DNA-protective activity of new ribonucleotide reductase inhibitors.
The DNA-protective activity of hydroxyurea (HU) and novel ribonucleotide reductase (RR) inhibitors amidox (AX), didox (DX) and trimidox (TX) was examined using hydrogen peroxide as the DNA-damaging agent. The exposure of superspiralized plasmid DNA molecules (pBR 322) to H2O2 under precisely defined in vitro conditions initiates a change in DNA topology (DNA from I relaxes to DNA form II). This electrophoretically monitored change in the plasmid DNA topology is related to the induction of ss-DNA breaks and corresponds with DNA exposition to free radicals. The inhibition of DNA relaxation (the prevention of DNA damage induced by hydrogen peroxide) depended on the free radical scavenging capacity of the drugs investigated. HU exerted DNA protective activity at a concentration of 4 mM, AX at concentration of 1 microM, TX at a concentration of 5 microM and DX at a concentration of 25 microM (the free radical scavenging activity increases from HU to AX in following manner: HU << DX < TX < AX). It can be concluded that the new synthetic RR-inhibitor AX which is being investigated at the preclinical level as a potential anti-cancer drug possess the highest capacity for scavenging of free radicals.
Rauko
P
P
Department of Experimental Therapy, Slovak Academy of Sciences, Bratislava, Slovak Republic.
Romanova
D
D
Miadokova
E
E
Macakova
K
K
Novotny
L
L
Elford
H L
HL
Szekeres
T
T
D000970:Antineoplastic Agents / Q000494:pharmacology; D001550:Benzamidines / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004278:DNA, Superhelical / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals; D006861:Hydrogen Peroxide; D006877:Hydroxamic Acids / Q000494:pharmacology; D006918:Hydroxyurea / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D010957:Plasmids; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*
C074761:3,4,5-trihydroxybenzamidoxime; D000970:Antineoplastic Agents; D001550:Benzamidines; D004278:DNA, Superhelical; D004791:Enzyme Inhibitors; D005609:Free Radicals; D006877:Hydroxamic Acids; D010091:Oximes; C070491:Amidox; D006861:Hydrogen Peroxide; D012264:Ribonucleotide Reductases; C035419:3,4-dihydroxybenzohydroxamic acid; D006918:Hydroxyurea