Abstract
The cancer chemotherapy drug bleomycin (BLM) is a potent inducer of genetic damage in a wide variety of assays. The radioprotectors cysteamine (CSM) and WR-1065 have been shown in previous studies to potentiate the induction of micronuclei and chromosome aberrations by BLM in Go human lymphocytes. By contrast, WR-1065 is reported to reduce the induction of hprt mutations by BLM in Chinese hamster cells. To elucidate the basis for these interactions, we examined the effects of CSM and WR-1065 on the induction of mitotic gene conversion by BLM in the yeast Saccharomyces cerevisiae. Treatment with BLM causes a dose-dependent increase in the frequency of mitotic gene conversion and gene mutations. Unlike its potentiation of BLM in G0 lymphocytes, WR-1065 protected against the recombinagenicity of BLM in yeast. CSM was also strongly antirecombinagenic under some conditions., but the nature of the interaction depended strongly on the treatment conditions. Under hypoxic conditions, cysteamine protected against BLM, but under oxygenrich conditions CSM potentiated the genetic activity og BLM. The protective effect of aminothiols against BLM may be ascribed to the depletion of oxygen required for the activation of BLM and the processing of BLM-induced damage. Aminothiols may potentiatc the effect of BLM by acting as an electron source for the activation of BLM and/or by causing conformational alterations that make DNA more accessible tc BLM. The results indicate that aminothiols have a strong modulating influence on the genotoxicity of BLM in yeast as they do in other genetic assays. Moreover, the modulation differs markedly depending on physiological conditions. Thus, yeast assays help to explain why aminothiols have been observed to potentiate BLM in some genetic systems and to protect against it in others.
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References
Cederberg H, Ramel C (1989) Modifications of the effect of bleomycin in the somatic mutation and recombination test in Drosophila melanogaster. Mutat Res 214:69–80
Chatterjee A, Jacob-Raman M, Mohapatra B (1989) Potentiation of bleomycin-induced chromosome aberrations by the radioprotector reduced glutathione. Mutat Res 214:207–213
Demopoulos NA, Stamatis ND, Yannopoulos G (1980) Induction of somatic and male crossing-over by bleomycin in Drosophila melanogaster. Mutat Res 78:347–351
Demopoulos NA, Kappas A, Pelecanos M (1982) Recombinogenic and mutagenic effects of the antitumour antibiotic bleomycin in Aspergillus nidulans. Mutat Res 102:51–57
Dresp J, Schmid E, Bauchinger M (1978) The cytogenetic effect of bleomycin on human peripheral lymphocytes in vitro and in vivo. Mutat Res 56:341–353
Ferguson LR, Turner PM (1988) Mitotic crossing-over by anticancer drugs in Saccharomyces cerevisiae strain D5. Mutat Res 204:239–249
Glover D, Fox KR, Weiler C, Kligerman MM, Turrisi A, Glick JH (1988) Clinical trails of WR-2721 prior to alkylating agent chemotherapy and radiotherapy. Parmacol Ther 39:3–7
Hall EJ (1988) Radiobiology for the radiologist, 3rd edn. Lippincott, Philadelphia
Hannan MA, Nasim A (1978) Genetic activity of bleomycin: differential effects on mitotic recombination and mutations in yeast. Mutat Res 53:309–316
Hay J, Shahzeidi S, Laurent G (1991) Mechanisms of bleomycininduced lung damage. Arch Toxicol 65:81–94
Hecht SM (1986) The chemistry of activated bleomycin. Ace Chem Res 19:383–391
Hoffmann GR (1994) Induction of genetic recombination: consequences and model systems. Environ Mol Mutagen 23(Suppl 24):59–66
Hoffmann GR, Littlefield LG (1995) Enhancement of the activity of bleomycin by cysteamine in a micronucleus assay in G0 human lymphocytes. Toxicol Lett 78:147–151
Hoffmann GR, Colyer SP, Littlefield LG (1993a) Induction of micronuclei by bleomycin in G0 human lymphocytes: I. Dose response and distribution. Environ Mol Mutagen 21:130–135
Hoffmann GR, Colyer SP, Littlefield LG (1993b) Induction of micronuclei by bleomycin in G0 human lymphocytes: II. Potentiation by radioprotectors. Environ Mol Mutagen 21:136–143
