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Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892 [E. C. K., L. A. L.], and Laboratory Animal Science Program, Program Resources, Inc./DynCorp, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702 [M. A. S.]
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.
1 Funded in part by the Department of Health and Human Services, Contract N01-CO-74102 with Program Resources, Inc./DynCorp. The contents of this paper do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
2 To whom requests for reprints should be addressed, at Laboratory of Pathology, National Cancer Institute, Building 10, Room 2A33, 9000 Rockville Pike, Bethesda, MD 20892.
Received 12/12/91. Accepted 3/25/92.
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