{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T11:03:20Z","timestamp":1793963000915,"version":"4.8.0"},"reference-count":42,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2012,7,11]],"date-time":"2012-07-11T00:00:00Z","timestamp":1341964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2012,9]]},"abstract":"Gemtuzumab ozogamicin (GO<\/jats:styled-content>) consists of theCD<\/jats:styled-content>33 antibody linked to calicheamicin. The binding ofGO<\/jats:styled-content>to theCD<\/jats:styled-content>33 antigen on leukemic cells results in internalization followed by the release of calicheamicin, thereby inducingDNA<\/jats:styled-content>strand breaks. We hypothesized that the induction ofDNA<\/jats:styled-content>strand breaks would be a surrogate marker ofGO<\/jats:styled-content>cytotoxcity. Here, twoGO<\/jats:styled-content>\u2010resistant variants (HL<\/jats:styled-content>\/GO<\/jats:styled-content>\u2010CSA<\/jats:styled-content>[225\u2010fold],HL<\/jats:styled-content>\/GO<\/jats:styled-content>[200\u2010fold]) were established by serially incubating human leukemiaHL<\/jats:styled-content>\u201060 cells withGO<\/jats:styled-content>with or without aP<\/jats:styled-content>\u2010glycoprotein (P<\/jats:styled-content>\u2010gp) inhibitor, cyclosporineA<\/jats:styled-content>, respectively. TheCD<\/jats:styled-content>33 positivity was reduced in both variants. TheHL<\/jats:styled-content>\/GO<\/jats:styled-content>\u2010CSA<\/jats:styled-content>cells showed an increased multidrug resistance protein\u20101 (MRP<\/jats:styled-content>1) transcript, and anMRP<\/jats:styled-content>1 inhibitor partially reversedGO<\/jats:styled-content>resistance. TheHL<\/jats:styled-content>\/GO<\/jats:styled-content>cells had neitherP<\/jats:styled-content>\u2010gp norMRP<\/jats:styled-content>1 overexpression. Microarray analysis andW<\/jats:styled-content>estern blotting indicated elevated levels ofDNA<\/jats:styled-content>repair\u2010associated proteins in both variants. Two other leukemic subclones, showing eitherP<\/jats:styled-content>\u2010gp orMRP<\/jats:styled-content>1 overexpression, were alsoGO<\/jats:styled-content>\u2010resistant. Using single cell gel electrophoresis analysis, it was determined thatGO<\/jats:styled-content>\u2010inducedDNA<\/jats:styled-content>strand breaks increased dose\u2010dependently inHL<\/jats:styled-content>\u201060 cells, whereas the number of breaks was reduced in theGO<\/jats:styled-content>\u2010resistant cell lines. The induction ofDNA<\/jats:styled-content>strand breaks was correlated withGO<\/jats:styled-content>sensitivity among these cell lines. TheCD<\/jats:styled-content>33 positivity and the expression levels of transporters were not proportional to drug sensitivity. Using primary leukemic cells, the induction ofDNA<\/jats:styled-content>strand breaks appeared to be associated withGO<\/jats:styled-content>sensitivity. Thus,GO<\/jats:styled-content>\u2010inducedDNA<\/jats:styled-content>strand breaks as the final output of the mechanism of action would be critical to predictGO<\/jats:styled-content>cytotoxicity.<\/jats:p>","DOI":"10.1111\/j.1349-7006.2012.02343.x","type":"journal-article","created":{"date-parts":[[2012,5,28]],"date-time":"2012-05-28T06:41:15Z","timestamp":1338187275000},"page":"1722-1729","source":"Crossref","is-referenced-by-count":8,"title":["Induction ofDNA<\/scp>strand breaks is critical to predict the cytotoxicity of gemtuzumab ozogamicin against leukemic cells"],"prefix":"10.1111","volume":"103","author":[{"given":"Takahiro","family":"Yamauchi","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology University of Fukui Eiheiji Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasufumi","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology University of Fukui Eiheiji 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Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology University of Fukui Eiheiji Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshimasa","family":"Urasaki","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology University of Fukui Eiheiji Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology University of Fukui Eiheiji 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