Hoffmann GR, Sayer AM, Littlefield LG (1994) Potentiation of bleomycin by the aminothiol WR-1065 in assays for chromosomal damage in G0 human lymphocytes. Mutat Res 307:273–283
Liquier J, Fort L, Nguyen Dai D, Cao A, Taillandier E (1983) DNA protection by aminothiols: study of the cysteamine-DNA interaction by vibrational spectroscopy. Int J Biol Macromol 5:89–93
Littlefield LG, Joiner EE, Colyer SP, Sallam F, Frome EL (1993) Concentration-dependent protection against X-ray-induced chromosome aberrations in human lymphocytes by the aminothiol WR-1065. Radiat Res 133:88–93
McKoy JF, Pleninger P, Wall L, Pramanik A, Martinez M, Moore CW (1995) Genetic changes and bioassays in bleomycin- and phleomycin-treated cells, and their relationship to chromosomal breaks. Mutat Res 336:19–27
Moore CW (1978) Bleomycin-induced mutation and recombination in Saccharomyces cerevisiae. Mutat Res 58:41–49
Nagy B, Grdina DJ (1986) Protective effects of 2-[(aminopropyl) amino] ethanethiol against bleomycin and nitrogen mustardinduced mutagenicity in V79 cells. Int J Radiat Oncol Biol Physiol 12:1475–1478
Povirk LF, Austin MJF (1991) Genotoxicity of bleomycin. Mutat Res 257:127–143
Purdie JW (1979) A comparative study of the radioprotective effects of cysteamine, WR-2721, and WR-1065 in cultured human cells. Radiat Res 77:303–311
Purdie JW, Inhaber ER, Schneider H, Labelle JL (1983) Interaction of cultured mammalian cells with WR-2721 and its thiol, WR-1065: implications for mechanisms of radioprotection. Int J Radiat Biol 43:517–527
Quaranta JL, Shorter RA, Littlefield LG, Hoffmann GR (1994) Effects of aminothiols on the genotoxicity of bleomycin and β-propiolactone in yeast. Environ Mol Mutagen 23(Suppl 23):55
Schwartz JL, Giovanazzi SM, Karrison T, Jones C, Grdina DJ (1988) 2-[(Aminopropyl) amino] ethanethiol-mediated reductions in 60Coγ- ray and fission-specturm neutroninduced chromosome damage in V79 cells. Radiat Res 113:145–154
Sengstag C (1994) The role of mitotic recombination in carcinogenesis. Crit Rev Toxicol 24:323–353
Shigematsu N, Schwartz JL, Grdina DJ (1994) Protection against radiation-induced mutagenesis at the hprt locus by spermine and N,N′-(dithiodi-2,1-ethanediyl)bis-1,3-propanediamine (WR-33278). Mutagenesis 9:355–360
Smoluk GD, Fahey RC, Ward JF (1986) Equilibrium dialysis studies of the binding of radioprotector compounds to DNA. Radiat Res 107:194–204
Smoluk GD, Fahey RC, Calabro-Jones PM, Aguilera JA, Ward JF (1988) Radioprotection of cells in culture by WR-2721 and derivatives: form of the drug responsible for protection. Cancer Res 48:3641–3647
Strekowski L, Harden DB, Wydra RL, Stewart KD, Wilson WD (1989) Molecular basis for the potentiation of bleomycin-mediated degradation of DNA by polyamines. Experimental and molecular mechanical studies. J Mol Recogn 2:158–166
Tahsildar HI, Biaglow JE, Kligerman MM, Varnes ME (1988) Factors influencing the oxidation of the radioprotector WR-1065. Radiat Res 113:243–251
Zimmermann FK (1975) Procedures used in the induction of mitotic recombination and mutation in the yeast Saccharomyces cerevisiae. Mutat Res 31:71–86
Zimmermann FK (1992) Tests for recombinagens in fungi. Mutat Res 284:147–158
Zimmermann FK, Kern R, Rasenberger H (1975) A yeast strain for the simultaneous detection of induced mitotic crossing over, mitotic gene conversion and reverse mutation. Mutat Res 28:381–388
Zimmermann FK, von Borstel RC, von Halle ES, Parry JM, Siebert D, Zetterberg G, Barale R, Loprieno N (1984) Testing of chemicals for genetic activity with Saccharomyces cerevisiae: a report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutat Res 133:199–244
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Hoffmann, G.R., Quaranta, J.L., Shorter, R.A. et al. Modulation of bleomycin-induced mitotic recombination in yeast by the aminothiols cysteamine and WR-1065. Molec. Gen. Genet. 249, 366–374 (1995). https://doi.org/10.1007/BF00287098
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DOI: https://doi.org/10.1007/BF00287098