A benzophenazine derivative, N-beta-dimethylaminoethyl 9-carboxy-5-hydroxy-10-methoxy-benzo[a]phenazine-6-carboxamide, as a new antitumor agent against multidrug-resistant and sensitive tumors.
NC-190, a benzophenazine derivative (N-beta-dimethylaminoethyl 9-carboxy-5-hydroxy-10-methoxy-benzo[a]phenazine-6-carboxamide), was effective against multidrug-resistant human and mouse tumor cells in vitro and in vivo. When vincristine (VCR)-resistant P388 leukemia-bearing mice were treated with an optimal dose of NC-190, four of six mice were cured, whereas treatment of mice with VCR resulted in only a marginal increase in life span. The compound also showed chemotherapeutic effect against Adriamycin-resistant P388 leukemia-bearing mice and was effective against various multidrug-resistant human and murine tumor cells in vitro. Its cytotoxicity to multidrug-resistant K562 cells was not enhanced by the addition of verapamil. The accumulation of NC-190 in multidrug-resistant K562 cells was slightly lower than that observed in sensitive K562 cells; the compound did not efficiently inhibit the binding of VCR to the plasma membrane of resistant cells, indicating that NC-190 has little affinity for P-glycoprotein. NC-190 inhibited the activity of DNA topoisomerase II. These observations suggest that NC-190 (1) is not transported out of resistant cells by P-glycoprotein and (2) inhibits DNA topoisomerase II activity in the cells, resulting in its likely effectiveness against various multidrug-resistant tumor cells.
Tsuruo
T
T
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
Naito
M
M
Takamori
R
R
Tsukahara
S
S
Yamabe-Mitsuhashi
J
J
Yamazaki
A
A
Oh-hara
T
T
Sudo
Y
Y
Nakaike
S
S
Yamagishi
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D007424:Intracellular Fluid / Q000378:metabolism; D007941:Leukemia P388 / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D010619:Phenazines / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors; D014316:Tritium; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D010619:Phenazines; D059005:Topoisomerase II Inhibitors; D014316:Tritium; C059048:NC 190; D014750:Vincristine; D004317:Doxorubicin; D014700:Verapamil