DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogues.
20(S)-Camptothecin, the 20(S)-camptothecin sodium salt, and 12 analogues with substituents on the A ring differ widely in their effectiveness in the treatment of murine L1210 lymphoblastic leukemia in vivo. The drugs were screened in the following systems: System 1, the cleavage of DNA in the presence of purified topoisomerase I; System 2, drug-induced trapping of topoisomerase I in a covalent complex with DNA; and System 3, the induction of protein-associated DNA breaks in drug-treated L1210 leukemia cells. 9-Amino-20(S), 10-amino-20(RS), and 10,11-methylenedioxy-20(RS), drugs effective against murine L1210 leukemia in vivo, stabilize topoisomerase I-DNA cleavable complexes in a purified system and in cultured L1210 cells. Other analogues, inactive against L1210 leukemia in vivo, were totally ineffective in topoisomerase I-directed screens. The rest of the analogues were intermediate in terms of their antitumor and topoisomerase I-directed activities. The study shows that the drug-induced accumulation of enzyme-DNA cleavable complexes is directly proportional to drug cytotoxicity and antitumor activity.
Hsiang
Y H
YH
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Liu
L F
LF
Wall
M E
ME
Wani
M C
MC
Nicholas
A W
AW
Manikumar
G
G
Kirschenbaum
S
S
Silber
R
R
Potmesil
M
M
D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004270:DNA, Circular / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D013329:Structure-Activity Relationship
D004270:DNA, Circular; D004273:DNA, Neoplasm; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin