In vivo efficacy of a novel inhibitor of selected signal transduction pathways including calcium, arachidonate, and inositol phosphates.
Aberrant signal transduction has been implicated in malignant transformation, growth, and progression. This has led to the proposal to use inhibitors of signal transduction pathways to treat cancer. One approach to circumventing potential toxicity and improving efficacy would be to target pathways upon which cancer cells selectively depend. Pathways associated with the malignant process involve calcium fluxes, the release of arachidonic acid, and the generation of phosphoinositides. In this report, CAI (L651582, NSC 609974), a substituted carboxyamido-imidazole and novel inhibitor of these selected signal transduction pathways, inhibits anchorage-dependent and -independent growth in a large series of human cancer cell lines. CAI pretreatment of HT-29 human colon cancer and 5R ras-transfected rat embryo fibroblast cells inhibits the formation and growth of experimental pulmonary metastases in nude mice. Oral administration of CAI in PEG-400 vehicle arrests growth and metastasis of transplanted human melanoma and ovarian cancer xenografts. No significant gross or histological toxicity was observed at CAI doses yielding blood levels in the concentration range demonstrated to inhibit select signal transduction pathways in vitro. These data indicate the feasibility and demonstrate a potential selectivity and sensitivity of using specific signal transduction inhibitors for the experimental treatment of cancer.
Kohn
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EC
Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892.
Sandeen
M A
MA
Liotta
L A
LA
D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001095:Arachidonic Acids / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D011905:Genes, ras; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D014183:Transplantation, Heterologous; D014230:Triazoles
D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D007295:Inositol Phosphates; D014230:Triazoles; D000620:Aminoimidazole Carboxamide; C062058:carboxyamido-triazole; D002118:Calcium