{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T17:29:47Z","timestamp":1764782987134},"reference-count":39,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2006,7,14]],"date-time":"2006-07-14T00:00:00Z","timestamp":1152835200000},"content-version":"vor","delay-in-days":4577,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Environ and Mol Mutagen"],"published-print":{"date-parts":[[1994,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The suspect human carcinogen, etoposide, is known to be genotoxic, producing both gene and chromosomal mutations, probably by virtue of its ability to inhibit topoisomerase II activity. The present paper describes assays conducted using the Salmonella assay, the mouse lymphoma <jats:italic>tk<\/jats:italic><jats:sup>+\/\u2010<\/jats:sup> assay (gene and chromosomal mutation analysis and molecular analysis of <jats:italic>tk<\/jats:italic><jats:sup>\u2010\/\u2010<\/jats:sup> mutants) and the mouse bone marrow micronu\u2010cleus assay. Nonreproducible, weak, dose\u2010related increases in mutation frequency in strain TA98 (but not TA1538 or TA1537) of <jats:italic>Salmonella typhimurium<\/jats:italic> were observed. Etoposide was highly mutagenic at the heterozygous thymidine kinase (<jats:italic>tk<\/jats:italic><jats:sup>+\/\u2010<\/jats:sup>) locus of L5178Y mouse lymphoma cells at concentrations below 0.1 \u03bcg\/ml. Mostly small colony mutants were induced, consistent with the potent clastogenicity also observed. Molecular analysis of mutants indicated that 83% and 92% of large and small colony mutants, respectively, had lost the entire target gene sequence. Chromosomally aberrant L5178Y cells were \u02dc2 to 600\u2010fold more prevalent than small <jats:italic>tk<\/jats:italic><jats:sup>\u2010\/\u2010<\/jats:sup> mutant colonies. This suggests that the viable target for etoposide\u2010mediated clastogenesis in the selective assay is \u02dcone\u2010fifth of chromosome 11b, itself being \u02dcone\u2010fortieth of the mouse genome. An unusually potent response was observed for etoposide in the mouse bone marrow micronucleus assay (63.1 \u00b1 18 MPE\/1,000 PE 24 hours after an oral dose of 1 mg\/kg). The minimum detectable dose level in the assay was between 0.01 and 0.1 mg\/kg. At dose levels between 1 and 15 mg\/kg, an inverse dose response was observed. This reduction in assay response was not due to the small concommitant decrease in the incidence of polychromatic erythrocytes, a conclusion based on studies with N\u2010methyl\u2010N\u2010ni\u2010trosourea. Animals sampled 48 hours after dosing with etoposide (10 mg\/kg) had no polychromatic erythrocytes in the bone marrow. These observations for the micronucleus assay await explanation. The chemical structure of etoposide is displayed and discussed within the context of such strong mutagenic activity being associated with a nonelectrophilic agent. \u00a9 1994 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/em.2850240107","type":"journal-article","created":{"date-parts":[[2007,2,21]],"date-time":"2007-02-21T18:59:18Z","timestamp":1172084358000},"page":"51-60","source":"Crossref","is-referenced-by-count":43,"title":["potent clastogenicity of the human carcinogen etoposide to the mouse bone marrow and mouse lymphoma L5178Y cells: Comparison to salmonella responses"],"prefix":"10.1002","volume":"24","author":[{"given":"J.","family":"Ashby","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.","family":"Tinwell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P.","family":"Glover","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P.","family":"Poorman\u2010Allen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R.","family":"Krehl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. 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In Moore MM DeMarini DM de Serres FJ Tindall KR (eds): \u201cBanbury Report 28: Mammalian Cell Mutagenesis \u201d Cold Spring Harbor NY: Cold Spring Harbor Laboratory pp213\u2013224."},{"key":"e_1_2_1_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.1.51"},{"key":"e_1_2_1_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0027-5107(93)90003-X"},{"key":"e_1_2_1_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/8.4.373"},{"key":"e_1_2_1_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-7992(85)90051-X"},{"key":"e_1_2_1_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2964(78)90002-6"},{"key":"e_1_2_1_9_1","doi-asserted-by":"crossref","first-page":"9182","DOI":"10.1016\/S0021-9258(17)47282-6","article-title":"Non\u2010intercalative antitumour agents interfere with breakage re\u2010union reaction of mammalian DNA topoisomerase II","volume":"259","author":"Chen GL","year":"1984","journal-title":"J Biol Chem"},{"key":"e_1_2_1_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/5.2.191"},{"key":"e_1_2_1_11_1","first-page":"15","volume-title":"Etoposide (VP\u201019) Current Status and New Developments","author":"Doyle TW","year":"1984"},{"key":"e_1_2_1_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/7.3.175"},{"key":"e_1_2_1_13_1","first-page":"1778","article-title":"Effect of an epipodophyllotoxin derivative (VP16) on macromolecular synthesis and mitosis in mastocytoma cells in vitro","volume":"34","author":"Grieder A","year":"1974","journal-title":"Cancer Res"},{"key":"e_1_2_1_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1218(90)90007-O"},{"key":"e_1_2_1_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/2.3.179"},{"key":"e_1_2_1_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-7992(93)90077-9"},{"key":"e_1_2_1_17_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1993.1007"},{"key":"e_1_2_1_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0027-5107(81)90060-9"},{"key":"e_1_2_1_19_1","unstructured":"LahdetieJ KeiskiA ToppariJ(1993): Spermatid micronucleus test and DNA flow cytometric studies of spermatogenesis after etoposide treatment of male rats. 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