title: Low direct cytotoxicity of loxoprofen on gastric mucosal cells.
abstract: Pro-drugs of non-steroidal anti-inflammatory drugs (NSAIDs), such as loxoprofen are widely used for clinical purposes because they are not so harmful to the gastrointestinal mucosa. We recently showed that NSAIDs such as indomethacin and celecoxib have direct cytotoxicity (ability to induce necrosis and apoptosis in gastric mucosal cells) due to their membrane permeabilizing activities, which is involved in NSAID-induced gastric lesions. We show here that under conditions where indomethacin and celecoxib clearly induce necrosis and apoptosis, loxoprofen and its active metabolite loxoprofen-OH, do not have such effects in primary culture of guinea pig gastric mucosal cells. Loxoprofen and loxoprofen-OH induced apoptosis more effectively in cultured human gastric cancer cells than in the primary culture. Loxoprofen and loxoprofen-OH exhibited much lower membrane permeabilizing activities than did indomethacin and celecoxib. We thus consider that the low direct cytotoxicity of loxoprofen observed in vitro is involved in its relative safety on production of gastric lesions in clinical situation.
authors.affiliation: Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamakawa
authors.forename: Shintaro
authors.initials: S
authors.lastname: Suemasu
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kimoto
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Arai
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ishihara
authors.forename: Kazumi
authors.initials: K
authors.lastname: Yokomizo
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Masami
authors.initials: M
authors.lastname: Otsuka
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Tanaka
authors.forename: Tohru
authors.initials: T
authors.lastname: Mizushima
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D006168:Guinea Pigs; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D009336:Necrosis; D010539:Permeability / Q000187:drug effects; D010666:Phenylpropionates / Q000009:adverse effects* / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000188:drug therapy*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D010666:Phenylpropionates; D011720:Pyrazoles; D013449:Sulfonamides; C040656:loxoprofen; D000068579:Celecoxib; D007213:Indomethacin