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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.

Author information

1
Institute of Cytology and Genetics, Siberian Branch of The Russian Academy of Sciences, Novosibirsk 630090, Russia.
2
Department of Natural Sciences, Novosibirsk State University, Novosibirsk 630090, Russia.
3
The State Research Center of Virology and Biotechnology VECTOR, Novosibirsk 630559, Russia.
4
Institute of Clinical Immunology, Siberian Branch of The Russian Academy of Medical Sciences, Novosibirsk 630099, Russia.
5
LLC Panagen, Gorno-Altaisk 649000, Russia.

Abstract

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.

KEYWORDS:

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

PMID:
26872383
PMCID:
PMC4905495
DOI:
10.18632/oncotarget.7311
[Indexed for MEDLINE]
Free PMC Article

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