Therapeutic effects of cyclophosphamide, dsDNA preparations and combinations thereof against Krebs-2 ascites cancer cells and various cancer transplants

Potter, A. M.; Долгова, В. Н.; Минкевич, М.; Efremov, Roman G.; Таранов, С.; Омигов, В. В.; Николин, П.; Popova, Antonia P.; Проскурина, С.; Vereshchagin, I A; Kozel, Valerie; Rogachev, Aleksey F.; Petrov, Blagovest; Ostanin, А. А.; Черных, Р.; Колчанов, А.; Богачев, С. С.

doi:10.18699/vj15.116

Cited by 3 publications

(3 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Earlier, we performed comprehensive analysis of cellular and molecular events accompanying the therapy [ 6 , unpublished data] and conclude that the effects observed are based on the selective targeting of Krebs-2 TISCs, which neutralizes the tumorigenic potential of cancer cells [ 2 ]. So, we suggested that multiple injections in the metronomic regimen could be substituted by a single injection of a composite dsDNA preparation at the 18 h timepoint post CP (6 mg total) to fully recapitulate the desired therapeutic effect.…”

Section: Resultsmentioning

confidence: 99%

A strategy to eradicate well-developed Krebs-2 ascites in mice

et al. 2016

View full text Add to dashboard Cite

We describe the strategy, which allows curing experimental mice engrafted with Krebs-2 ascites. The strategy is based on the facts that i) Krebs-2 tumor-initiating stem cells (TISCs) are naturally capable of internalizing fragments of extracellular double-stranded DNA (dsDNA); ii) upon delivery into TISCs, these dsDNA fragments interfere with the on-going DNA repair process so that TISCs either die or lose their tumorigenic potential. The following 3-step regimen of therapeutic procedures leading to eradication of Krebs-2 ascites is considered. Firstly, three timed injections of cyclophosphamide (CP) exactly matching the interstrand cross-link (ICL) repair phases that lead to synchronization of ascites cells in late S/G2/M. Secondly, additional treatment of ascites 18 hours post each CP injection (at NER/HR transition timepoint) with a composite dsDNA-based preparation interfering with the NER and HR repair pathways, so that tumorigenic properties of ascites cells are compromised. Thirdly, final treatment of mice with a combination of CP and dsDNA injections as ascites cells undergo apoptotic destruction, and the surviving TAMRA+ TISCs arrested in late S/G2/M phases massively enter into G1/S, when they regain sensitivity to CP+dsDNA treatment. Thus, this regimen assures that no viable cells, particularly Krebs-2 TISCs, remain.

show abstract

Section: Resultsmentioning

confidence: 99%

A strategy to eradicate well-developed Krebs-2 ascites in mice

et al. 2016

View full text Add to dashboard Cite

show abstract

“…An increased percentage of this type of cells over the background of a drastic decrease in the number of committed tumor cells (the bulk of tumor cells) testified for exactly the such events flow. This finding denoted the most important time point in the therapy, when all remaining tumor cells, both committed and stem-like, are synchronized in G2/M phases [29][30][31][32][33].…”

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

confidence: 72%

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.

View full text Add to dashboard Cite

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.

show abstract

“…6, 3) схематично изображена динамика накопления, репарации и исчезновения двуцепочечных разрывов, вызванных действием цитостатика ЦФ. Сплошными линиями изображены ранее полученные экспериментальные данные, пунктиром -предположительный путь развития репаративных событий на основании уже имеющихся данных (Поттер и др., 2016;Dolgova et al, 2014).…”

Section: характеристика токсического синергичного действия циклофосфаunclassified

Analysis of different therapeutic schemes combining cyclophosphamide and doublestranded DNA preparation for eradication of Krebs-2 primary ascites in mice

Potter¹,

Долгова²,

Минкевич³

et al. 2016

Vestn. VOGiS

Self Cite

View full text Add to dashboard Cite

Федеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук», Новосибирск, Россия 2 Федеральное государственное автономное образовательное учреждение высшего образования «Новосибирский национальный исследовательский государственный университет», Новосибирск, Россия 3 Федеральное бюджетное учреждение науки Государственный научный центр вирусологии и биотехнологии «Вектор», р. п. Кольцово,

show abstract

Therapeutic effects of cyclophosphamide, dsDNA preparations and combinations thereof against Krebs-2 ascites cancer cells and various cancer transplants

Cited by 3 publications

References 8 publications

A strategy to eradicate well-developed Krebs-2 ascites in mice

A strategy to eradicate well-developed Krebs-2 ascites in mice

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

Analysis of different therapeutic schemes combining cyclophosphamide and doublestranded DNA preparation for eradication of Krebs-2 primary ascites in mice

Contact Info

Product

Resources

About