Analysis of chromosome aberrations, sister chromatid exchanges [SCE] and cell division kinetics in human lymphocytes exposed in vitro to new monophosphates of pyrimidine acyclonucleosides

• Autorzy: Ferenc T , Rutkowski M. , Bratkowska W. , Hubner H. , Draminski M.
• Języki publikacji: EN

Abstrakty

EN

Five newly synthesised monophosphates of two pyrimidine acyclonucleoside series, namely 1-N-[(2’-hydroxy)ethoxymethyl] and l-N-[(l’,3’-dihydroxy)- 2’-propoxymethyl] derivatives of 5- and 5,6-alkylated uracils were tested in vitro for chromosome aberrations and sister chromatid exchanges (SCE). Metaphase plates were obtained via microculture of human lymphocytes from heparinized peripheral blood. The compounds were tested in doses: 10, 20, 40, 80 and 150 µg per mL of culture. The tested compounds induced mainly chromatid gaps, less frequently chromosome gaps. A low number of mitoses with chromatid and chromosome breaks, acentric fragments, dicentric chromosomes and exchange figures were also observed. The tested compounds in doses: 40, 80 and 150 µg per mL, doubled or tripled the percentage of cells with chromatid gaps and chromosome gaps as compared to the control. The percentage o cells with aberrations (excluding gaps) induced by the tested compounds in all doses did not exceed 2%. The tested compounds induced a higher number of SCE per cell but less than double frequency as compared to the control. SCE frequencies and replication index (RI) values varied depending on the examined compounds. For the highest dose of the tested compounds (150 µg per mL) a significant decrease in RI values was observed for l-N-[(2’-hydroxy)ethoxymethyl]-5,6-tetramethyleneuracil monophosphate and for l-N-[(2’-hydroxy)ethoxymethyl]-5,6-dimethyluracil monophosphate. So far, the results have indicated potential clastogenicity of all the tested compounds except acycloguanosine monophosphate.

Słowa kluczowe

EN

statistical analysis; chromatid gap; chromosome number; enzyme activity; chromosome aberration; in vitro; chromosome gap; pyrimidine; phosphorylase; acyclonucleoside monophosphate; human lymphocyte; sister chromatid exchange; cell division

• Wydawca: -
• Czasopismo: Journal of Applied Genetics
• Rocznik: 1998
• Tom: 39
• Numer: 1
• Opis fizyczny: p.113-127,fig.

Twórcy

autor

Ferenc T

• Military Medical Academy, Pl.Gen.J.Hallera 1, 90-647 Lodz,Poland

autor

Rutkowski M.

autor

Bratkowska W.

autor

Hubner H.

autor

Draminski M.

