Flat revertant inducers, styryl diphenylamine derivatives, inhibit growth and metastasis of murine tumor cells in vivo.
Previously, we reported that a novel styryl diphenylamine derivative, RX-465, reverts the transformed phenotype of human fibrosarcoma HT1080 cells in vitro. To determine whether agents inducing such phenotypic reversion show antitumor and/or antimetastatic effects in vivo, we assessed tumor growth and metastasis in mice inoculated with either murine B16-, B16BL6 melanoma or M5076 reticulosarcoma. These mice received orally our new derivatives of RX-465, namely RX-512 and RX-549. We found that these-derivatives inhibited B16 melanoma and M5076 reticulosarcoma growth by greater than 80% in vivo. RX-512 also inhibited the metastatic dissemination of B16BL6 melanoma into the lung and that of M5076 reticulosarcoma into the liver by 98% and 100% at doses of 60 and 40 mg/kg/day, respectively. These treatments did not cause significant decreases in body weight. Our data strongly demonstrate that styryl diphenylamine derivatives that revert transformed phenotype in vitro potentially inhibit tumor growth and metastasis in mice with negligible toxicity at effective doses.
Ohizumi
I
I
Department of Cancer Research, Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Shizuoka, Japan. ooizumiiwo@gt.chugai-pharm.co.jp
Tanemura
M
M
Tsunenari
T
T
Sato
K
K
Kozono
T
T
Kaiho
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D009525:Niacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000473:pathology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C096849:RX 465; C104943:RX 512; C104944:RX 549; D009525:Niacin; D004159:Diphenylamine