Induction of anchorage independence in human diploid foreskin fibroblasts by carcinogenic metal salts.

We studied whether arsenic, nickel, and chromium compounds that are human carcinogens could induce transformation of cultured primary human diploid foreskin cells (HFC). All nickel compounds tested, PbCrO4, K2Cr2O7, CrO3, Na2HAsO4, NaAsO2, and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) caused significant (p = 0.001) dose-dependent inductions of anchorage-independent colonies in HFC. KH2AsO4, CaCl2, MnCl2, and Hg(CH3CO2)2 did not induce anchorage independence. Optimal expression times for induction of anchorage independence in HFC were observed as early as 11 days following treatment with MNNG, Ni3S2, Ni(C2H3O2), or NiSO4. Cell strains derived from anchorage-independent colonies showed 33 to 429-fold higher plating efficiencies in soft agar than parental populations, and the anchorage-independent phenotype was stable for eight passages, at which time cells senesced. Anchorage-independent cell strains derived from metal salt-treated cells were not resistant to the cytotoxicity of metal salts, indicating metal salts induced rather than selected for anchorage independence. Nine of 10 cell strains derived from metal compound- or MNNG-induced anchorage-independent colonies displayed the same or lower saturation densities than untreated human fibroblasts. None of these cell strains escaped senescence or showed definitive morphological transformation. MNNG (1 micrograms/ml) induced anchorage independence and mutation to ouabain resistance and 6-thioguanine resistance in HFC, but concentrations of Ni2S3 that induced anchorage independence did not induce mutation at either locus in HFC. These results demonstrate that carcinogenic metal salts induce stable anchorage independence early in human diploid foreskin fibroblasts, and this anchorage independence is independent of other in vitro markers of fibroblast transformation, such as focus formation or immortality. Metal salt induction of anchorage independence can now be used as an assay to study mechanisms of genotoxicity exerted by carcinogenic metal compounds in human cells.

[1]  K. Wetterhahn,et al.  Binding of chromium to chromatin and DNA from liver and kidney of rats treated with sodium dichromate and chromium(III) chloride in vivo. , 1985, Cancer research.

[2]  J. Landolph,et al.  Chemical transformation in C3H 10T1/2 Cl 8 mouse embryo fibroblasts: historical background, assessment of the transformation assay, and evolution and optimization of the transformation assay protocol. , 1985, IARC scientific publications.

[3]  J. Landolph.  Mechanisms of chemically induced multistep neoplastic transformation in C3H 10T 1/2 cells. , 1985, Carcinogenesis; a comprehensive survey.

[4]  A. Haugen,et al.  Effects of nickel sulfate on growth and differentiation of normal human bronchial epithelial cells. , 1984, Carcinogenesis.

[5]  J. Little,et al.  Persistence of X-ray-induced chromosomal rearrangements in long-term cultures of human diploid fibroblasts. , 1984, Cancer research.

[6]  R. Ciccarelli,et al.  Nickel-bound chromatin, nucleic acids, and nuclear proteins from kidney and liver of rats treated with nickel carbonate in vivo. , 1984, Cancer research.

[7]  A. Kraker,et al.  Toxicity and Carcinogenicity of Essential and Non-essential Metals , 1984 .

[8]  M. Costa,et al.  Influence of surface charge and dissolution on the selective phagocytosis of potentially carcinogenic particulate metal compounds. , 1983, Cancer research.

[9]  R. Stern,et al.  In vitro toxicity and transformation potency of nickel compounds. , 1983, Environmental health perspectives.

[10]  T. Hampton,et al.  The carcinogen chromate causes DNA damage and inhibits drug-mediated induction of porphyrin accumulation and glucuronidation in chick embryo hepatocytes. , 1983, Carcinogenesis.

[11]  R. Ciccarelli,et al.  Nickel distribution and DNA lesions induced in rat tissues by the carcinogen nickel carbonate. , 1982, Cancer research.

[12]  A. Reith,et al.  Oncogenic transformation and cell lysis in C3H/10T 1/2 cells and increased sister chromatid exchange in human lymphocytes by nickel subsulfide. , 1981, Cancer research.

[13]  C. Harris,et al.  DNA-protein cross-linking by chromium salts. , 1981, Chemico-biological interactions.

