The modulation of the DNA-damaging effect of polycyclic aromatic agents by xanthines: Part I. Reduction of cytostatic effects of quinacrine mustard by caffeine☆

摘要: Abstract Recently, accumulated statistical data indicate the protective effect of caffeine consumption against several types cancer diseases. There are also reports about and other xanthines tumors induced by polycyclic aromatic hydrocarbons. One explanations is based on biological activation such carcinogens cytochromes that known for metabolism caffeine. However, there numerous indicating reverse cytotoxicity anticancer drugs inhibit action topoisomerase I (e.g. Camptothecin or Topotecan) II inhibitors Doxorubicin, Mitoxantrone mAMSA). In this work we tested hypothesis result sequestering mutagens formation stacking (π–π) complexes. As models study have chosen two well-known mutagens, do not require metabolical activation: quinacrine mustard(QM, aromatic, heterocyclic nitrogen mustard) mechlorethamine (NM2, aliphatic mustard). The flow cytometry these agents’ cell cycle HL-60 cells indicated prevents cytotoxic QM, but NM2. formations complexes QM with were confirmed light absorption, calorimetric measurements molecular modeling calculation. Using thermodynamics calculations calculated “neighborhood” association constant (KAC=59±2 M−1) enthalpy change ( Δ H 0′ =−116 cal mol −1 ); favorable entropy complex S =7.72 K , due to release water molecules, associated components in process formation). Gibbs’ free energy QM–CAF G =−2.41 kcal . We unable detect any interaction between NM2 either spectroscopic measurement. order establish, whether intercalation plays role tested, as a control, non-alkylatiatig, intercalating derivative—quinacrine (Q). later had no cytostatic even at higher concentration than but, similar forms (which demonstrated) (KAC=75±3 M−1). These results strongly indicate, attenuating mutagenic effects some metabolic processes cells, simply physicochemical molecules (potential mutagens) them. may then act “interceptor” potential (especially upper part digesting track where its can reach mM level). is, however, indication literature our experiments damage nucleic acids when DNA has already occurred.