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.

Abstract	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.
Authors	T Tsuruo, M Naito, R Takamori, S Tsukahara, J Yamabe-Mitsuhashi, A Yamazaki, T Oh-hara, Y Sudo, S Nakaike, T Yamagishi
Journal	Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 26 Issue 2 Pg. 83-7 ( 1990) ISSN: 0344-5704 [Print] Germany
PMID	2161296 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Phenazines Topoisomerase II Inhibitors Tritium NC 190 Vincristine Doxorubicin Verapamil
Topics	Animals Antineoplastic Agents (pharmacology) Cell Membrane (metabolism) Doxorubicin (pharmacology) Drug Resistance Drug Screening Assays, Antitumor Intracellular Fluid (metabolism) Leukemia P388 (drug therapy, genetics, pathology) Mice Mice, Inbred Strains Neoplasm Transplantation Phenazines (pharmacology) Topoisomerase II Inhibitors Tritium Tumor Cells, Cultured Verapamil (pharmacology) Vincristine (pharmacology)

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