Bibliografia

• Bardot V., Dutrillaux A.M., Delattre J.Y., Vega F., Poisson M., Detriullaux B., LuccionimC. (1994). Purine and pyrimidine metabolism in human gliomas: relation to chromosomal aberrations. Br. J. Cancer 70: 212-218.
• Bardot V., Luccioni C., Lefrancois D., Muleris M., Dutrillaux B. (1991). Activity of thymidylate synthetase, thymidine kinase and galactokinase in primary and xenografted human colorectal cancers in relation to their chromosomal patterns. Int. J. Cancer 47: 670-674.
• Blackburn G.M., Gait M.J. (1990). Nucleic acids in chemistry and biology. Oxford University Press, Oxford, New York, Tokyo: 88.
• Brawermann G., Chargraff E. (1955). On the distribution and biological significance of nucleoside phosphotransferases. Biochim. Biophys. Acta 16: 524-532.
• Caporossi D., Vernole P., Nicoletti B., Tedeschi B. (1995). Characteristic chromosomal fragility of human embryonic cells exposed in vitro to aphidicolin. Hum. Genet. 96: 269-274.
• Сhu Ch.K., Cutler S.J. (1986). Chemistry and antiviral activities of acyclonucleosides. J. Heterocycl. Chem. 23: 289-319.
• De Clerq E. (1990). Targets and strategies for the antiviral chemotherapy of AIDS. TIPS Rev. 11: 198-205.
• Drabikowska A.K., Lissowska L., Dramiński M., Zgit-Wróblewska A., Shugar D. (1987). Acyclonucleoside analogues consisting of 5-and 5,6-substituted uracils and different acyclic chains. Z. Naturforsch. 42c: 288-296.
• Elion G.B., Furman P.A., Fyfe J.A., De Miranda P., Beauchamp L., Schaeffer H.J. (1977). Selectivity of action of an antiherpetic agent 9-(2-hydroxyethoxymethyl) guanine. Proc. Natl. Acad. Sci. USA 74: 5716-5720.
• Ferenc T., Rutkowski M., Bratkowska W., Hübner H., Dramiński M. (1995). In vitro analysis of mitostatic and mutagenic effects of new monophosphates of pyrimidine acyclonucleosides. 25th Annual Meeting of the European Environmental Mutagen Society, Noordwijkerhout, The Netherlands, June 18-23, 1995. Abstract book: 228.
• Furman P.A., St. Clair M.H., Fyfe J.A., Rideout J.L., Keller P.M., Elion G.B. (1979). Inhibition of Herpes Simplex Virus-induced DNA polymerase activity and viral DNA replication by 9-(2-hydroxyethoxymethyl) guanine and its triphosphate. J. Virol. 32: 72-77.
• Gallo-Mezo M.A., Espinosa A., Campos J., Entrena A., Pineda De Las Infantas M.J., Gomez J.A. (1995). Anticancer pyrimidine acyclonucleosides. Farmaco 50: 395-400.
• Glover T.W., Berger C., Coyle J., Echo B. (1984). DNA polymerase inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes. Hum. Genet. 67: 136-142.
• Greger J., Dramiński M. (1989). Growth inhibition of Kirkman-Robbins hepatoma by l-(l,3-dihydroxy-2-propoxymethyl)-5,6-tetramethyleneuracil and possible mechanism of its biological activity. Z. Naturforsch. 44c: 985-991.
• ISCN (1985). An international system for human cytogenetics nomenclature. Report of the standing committee on human cytogenetic nomenclature (S. Karger, ed.). Basel, München, Paris, London, New York, New Delhi, Singapore, Tokyo, Sydney: 66-69.
• Klug S., Lewandowski C., Merker H.J., Stahlmann R., Wildi L., Neubert D. (1991). In vitro and in vivo studies on the prenatal toxicity of five virustatic nucleoside analogues in comparison to acyclovir. Arch. Toxicol. 65: 283-291.
• Laca Z., Brankovic S. (1986). Some characteristics of fra (Xq) lymphocytes. Abstracts of the 7th International Congress of Human Genetics. Berlin, II: 219.
• Luccioni C., Muleris M., Sabatier L., Dutrillaux B. (1988). Chromosomal and enzymatic patterns provide evidence for two types of human colon cancers with abnormal nucleotide metabolism. Mutation Res. 200: 55-62.
• Modrzejewska H., Greger J., Dramiński M., Rutkowski M. (1996). The influence of allyloxymethyl purine and pyrimidyne acyclonucleosides on growth inhibition of Kirkman Robbins hepatoma and possible mechanism of cytostatic activity. Z. Naturforsch. 51c: 75-80.
• Morris S.M. (1991). The genetic toxicology of 5-bromodeoxyuridinc in mammalian cells. Mutation Res. 258: 161-188.
• Nakagome Y., Chiyo H. (1976). Nonrandom distribution of exchange in patiens with structural rearrangements. Am. J. Hum. Genet. 28: 31-41.
• O’Neill K.L., Grigsby R.V., Fairbairn D.W. (1995). Thymidine kinase: the future in brest cancer prognosis. The Breast 4: 79-83.
• Perry P., Wolff S. (1974). New Giemsa method for the differential staining of sister chromatids. Nature (London) 251: 156-158.
• Preston J.R., San Sebastian J.R., Me Fee A.F. (1987). The in vitro human lymphocyte assay for assessing the clastogenicity of chemical agents. Mutation Res. 189: 175-183.
• Prisbe E.J., Martin J.C., Me Gee D.P.C., Barker M.F., Smee D.F., Duke A.F., Matthews T.R., Verheyden J.P.H. (1986). Synthesis and antiherpes virus activity of phosphate and phosphonate derivates of 9-[(l,3-dihydroxy-2-propoxy) methyl] guanine. J. Med. Chem. 29: 671-675.
• Rao P.N., Heerema N.A., Palmer C.G. (1988). Fragile sites by FUdR, caffeine, and aphidicolin. Hum. Genet. 78: 21-26.
• Reardon J.E., Spector T. (1989). Herpes Simplex Virus type 1 DNA polymerase. J. Biol. Chem. 264: 7405-7411.
• Rojas E., Montero R., Herrera L.A., Sordo M., Gonsebatt M.E., Rodriguez R., Ostrosky-Wegman P. (1992). Are mitotic index and lymphocyte proliferation kinetics reproducible endpoints in genetic toxicology testing? Mutation Res. 282: 283-286.
• Rosowsky A., Kim S.H., Wick M. (1981). Synthesis and antitumor activity of an acyclonucleoside derivate of 5-fluorouracil. J. Med. Chem. 24: 1177-1181.
• Rutkowski M., Dramiński M. (1991). Phosphorylation of acyclonucleosides by nucleoside phosphotransferase from higher plants and bacteria. Acta Biochim. Polon. 38: 449-454.
• Rutkowski M., Korczak E. (1992). Biotransformation by Enterobacter agglomerans of pyrimidine acyclonucleosides to acyclonucleotides. Experientia 48: 600-603.
• Stolarski R., Lassota P., Kazimierczuk Z., Shugar D. (1988). Solution conformations of some acyclonucleoside and nucleotide analogues of antiviral acyclonucleosides and their substrate inhibitor properties in several enzyme systems. Z. Naturforsch. 43c: 231-242.
• Stoll C. (1980). Nonrandom distribution of exchange points in patiens with reciprocal translocations. Hum. Genet. 65: 89-93.
• Sutherland G.R. (1979). Heritable fragile sites on human chromosomes. I. Factors affecting expression in lymphocyte cultures. Am. J. Hum. Genet. 31: 125-135.
• Sutherland G.R., Baker E., Foratini A. (1985). Excess thymidine induces folate-sensitive fragile sites. Am. J. Med. Genet. 22: 433-443.
• Tanaka H., Baba M., Saito S., Miyasaka T., Takashima H., Sekiya K., Ubasawa M., Nitta I., Walker R.T., Nakashima H., De Clerq E. (1991). Specific anti-HIV-1 "acyclonucleosides" which cannot be phosphorylatcd: synthesis of some deoxy analogues of l-[(2-hydroxyethoxy)methyl]-6-(phenylthio) thymine. J. Med. Chem. 34: 1508-1511.
• Yoshikawa M., Kato T., Takenishi T. (1969). Studies of phosphorylation. III. Selective phosphorylation of unprotected nucleosides. Bull. Chem. Soc. Japan 42: 3505-3508.
• Yunis J.J., Soreng A.L., Bowe A.E. (1987). Fragile sites are target of diverse mutagens and carcinogens. Oncogene 1: 59-69.