Summary
The induction of mitotic gene conversion after direct treatment of yeasts with the test compounds was compared with their genetic effects in two host-mediated assays: 1. Injection of yeasts into the intraperitoneal cavity of treated rats and 2. treatment of yeasts with urine of treated rats. Given directly to yeasts, only trofosfamide showed a moderate genetic effect. In the injection test, only cyclophosphamide, when applied orally, was weakly active. After the additional application of probenecid (Benemid®), a blocker of the renal tubular excretion, all three compounds were genetically active. In the urinary assay, trofosfamide displayed a very strong genetic effect, followed by cyclophosphamide and ifosfamide. It is discussed that the different genetic activities of these compounds in the host-mediated assays are the result of their different speed of excretion.
Zusammenfassung
Die Auslösung mitotischer Genkonversion in der Hefe Saccharomyces cerevisiae nach direkter Behandlung mit den Testsubstanzen wurde mit ihrer genetischen Wirkung in zwei „host-mediated assays“ verglichen: 1. Injektion der Hefe in die Bauchhöhle behandelter Ratten und 2. Behandlung der Hefe mit Urin behandelter Ratten. Nach Direktbehandlung der Hefe zeigte nur Trofosfamid eine mittlere genetische Wirkung. Im Injektionstest war nach oraler Gabe nur Cyclophosphamid schwach wirksam. Nach der zusätzlichen Gabe von Probenecid (Benemid®), einem Blocker der Ausscheidung über die Niere, waren alle drei Verbindungen genetisch aktiv. Im Urintest entfaltete Trofosfamid eine sehr starke genetische Wirkung, gefolgt von Cyclophosphamid und Ifosfamid. Es wird diskutiert, daß die unterschiedliche genetische Wirkung dieser drei Substanzen in host-mediated assays auf einer unterschiedlichen Ausscheidungsgeschwindigkeit beruht.
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Abbreviations
- Cy:
-
cyclophosphamide
- Ifo:
-
ifosfamide
- Tro:
-
trofosfamide
- Prob:
-
probenecid
- La:
-
Lasix
References
Bertram,C., Höhne,G.: Über die radiometrische Wirkung einiger Cytostatika im Mutationsversuch an Drosophila. Strahlentherapie 43, 388–391 (1959)
Boger,W.P., Pitts,F.W.: Plasma concentrations of p-aminosalicylic acid (PAS) increased by p-(di-n-propylsulfamyl)-benzoic acid. Science 112, 149 (1950)
Brock,N., Hohorst,H.-J.: Über die Aktivierung von Cyclophosphamid. Arzneimittel-Forsch. 13, 1021–1031 (1963)
Brock,N., Hoefer-Janker,H., Hohorst,H.-J., Scheef,W., Schneider,B., Wolf,H.C.: Die Aktivierung von Ifosfamid an Mensch und Tier. Arzneimittel-Forsch. 23, 1–14 (1973)
Bus,J.S., Gibson,J.E.: Teratogenicity and neonatal toxicity of ifosfamide in mice. Proc. Soc. exp. Biol. (N.Y.) 143, 965–970 (1973)
von Kreybig,T.: Die teratogene Wirkung von Cyclophosphamid während der embryonalen Entwicklungsphase bei der Ratte. Naunyn-Schmiedebergers Arch. exp. Path. Pharmak. 252, 173–195 (1965)
Marquardt,H., Zimmermann,F.K., Dannenberg,H., Neumann,H.-G., Bodenberger,A.,Metzler,M.: Die genetische Wirkung von aromatischen Aminen und ihren Derivaten: Induktion mitotischer Konversionen bei der Hefe Saccharomyces cerevisiae Z. Krebsforsch.74, 412–433 (1970)
Oltmanns,O., Bacher,A., Lingens,F., Zimmermann,F.K.: Biochemical and genetic classification of riboflavine deficient mutants of Saccharomyces cerevisiae. Molec. Gen. Genetics 105, 306–313 (1969)
Potel,J., Brock,N.: Die immunsuppressive Wirkung verschiedener Cytostatika auf die humorale Antikörperbildung. Arzneimittel-Forsch. 21, 1250–1254 (1971)
Propping,P., Röhrborn,G., Buselmaier,W.: Comparative investigations on the chemical induction of point mutations and dominant lethal mutations in mice. Molec. Gen. Genetics 117, 197–209 (1972)
Schmid,W., Staiger,G.R.: Chromosome studies on bone marrow from chinese hamsters treated with benzodiazepine tranquilizers and cyclophosphamide. Mutation Res. 7, 99–108 (1969)
Siebert,D.: A new method for testing genetically active metabolites. Urinary assay with cyclophosphamide (Endoxan, Cytoxan) and Saccharomyces cerevisiae. Mutation Res. 17, 307–314 (1973)
Siebert,D.: Host-mediated assay with yeast and rats using probenecid (Benemid®) as a blocker of the renal tubular excretion of cyclophosphamide metabolites. Mutation Res. (in press)
Siebert,D., Simon,U.: Cyclophosphamide: Pilot study of genetically active metabolites in the urine of a treated human patient Induction of mitotic gene conversions in yeast. Mutation Res. 19, 65–72 (1973a)
Siebert,D., Simon,U.: Genetic activity of metabolites in the ascitic fluid and in the urine of a human patient treated with cyclophosphamide: Induction of mitotic gene conversion in Saccharomyces cerevisiae. Mutation Res. 21, 257–262 (1973b)
Siebert,D., Zimmermann,F.K., Lemperle,E.: Genetic effects of fungicides. Mutation Res. 10, 533–543 (1970)
Tokuoka,S.: Induction of tumor in mice with N,N-bis-(2-chloroeihyl)-N′, O-propylenephosphoric acid ester diamide (cyclophosphamide). Gann 56, 537–541 (1965)
Zimmermann,F.K.: The effect of liquid holding on chemical induced lethality and mitotic gene conversion in Saccharomyces cerevisiae. Molec. Gen. Genetics 103, 11–20 (1968)
Zimmermann,F.K.: Induction of mitotic gene conversion by mutagens. Mutation Res. 11, 327–337 (1971)
Zimmermann,F.K., Schwaier,R.: Induction of mitotic gene conversion with nitrous acid, 1-methyl-3-nitro-1-nitroso-guanidine and other alkylating agents in Saccharomyces cerevisiae. Molec. Gen. Genetics 100, 63–76 (1967)
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Dedicated to Professor Dr. H. Druckrey on his seventieth birthday.
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Siebert, D. Comparison of the genetic activity of cyclophosphamide, ifosfamide and trofosfamide in host-mediated assays with the gene conversion system of yeast. Z. Krebsforsch. 81, 261–267 (1974). https://doi.org/10.1007/BF00305028
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DOI: https://doi.org/10.1007/BF00305028