title: A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors.
abstract: Synthetic benzamide derivatives were investigated for their ability to inhibit histone deacetylase (HDA). In this study, one of the most active benzamide derivatives, MS-27-275, was examined with regard to its biological properties and antitumor efficacy. MS-27-275 inhibited partially purified human HDA and caused hyperacetylation of nuclear histones in various tumor cell lines. It behaved in a manner similar to other HDA inhibitors, such as sodium butyrate and trichostatin A; MS-27-275 induced p21(WAF1/CIP1) and gelsolin and changed the cell cycle distribution, decrease of S-phase cells, and increase of G1-phase cells. The in vitro sensitivity spectrum of MS-27-275 against various human tumor cell lines showed a pattern different than that of a commonly used antitumor agent, 5-fluorouracil, and, of interest, the accumulation of p21(WAF1/CIP1) tended to be faster and greater in the cell lines sensitive to MS-27-275. MS-27-275 administered orally strongly inhibited the growth in seven of eight tumor lines implanted into nude mice, although most of these did not respond to 5-fluorouracil. A structurally analogous compound to MS-27-275 without HDA-inhibiting activity showed neither the biological effects in cell culture nor the in vivo therapeutic efficacy. These results suggest that MS-27-275 acts as an antitumor agent through HDA inhibition and may provide a novel chemotherapeutic strategy for cancers insensitive to traditional antitumor agents.
authors: Institute of Biological Science, Mitsui Pharmaceuticals, 1900-1 Togo, Mobara-shi, Chiba 297-0017, Japan.
authors: A
authors: A
authors: Saito
authors: T
authors: T
authors: Yamashita
authors: Y
authors: Y
authors: Mariko
authors: Y
authors: Y
authors: Nosaka
authors: K
authors: K
authors: Tsuchiya
authors: T
authors: T
authors: Ando
authors: T
authors: T
authors: Suzuki
authors: T
authors: T
authors: Tsuruo
authors: O
authors: O
authors: Nakanishi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001549:Benzamides / Q000627:therapeutic use / Q000633:toxicity*; D002087:Butyrates / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D005472:Fluorouracil / Q000633:toxicity; D018260:Gelsolin / Q000633:toxicity; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000633:toxicity; D020014:K562 Cells; D007624:KB Cells; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D010190:Pancreatic Neoplasms; D011725:Pyridines / Q000627:therapeutic use / Q000633:toxicity*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D002087:Butyrates; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D018260:Gelsolin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011725:Pyridines; C118739:entinostat; C012589:trichostatin A; D005472:Fluorouracil