RT Journal Article SR Electronic T1 Activation of DNA Damage Response by Antitumor Therapy Counteracts the Activity of Vinca Alkaloids JF Anticancer Research JO Anticancer Res FD International Institute of Anticancer Research SP 5273 OP 5287 VO 33 IS 12 A1 HARALD EHRHARDT A1 SARAH PFEIFFER A1 DAVID SCHREMBS A1 FRANZISKA WACHTER A1 MICHAELA GRUNERT A1 IRMELA JEREMIAS YR 2013 UL http://ar.iiarjournals.org/content/33/12/5273.abstract AB Background/Aim: Anthracyclines have been proven able to reduce the activity of vinca alkaloids by induction of cell-cycle arrest. The present study aims at identifying the critical initiation steps of signal transduction which transduce the inhibitory effects on the cytotoxicity of vinca alkaloids. Materials and Methods: Several new cytostatic drug classes were evaluated together with vincristine in tumor cell lines and patients' tumor cells. RNA interference was used for molecular analyses. Results: Inhibition of vincristine was observed by all cytostatic drugs, which induced cell-cycle arrest. Knockdown of proteins of the DNA damage response ascribed the inhibitory effect to a common pathway involving Chk-1, p53 and p21. Upstream of Chk-1 signal transduction depended on both ATM and ATR for all drugs except methotrexate. Conclusion: We have identified critical signaling steps of the DNA damage response system activated by cytostatic drugs, which reduce the anti-tumor activity of vinca alkaloids. The obtained results encourage the development of novel therapeutic strategies to prevent pathway interactions based on the molecular understanding of drug action and drug-drug interactions.