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
| Autor: | Takuya Honmura, Ikumi Nishimura, Reiko Yamaguchi, Manabu Takagi, Fumitaka Katoh, Hiroyoshi Hidaka, Masaki Nogawa, Masato Matsuda, Shuuji Watanabe |
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| Rok vydání: | 2003 |
| Předmět: |
Male
Vincristine Pyridines Metabolite Mice Nude Antineoplastic Agents Pharmacology Benzylidene Compounds Cyclic N-Oxides Rats Sprague-Dawley chemistry.chemical_compound Mice In vivo Cell Line Tumor Medicine Animals Humans Pharmacology (medical) Cytotoxicity Active metabolite Etoposide Mice Inbred BALB C Sulfonamides business.industry Biological activity Prodrug Xenograft Model Antitumor Assays Rats Oncology chemistry Rabbits business medicine.drug |
| Zdroj: | Investigational new drugs. 21(4) |
| ISSN: | 0167-6997 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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