title: A novel combretastatin A-4 derivative, AC-7700, shows marked antitumor activity against advanced solid tumors and orthotopically transplanted tumors.
abstract: AC-7700, a novel combretastatin A-4 derivative, suppresses the growth of solid tumors by inhibiting tumor perfusion. We evaluated the antitumor activity of AC-7700 on solid tumors in two experimental models, an advanced tumor model (murine colon 26 (c26) adenocarcinoma, colon 38 (c38) adenocarcinoma, MethA fibrosarcoma, Sarcoma 180 (S180), Lewis lung carcinoma (3LL), human LS180 adenocarcinoma) and an orthotopically transplanted tumor model (c26), compared with that of cisplatin (CDDP). The maximum tolerable dose (MTD) of CDDP suppressed early-stage c26 and c38 tumor growth when treatment was started after the tumor volume (TV) reached 0.2-0.5 cm3, but it showed reduced activity against the same tumors at an advanced growth stage when TV exceeded 2 cm3. At its MTD, AC-7700 was active against all tumors tested except 3LL in both early and advanced growth stages, reducing the tumor mass and having a curative effect in advanced c38 tumors. AC-7700 was also effective on orthotopically transplanted c26 tumors, showing a comparable activity to that on subcutaneous tumors. Unlike flavon acetic acid, which damages tumor vasculature by inducing endogenous tumor necrosis factor-alpha production, AC-7700 potently suppressed the growth of advanced c26 tumors in athymic as well as euthymic mice. These results suggest that AC-7700 is a novel antivascular agent that may have potent activity against advanced-stage cancer in the clinical setting.
authors.affiliation: Pharmaceutical Research Laboratories, Ajinomoto Co., Inc., Kawasaki. nihei@ea.mbn.or.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Nihei
authors.forename: Y
authors.initials: Y
authors.lastname: Suga
authors.forename: Y
authors.initials: Y
authors.lastname: Morinaga
authors.forename: K
authors.initials: K
authors.lastname: Ohishi
authors.forename: A
authors.initials: A
authors.lastname: Okano
authors.forename: K
authors.initials: K
authors.lastname: Ohsumi
authors.forename: T
authors.initials: T
authors.lastname: Hatanaka
authors.forename: R
authors.initials: R
authors.lastname: Nakagawa
authors.forename: T
authors.initials: T
authors.lastname: Tsuji
authors.forename: Y
authors.initials: Y
authors.lastname: Akiyama
authors.forename: S
authors.initials: S
authors.lastname: Saito
authors.forename: K
authors.initials: K
authors.lastname: Hori
authors.forename: Y
authors.initials: Y
authors.lastname: Sato
authors.forename: T
authors.initials: T
authors.lastname: Tsuruo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D012694:Serine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013267:Stilbenes / Q000737:chemistry / Q000627:therapeutic use; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D012694:Serine; C058728:fosbretabulin; C400245:AC 7700