DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogues

Author(s): Hsiang YH, Liu LF, Wall ME, Wani MC, Nicholas AW

Abstract

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.

Similar Articles

Medicinal plants and phytomedicines

Author(s): Briskin DP

New natural products as new leads for antibacterial drug discovery

Author(s): Brown DG, T Lister, TL May-Dracka

Amazonian plant natural products: perspectives for discovery of new antimalarial drug leads

Author(s): Pohlit AM, Souza Lima RB,Frausin G,Rocha e SilvaLF,Pinto Lopes SC, et al.

Natural products: promising resources for cancer drug discovery

Author(s): Mondal S, Bandyopadhyay S, Ghosh MK, Mukhopadhyay S, Roy S, et al.

Plant antitumor agents

Author(s): Wall ME, MC Wani, CE Cook, KH Palmer, AT McPhail, et al.

Plant antitumor agents

Author(s): Wani MC, Taylor HL, WallME, Coggon P, McPhail AT, et al.

3D-QSAR study of 20 (S)-camptothecin analogs

Author(s): Lu AJ, Zhang ZS, Zheng MY, Zou HJ, Luo XM, et al.

Plants used against cancer

Author(s): Hartwell JL

Plants used against cancer

Author(s): Hartwell JL

Screening plants for antitumor activity

Author(s): Perdue RE Jr, Abbott BJ, Hartwell JL

Antineoplastic components of marine animals

Author(s): Pettit GR, Day JF, Hartwell JL, Wood HB

Studies on Camptothecin

Author(s): Horwitz SB, Chang CK, Grollman AP

Grollman, Antiviral action of camptothecin

Author(s): Horwitz SB, Chang CK, Grollman AP

Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA

Author(s): Redinbo MR, Stewart L, Kuhn P, Champoux JJ, Hol WG

Mechanism of action of camptothecin

Author(s): Liu LF, Desai SD, Li TK, Mao Y, Sun M, et al.

Antitumour drugs impede DNA uncoiling by topoisomerase I

Author(s): Koster DA, Palle K, Bot ES, Bjornsti MA, Dekker NH

Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor

Author(s): Rowinsky EK, Grochow LB, Hendricks CB, Ettinger DS, Forastiere AA, et al.

Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer

Author(s): ten Bokkel Huinink W, Gore M, Carmichael J, Gordon A, Malfetano J, et al.

Phase I clinical trial of topotecan and pegylated liposomal doxorubicin

Author(s): Garcia AA, Roman L, Muderspach L, O'meara A, Facio G, et al.

Preclinical evaluation of the anticancer activity and toxicity of 9-nitro-20(S)-camptothecin (Rubitecan)

Author(s): Giovanella BC, Stehlin JS, Hinz HR, Kozielski AJ, Harris NJ, etal.

A phase II trial with RFS2000 (rubitecan) in patients with advanced non-small cell lung cancer

Author(s): Baka S, Ranson M, Lorigan P, Danson S, Linton K, et al.

Phase II trial of oral rubitecan in previously treated pancreatic cancer patients

Author(s): Burris HA, Rivkin S, Reynolds R, Harris J, Wax A, et al.

Anti-apoptotic mechanisms of drug resistance in cancer

Author(s): Wilson TR, Johnston PG, Longley DB