Summary
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1.
Endoxan and Trenimon, the alkylating agents tested, are potent cytostatic drugs, therapeutically acting through their mutagenic effects. To demonstrate their chromosome breaking effects in bone marrow, higher than the usual therapeutic doses in man had to be applied. Starting from these practical threshold doses the dose-response curves were, however, rising very steeply.
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2.
The extent of chromsome damage in individual cells was dose-dependent: after treatments in the lower dose range only metaphases with one or few chromatid aberrations were observed in a small percentage of the mitotic figures. With increasing doses the number of aberrations per cell steadily rose to the point of complete pulverization of the chromosome complement.
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3.
After the last application of the test substances the cell population with visible chromosome damage diminuishes soon. The maximum incidence of aberrations was observed after 6–8 hrs.
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4.
The effect was several times higher after two applications spaced by 24 hrs than after a single application. With Endoxan given per os the incidence of affected cells was 8 times higher, with Trenimon i.p. 2–3 times. A longer oral treatment is less effective due to the radiomimetic damage to the intestinal mucosa thereby reducing further resorption of the mutagenic compound. Only a relatively small increase in effect is gained with more than two intraperitoneal applications; if there is a severe mutagenic effect, the animals begin to succumb to the treatment after 4 days.
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5.
A prolonged treatment with low doses of Endoxan (8 mg/kg daily for 7 weeks) produced no increase in the very low aberration incidence.
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With support by the Swiss National Foundation and F. Hoffmann-La Roche and Co. Ltd. Basle (Switzerland).
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Schmid, W., Arakaki, D.T., Breslau, N.A. et al. Chemical mutagenesis the Chinese hamster bone marrow as an in vivo test system. Hum Genet 11, 103–118 (1971). https://doi.org/10.1007/BF00393791
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DOI: https://doi.org/10.1007/BF00393791