L651582: a novel antiproliferative and antimetastasis agent.
L651582 (Merck Institute for Therapeutic Research, Rahway, NJ) is a novel carboxyamide-amino-imidazole compound originally developed as a coccidiostat (U.S. patent No. 4,590,201). We studied the inhibitory effects of this compound on cancer proliferation, adhesion, and motility in vitro and in vivo in a model of ovarian cancer progression. L651582 reversibly inhibited up to 60% of the autocrine motility factor-stimulated tumor cell motility and tumor cell adhesion to tissue culture plastic. Autocrine motility factor-stimulated phosphoinositide metabolism was reduced significantly by treatment of the cells with 3 microM L651582 (P = .022). Thymidine incorporation and clonogenic growth of A2058 human melanoma, MDA-MB-231 human breast cancer, OVCAR-3 human ovarian cancer, and 5R-transformed rat embryo fibroblast cell lines were inhibited 60%-80% by 1-10 microM L651582. Intraperitoneal injection of OVCAR-3 cells causes malignant ascites, peritoneal carcinomatosis, and serosal and visceral seeding that, if left untreated, are lethal to nude mice. Intraperitoneal L651582 markedly prolonged survival of nude mice heavily laden with ovarian cancer [mean survival time of treated group divided by mean survival time of control group = 220% (P less than .03)]. The apparent mechanism of action of L651582 is via inhibition of the receptor-mediated stimulation of effector enzymes utilizing guanine nucleotide-binding protein signal transduction, which thus makes L651582 a novel anticancer agent. L651582 should be considered for further clinical development.
Kohn
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Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20892.
Liotta
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D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D009362:Neoplasm Metastasis; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D014230:Triazoles; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D007093:Imidazoles; D010716:Phosphatidylinositols; D014230:Triazoles; D000620:Aminoimidazole Carboxamide; C062058:carboxyamido-triazole; D019204:GTP-Binding Proteins