovich, Svetlana

AU - Ritter, Genrikh

AU - Levites, Evgenii

AU - Dolgova, Evgenia

AU - Potter, Ekaterina

AU - Babaeva, Oksana

AU - Sidorov, Sergey

AU - Taranov, Oleg

AU - Ostanin, Alexandr

AU - Chernykh, Elena

AU - Bogachev, Sergey

N1 - Funding Information: The work was supported by the Russian Ministry of Science and Higher Education via the Institute of Cytology and Genetics under State Budget Project No. FWNR-2022-0016 and the Russian Foundation for Basic Research under Grant No. 18-29-09045. Publisher Copyright: Copyright © 2022 Ruzanova, Proskurina, Efremov, Kirikovich, Ritter, Levites, Dolgova, Potter, Babaeva, Sidorov, Taranov, Ostanin, Chernykh and Bogachev.

PY - 2022/5/27

Y1 - 2022/5/27

N2 - Background and Aims: 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. Methods: 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. Results: 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. Conclusion: 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.

AB - Background and Aims: 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. Methods: 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. Results: 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. Conclusion: 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.

KW - cancer stem cells

KW - committed tumor cells

KW - cytostatic agent

KW - dsDNA

KW - interstrand crosslink repair

KW - Karanahan approach

KW - Lewis lung carcinoma

KW - tumor growth site

KW - Antigens, CD34

KW - Cyclophosphamide/pharmacology

KW - Humans

KW - Mice, Inbred C57BL

KW - Neoplastic Stem Cells/pathology

KW - DNA/genetics

KW - Animals

KW - Carcinoma/pathology

KW - Mice

UR - http://www.scopus.com/inward/record.url?scp=85131852523&partnerID=8YFLogxK

U2 - 10.3389/pore.2022.1610180

DO - 10.3389/pore.2022.1610180

M3 - Article

C2 - 35693632

AN - SCOPUS:85131852523

VL - 28

JO - Pathology and Oncology Research

JF - Pathology and Oncology Research

SN - 1219-4956

M1 - 1610180

ER -