Experimental Comparison of the <i>In Vivo</i> Efficacy of Two Novel Anticancer Therapies

Ruzanova, Vera S.; Proskurina, Anastasia S.; Ritter, Genrikh S.; Efremov, Yaroslav R.; Николин, В. П.; Попова, Н. А.; Naprimerov, Vasiliy A; Долгова, Е. В.; Potter, Ekaterina A.; Кирикович, С. С.; Левитес, Е. В.; Мустафин, З. С.; Lashin, Sergey A.; Буракова, Е. А.; Stetsenko, Dmitry A.; Останин, А. А.; Черных, Е. Р.; Bogachev, Sergey S.

doi:10.21873/anticanres.15125

Cited by 8 publications

(15 citation statements)

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“…We have put forward a hypothesis that the antitumor effect of GcMAF-RF can be induced only in the case of a significant reduction in the humoral activity of the tumor. Based on the data obtained, we decided to combine two approaches: in situ vaccination with GcMAF-RF and Karanahan therapy [ 35 , 45 ]. We hypothesized that the cytoreductive effect of the Karanahan approach would enable the antitumor properties of GcMAF-RF used in the in situ vaccination regimen.…”

Section: Resultsmentioning

confidence: 99%

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Analysis of the Biological Properties of Blood Plasma Protein with GcMAF Functional Activity

Долгова

Кирикович

Левитес

et al. 2022

IJMS

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The main problem related to the studies focusing on group-specific component protein-derived macrophage-activating factor (GcMAF) is the lack of clarity about changes occurring in different types of macrophages and related changes in their properties under the effect of GcMAF in various clinical conditions. We analyzed the antitumor therapeutic properties of GcMAF in a Lewis carcinoma model in two clinical conditions: untreated tumor lesion and tumor resorption after exposure to Karanahan therapy. GcMAF is formed during site-specific deglycosylation of vitamin D3 binding protein (DBP). DBP was obtained from the blood of healthy donors using affinity chromatography on a column with covalently bound actin. GcMAF-related factor (GcMAF-RF) was converted in a mixture with induced lymphocytes through the cellular enzymatic pathway. The obtained GcMAF-RF activates murine peritoneal macrophages (p < 0.05), induces functional properties of dendritic cells (p < 0.05) and promotes in vitro polarization of human M0 macrophages to M1 macrophages (p < 0.01). Treatment of whole blood cells with GcMAF-RF results in active production of both pro- and anti-inflammatory cytokines. It is shown that macrophage activation by GcMAF-RF is inhibited by tumor-secreted factors. In order to identify the specific antitumor effect of GcMAF-RF-activated macrophages, an approach to primary reduction of humoral suppressor activity of the tumor using the Karanahan therapy followed by macrophage activation in the tumor-associated stroma (TAS) was proposed. A prominent additive effect of GcMAF-RF, which enhances the primary immune response activation by the Karanahan therapy, was shown in the model of murine Lewis carcinoma. Inhibition of the suppressive effect of TAS is the main condition required for the manifestation of the antitumor effect of GcMAF-RF. When properly applied in combination with any chemotherapy, significantly reducing the humoral immune response at the advanced tumor site, GcMAF-RF is a promising antitumor therapeutic agent that additively destroys the pro-tumor properties of macrophages of the tumor stroma.

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Section: Resultsmentioning

confidence: 99%

“…When the tumor reached a volume of 64–340 mm 3 , mice were injected with the drugs. The Karanahan Group was injected with 100 mg/kg of CP intraperitoneally and 0.5 mg/mouse of DNAmix in 200 μL of saline intratumorally according to the therapeutic regimen ( Figure 6 A) [ 45 ]. The production of DNAmix is described in detail in [ 32 ].…”

Section: Methodsmentioning

confidence: 99%

Analysis of the Biological Properties of Blood Plasma Protein with GcMAF Functional Activity

