Cytotoxic and DNA-damaging properties of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and its analogues.
An antitumor drug N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and its three close structural analogs N-[2-(hydroxyethylamino)ethyl]acridine-4-carboxamide (DACAH), N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide (amino-DACA), and N-[2-(hydroxyethylamino)ethyl]-9-aminoacridine-4-carboxamide (amino-DACAH) were studied for their ability to inhibit RNA synthesis in vitro and to form topoisomerase II-mediated DNA lesions in relation to cell-killing activity. All tested compounds induced chromatin lesions characteristic of topoisomerase II-blocking drugs (DNA breaks and DNA-protein cross-links) in treated cells, but were much less active than reference antileukemic acridine m-AMSA (4'-(9-acridinylamino)-methanesulfon-m-anisidide). The ability to form these lesions was dependent on the structure of the 4-carboxamide side-chain, which seems to be an important factor affecting the drug transport rate through cell membrane. A 4-carboxamide chain with an N-2-(dimethylamino)ethyl moiety resulted in more efficient transport through cell membranes, higher cytotoxicity, and DNA-damaging activity. The mode of action of acridine-4-carboxamides was further elucidated by their incubation with cells in the presence of antitopoisomerase II agents of a known mechanism of inhibition. These were: bisdioxopiperazine (ICRF-187), a catalytic inhibitor of topoisomerase II, and etoposide (VP-16), an inducer of a cleavable complex of the enzyme with DNA. The cytotoxicity of DACA and its analogs was not antagonized by preincubating cells with ICRF-187. All tested acridines protected cells against DNA breakage induced by VP-16, but the extent of protection varied significantly. Amino-DACA, which easily penetrates cell membrane, fully inhibited DNA break formation, whereas other analogs exhibited a low degree of protection when used at high concentration. Our results suggest that the acridine-4-carboxamides discussed here are poor topoisomerase II poisons and that this enzyme is not their main target.
Pastwa
E
E
Department of General Chemistry, Institute of Physiology and Biochemistry, Medical University of Lódź, Poland.
Ciesielska
E
E
Piestrzeniewicz
M K
MK
Denny
W A
WA
Gniazdowski
M
M
Szmigiero
L
L
D000166:Acridines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D051379:Mice; D012313:RNA / Q000096:biosynthesis; D011929:Razoxane / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
D000166:Acridines; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D011929:Razoxane; D012313:RNA; D005047:Etoposide; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide; D004247:DNA