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.
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.
Discovery Research Laboratories and Developmental Research Laboratories, Nippon Shinyaku Co., Kyoto, Japan.
Manabu
M
Takagi
Takuya
T
Honmura
Shuuji
S
Watanabe
Reiko
R
Yamaguchi
Masaki
M
Nogawa
Ikumi
I
Nishimura
Fumitaka
F
Katoh
Masato
M
Matsuda
Hiroyoshi
H
Hidaka
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D001597:Benzylidene Compounds / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
C479799:(E)-4-((2-N-(4-methoxybenzenesulfonyl)amino)stilbazole)1-oxide; C487781:(E)-4-(2-(2-(N-acetyl-N-(4-methoxybenzenesulfonyl)amino)stilbazole)) 1-oxide; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D003497:Cyclic N-Oxides; D011725:Pyridines; D013449:Sulfonamides