Долгова

Кирикович

Левитес

et al. 2022

IJMS

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“…These approaches are (I) in situ vaccination, aimed to expand the population of tumor-specific cytotoxic T cells and to initiate a systemic immune response that would have an abscopal effect and affect “nonvaccinated” cancer foci ( 3 , 10 , 16 ); (II) CMLD CP-based chemotherapy, aimed to inactivate the immunosuppressive activity of tumor-resident myeloid-derived suppressor cells (MDSCs) ( 5 - 8 , 17 , 18 ) and to restore the activity of anticancer immune cells; (III) our Karanahan technology, which induces the massive apoptosis of cancer cells and reduces cancer grafts by eradicating TISCs. Our analysis indicates that the first 2 approaches are applicable in the context of immunogenic tumors, whereas Karanahan demonstrates sustained activity regardless of the “hot” or “cold” immune status of the tumor ( 19 ).…”

Section: Introductionmentioning

confidence: 89%

“…The process of repairing interstrand crosslinks after exposure to a crosslinking cytostatic, the main events occurring in the population of tumor cells following the application of Karanahan technology, and principles of CP and DNAmix administration within the Karanahan framework have been previously conceptualized in the figure published in a previous work ( 19 ).…”

Section: Cmld Cp-based Chemotherapymentioning

confidence: 99%

Theoretical premises of a “three in one” therapeutic approach to treat immunogenic and nonimmunogenic cancers: a narrative review

Proskurina¹,

Ruzanova²,

Останин³

et al. 2021

Transl Cancer Res TCR

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Objective We describe experimental and theoretical premises of a powerful cancer therapy based on the combination of three approaches. These include (I) in situ vaccination (intratumoral injections of CpG oligonucleotides and anti-OX40 antibody); (II) chronometric or metronomic low-dose cyclophosphamide (CMLD CP)-based chemotherapy; (III) cancer stem cell-eradicating therapy referred to as Karanahan (from the Sanskrit kāraṇa [“source”] + han [“to kill”]). Background In murine models, the first two approaches are particularly potent in targeting immunogenic tumors for destruction. In situ vaccination activates a fully fledged anticancer immune response via an intricate network of ligand–receptor–cytokine interactions. CMLD CP-based chemotherapy primarily targets the suppressive tumor microenvironment and activates tumor-infiltrating effectors. In contrast, Karanahan technology, being aimed at replicative machinery of tumor cells (both stem-like and committed), does not depend on tumor immunogenicity. With this technology, mice engrafted with ascites and/or solid tumors can be successfully cured. There is a significant degree of mechanistic and therapeutic overlap between these three approaches. For instance, the similarities shared between in situ vaccination and Karanahan technology include the therapeutic procedure, the cell target [antigen-presenting cells (APC) and dendritic cells (DC)], and the use of DNA-based preparations (CpG and DNAmix). Features shared between CMLD CP-based chemotherapy and Karanahan technology are the timing and the dose of the cytostatic drug administration, which lead to tumor regression. Methods The following keywords were used to search PubMed for the latest research reporting successful eradication of transplantable cancers in animal models that relied on approaches distinct from those used in the Karanahan technology: eradication of malignancy, cure cancer, complete tumor regression, permanently eradicating advanced mouse tumor, metronomic chemotherapy, in situ vaccination, immunotherapy, and others. Conclusion We hypothesize, therefore, that very potent anticancer activity can be achieved once these three therapeutic modalities are combined into a single approach. This multimodal approach is theoretically curative for any type of cancer that depends on the presence of tumor-inducing cancer stem cells, provided that the active therapeutic components are efficiently delivered into the tumor and the specific biological features of a given patient’s tumor are properly addressed. We expect this multimodal approach to be primarily applicable to late-stage or terminal cancer patients who have...

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“…~25% of the mice died due to severe systemic inflammation and ~50% of the animals survived with no relapse until the end of the monitoring span (180 days from the experiment beginning). Moreover, two females born healthy offspring [33,[36][37][38][39][40]. Over 20 years of research, countless experiments with all possibles controls in every case have been conducted.…”

Section: Brief History and Main Stages Of The "Karanahan" Developmentmentioning

confidence: 99%

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

Ruzanova

Proskurina

Efremov

et al. 2022

Pathol. Oncol. Res.

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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.

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Experimental Comparison of the In Vivo Efficacy of Two Novel Anticancer Therapies

Cited by 8 publications

References 53 publications

Analysis of the Biological Properties of Blood Plasma Protein with GcMAF Functional Activity

Analysis of the Biological Properties of Blood Plasma Protein with GcMAF Functional Activity

Theoretical premises of a “three in one” therapeutic approach to treat immunogenic and nonimmunogenic cancers: a narrative review

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

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