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Oncotarget. 2016 Mar 8;7(10):11580-94. doi: 10.18632/oncotarget.7311.

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

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Institute of Cytology and Genetics, Siberian Branch of The Russian Academy of Sciences, Novosibirsk 630090, Russia.
Department of Natural Sciences, Novosibirsk State University, Novosibirsk 630090, Russia.
The State Research Center of Virology and Biotechnology VECTOR, Novosibirsk 630559, Russia.
Institute of Clinical Immunology, Siberian Branch of The Russian Academy of Medical Sciences, Novosibirsk 630099, Russia.
LLC Panagen, Gorno-Altaisk 649000, Russia.


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.


ascites Krebs-2; cyclophosphamide; extracellular dsDNA; repair; tumor-initiating stem cells

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