RRC ID 42019
Author Takagi M, Honmura T, Watanabe S, Yamaguchi R, Nogawa M, Nishimura I, Katoh F, Matsuda M, Hidaka H.
Title In vivo antitumor activity of a novel sulfonamide, HMN-214, against human tumor xenografts in mice and the spectrum of cytotoxicity of its active metabolite, HMN-176.
Journal Invest New Drugs
Abstract The cytotoxic effects of HMN-176 ((E)-4-[[2-N-[4-methoxybenzenesulfonyl] amino] stilbazole] 1-oxide; a newly synthesized compound, were evaluated and compared with those of the clinically used antitumor agents cis-platinum, adriamycin, etoposide, taxol, and vincristine in 22 human tumor cell lines isolated from various organs. HMN-176 exhibited potent cytotoxicity with IC(50) values in the nM range, and the variance of its cytotoxic efficacy was remarkably small. Drug-resistant cell lines also showed low cross-resistance to HMN-176 corresponding to overall resistance indices of less than 14.3. HMN-214 was synthesized as an oral prodrug because of the poor oral absorption of HMN-176 itself. Pharmacokinetic studies showed that HMN-214 was an acceptable oral prodrug of HMN-176. In the in vivo analysis of the schedule-dependency of HMN-214, the repeated administration for over 5 days elicited potent antitumor activity, as expected from the exposure-dependency of the cytotoxicity of HMN-176 and from the cytometric studies. The antitumor activity of HMN-214 against human tumor xenografts was equal or superior to that of clinically available agents, including cis-platinum, adriamycin, vincristine, and UFT without severe toxicity such as neurotoxicity. Because of its good activity in preclinical trials, HMN-214 has entered Phase I clinical trials in the USA.
Volume 21(4)
Pages 387-99
Published 2003-11
DOI 10.1023/a:1026282716250
PII 5145867
PMID 14586206
MeSH Animals Antineoplastic Agents / chemistry Antineoplastic Agents / metabolism* Antineoplastic Agents / toxicity* Benzylidene Compounds / chemistry Benzylidene Compounds / metabolism* Benzylidene Compounds / toxicity* Cell Line, Tumor Cyclic N-Oxides / chemistry Cyclic N-Oxides / metabolism* Cyclic N-Oxides / toxicity* Humans Male Mice Mice, Inbred BALB C Mice, Nude Pyridines / chemistry Pyridines / metabolism* Pyridines / toxicity* Rabbits Rats Rats, Sprague-Dawley Sulfonamides / chemistry Sulfonamides / metabolism* Sulfonamides / toxicity* Xenograft Model Antitumor Assays / methods*
IF 2.663
Times Cited 38
Human and Animal Cells