Screening of potential chemopreventive agents using biochemical markers of carcinogenesis.
Ninety potential chemopreventive agents were screened using 6 chemoprevention-associated biochemical end points. These compounds were tested using rodent (tracheal epithelial or liver) cells and human cells [neonatal foreskin fibroblasts, bronchial epithelial cells, or human leukemic cells (HL-60)]. The effects measured were: (a) inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tyrosine kinase activity in HL-60 cells; (b) inhibition of TPA-induced ornithine decarboxylase (ODC) activity in rat tracheal epithelial cells; (c) inhibition of poly(ADP-ribose)polymerase in propane sultone-treated primary human fibroblasts; (d) inhibition of benzo[a]pyrene(B[a]P)-DNA binding in human bronchial epithelial cells; (e) induction of reduced glutathione in Buffalo rat liver cells; and (f) inhibition of TPA-induced free radical formation in primary human fibroblasts or HL-60 cells. Fifty compounds were highly effective in inhibiting TPA-induced tyrosine kinase activity. This assay identified compounds from a wide variety of chemical classes as effective inhibitors, including all the vitamins, retinoic acid analogues, protein kinase C inhibitors, and chemicals belonging to the amino acid category. Fifty-two chemicals were classified as highly positive compounds when examined for their ability to inhibit TPA-induced ODC activity. These agents showed a dose-dependent inhibition or inhibition at all doses. Retinoids, in general, exhibited strong inhibition of ODC activity. A category of compounds showing dose-dependent inhibition were the sulfur compounds, especially the thiols and thiones. Among the natural products, terpenes were strong inhibitors of ODC. Forty-seven compounds were classified as strong inhibitors of poly(ADP-ribose)polymerase. In the carcinogen-DNA binding inhibition assay, 21 compounds were identified as strong inhibitors, which include phenolic compounds as well as sulfur compounds. Vitamins and their analogues were also good inhibitors. Testing for induced glutathione yielded 19 compounds that were good inducers. Sulfur-containing compounds and most of the phenolic compounds were also inducers of glutathione. Twenty compounds were highly positive for inhibition of TPA-induced free radical formation. A significant number of phenolic and sulfur compounds were again strong oxygen radical scavengers. Some antiinflammatory agents were also identified as free radical inhibitors. In general, retinoids were quite active in all the assays. Eight compounds were positive in all of the six assays; these were vitamin C (ascorbic acid), bismuththiol, esculetin, etoperidone, folic acid, hydrocortisone, indole-3-carbinol, and tocopherol succinate. Agents that were positive in these assays may inhibit the carcinogenesis process by similar mechanisms in humans and are identified as candidates for development as chemopreventive agents.(ABSTRACT TRUNCATED AT 400 WORDS)
ManTech Environmental Technology, Inc., Research Triangle Park, North Carolina 27709.
S
S
Sharma
J D
JD
Stutzman
G J
GJ
Kelloff
V E
VE
Steele
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000494:pharmacology; D001681:Biological Assay; D018736:DNA Adducts / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004848:Epithelium / Q000201:enzymology / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D005978:Glutathione / Q000037:antagonists & inhibitors*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000473:pathology; D008099:Liver / Q000201:enzymology; D065108:Ornithine Decarboxylase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011915:Rats, Inbred BUF; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014132:Trachea / Q000201:enzymology / Q000473:pathology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018736:DNA Adducts; D005609:Free Radicals; D065108:Ornithine Decarboxylase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013876:Thiophenes; D001564:Benzo(a)pyrene; D011505:Protein-Tyrosine Kinases; D005978:Glutathione; C003218:1,3-propane sultone; D013755:Tetradecanoylphorbol Acetate