[14]  M. Barile.  Mycoplasma infections of cell cultures. , 1981, Israel journal of medical sciences.

[15]  T. Sanner,et al.  Metal salts as promoters of in vitro morphological transformation of hamster embryo cells initiated by benzo(a)pyrene. , 1981, Cancer research.

[16]  J. Mccormick,et al.  Induction of anchorage-independent growth in human fibroblasts by propane sultone. , 1981, Cancer research.

[17]  J. DiPaolo,et al.  Induction by inorganic metal salts of sister chromatid exchanges and chromosome aberrations in human and syrian hamster cell strains , 1981 .

[18]  C. Richardson,et al.  Metal mutagens and carcinogens effectively displace acridine orange from DNA as measured by fluorescence polarization. , 1981, Environmental mutagenesis.

[19]  J. DiPaolo,et al.  Carcinogen-induced anchorage-independent growth and in vivo lethality of human MRC-5 cells. , 1981, Carcinogenesis.

[20]  H. Mollenhauer,et al.  Carcinogenic activity of particulate nickel compounds is proportional to their cellular uptake. , 1980, Science.

[21]  S. Paillet,et al.  Induction of trifluorothymidine-resistant mutants by metal ions in L5178Y/TK+/- cells. , 1980, Mutation research.

[22]  R. L. Carter,et al.  IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans , 1980, IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans.

[23]  M. Umeda,et al.  Inducation of chromosomal aberrations in cultured mammalian cells by nickel compounds. , 1979, Mutation research.

[24]  M. Miyaki,et al.  Mutagenicity of metal cations in cultured cells from Chinese hamster. , 1979, Mutation research.

[25]  F. Sunderman,et al.  Induction of sarcomas in nude mice by implantation of Syrian hamster fetal cells exposed in vitro to nickel subsulfide. , 1979, Cancer research.

[26]  B. Casto,et al.  Quantitative studies of in vitro morphological transformation of Syrian hamster cells by inorganic metal salts. , 1979, Cancer research.

[27]  C. Heidelberger,et al.  Chemical carcinogens produce mutations to ouabain resistance in transformable C3H/10T1/2 Cl 8 mouse fibroblasts. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[28]  G. Milo,et al.  Neoplastic transformation of human diploid cells in vitro after chemical carcinogen treatment , 1978, Nature.

[29]  J. Barrett,et al.  Evidence for the progressive nature of neoplastic transformation in vitro. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[30]  T. Kakunaga.  Neoplastic transformation of human diploid fibroblast cells by chemical carcinogens. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[31]  R. Demars,et al.  Quantification of chemical mutagenesis in diploid human fibroblasts: induction of azaguanine-resistant mutants by N-methyl-N'-nitro-N-nitrosoguanidine. , 1978, Mutation research.

[32]  Sunderman Fw.  Carcinogenic effects of metals. , 1978 .

[33]  F. Sunderman.  Carcinogenic effects of metals. , 1978, Federation proceedings.

[34]  M. Buchwald.  Mutagenesis at the ouabain-resistance locus in human diploid fibroblasts. , 1977, Mutation research.

[35]  L. Loeb,et al.  Infidelity of DNA synthesis in vitro: screening for potential metal mutagens or carcinogens. , 1976, Science.

[36]  F. Sunderman,et al.  Comparisons of carcinogenicities of nickel compounds in rats. , 1976, Research communications in chemical pathology and pharmacology.

[37]  B. Terracini.  Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. , 1975 .

[38]  J. Haseman,et al.  Inhalation studies of nickel sulfide in pulmonary carcinogenesis of rats. , 1975, Journal of the National Cancer Institute.

[39]  C. Heidelberger,et al.  Quantitative and qualitative studies of chemical transformation of cloned C3H mouse embryo cells sensitive to postconfluence inhibition of cell division. , 1973, Cancer research.

[40]  I. Macpherson.  Soft Agar Techniques , 1973 .

[41]  B. Terracini.  Evaluation of Carcinogenic Risk of Chemicals to Man , 1972 .

[42]  L. Hayflick.  Tissue cultures and mycoplasmas. , 1965, Texas reports on biology and medicine.