Cell-killing activity and kinetic analysis of a novel antitumor compound NC-190, a benzo[a]phenazine derivative.
A novel antitumor compound, N-beta-dimethylaminoethyl 9-carboxy-5-hydroxy-10-methoxybenzo[a]-phenazine-6-carboxamide sodium salt (NC-190), was evaluated for antitumor activity in vitro against cultured tumor cell lines, and the kinetics of cell killing was elucidated. NC-190 strongly inhibited the growth of all of 3 murine tumor cell lines, 7 human tumor cell lines and 2 normal cell lines. With continuous exposure, the 50% inhibition concentrations were in the range of 0.005-0.06 micrograms/ml, except for KATO-III (2.15 micrograms/ml). By colony-forming assay, concentrations of NC-190 giving 90% cell kill (IC90) at various exposure times were obtained with HeLa S3 cells. The plot of IC90-exposure time on a log-log scale was linear for NC-190 with a slope of -1, which is typical for cell cycle phase-nonspecific agents. A 2 h treatment with NC-190 induced a rapid reduction in cell viability at doses of more than 3 micrograms/ml. At the dose where colony formation was completely inhibited, cell viability was persistently reduced to below 20% during the cell culture period. NC-190 caused a dose- and time-dependent reduction in DNA synthesis. The inhibitions of RNA and protein synthesis were less than that of DNA synthesis. Spectroscopic studies of NC-190 mixed with calf thymus DNA demonstrated that NC-190 was capable of interacting with DNA. However, DNA thermal denaturation studies suggested that intercalation of NC-190 was weak in comparison with those of classical intercalating drugs.
Nakaike
S
S
Research Center, Taisho Pharmaceutical Co., Ltd., Saitama.
Yamagishi
T
T
Nanaumi
K
K
Otomo
S
S
Tsukagoshi
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007700:Kinetics; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D010619:Phenazines / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D010619:Phenazines; C059048:NC 190; D004317:Doxorubicin; D004247:DNA