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.
Highlights
We report on the studies performed in the laboratory of induced cellular processes at the Institute of Cytology and Genetics, SB RAS (Novosibirsk, Russia) which aimed at developing an efficient protocol to eradicate Krebs-2 ascites in experimental mice
We showed that dsDNA fragments that become internalized by the cells during the repair of interstrand CP-induced cross-links potently interfere with the repair process, thereby completely abrogating the tumor-inducing potential of the tumor graft [2]
Our initial proof-of-concept study uncovered several basic effects of how dsDNA fragments internalized by there exists a particular cell subpopulation (TISCs)-like Krebs-2 cells interfere with the repair of interstrand DNA cross-links (ICLs) induced by CP pretreatment
Summary
We showed that dsDNA fragments that become internalized by the cells during the repair of interstrand CP-induced cross-links potently interfere with the repair process, thereby completely abrogating the tumor-inducing potential of the tumor graft [2]. These phenomena were highly suggestive of an opportunity to completely eradicate TISCs and so to reduce the graft tumorigenicity to zero. The linear order of chromatin would not be www.impactjournals.com/oncotarget recoverable, as internalized dsDNA fragments would completely block the NER and HR stages of repair
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
