{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T20:57:37Z","timestamp":1770325057069,"version":"3.49.0"},"reference-count":68,"publisher":"Proceedings of the National Academy of Sciences","issue":"22","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1998,10,27]]},"abstract":"<jats:p>\n            Epipodophyllotoxins are associated with leukemias characterized by translocations of the\n            <jats:italic>MLL<\/jats:italic>\n            gene at chromosome band 11q23 and other translocations. Cytochrome P450 (CYP) 3A metabolizes epipodophyllotoxins and other chemotherapeutic agents. CYP3A metabolism generates epipodophyllotoxin catechol and quinone metabolites, which could damage DNA. There is a polymorphism in the 5\u2032 promoter region of the\n            <jats:italic>CYP3A4<\/jats:italic>\n            gene (\n            <jats:italic>CYP3A4-V<\/jats:italic>\n            ) that might alter the metabolism of anticancer drugs. We examined 99\n            <jats:italic>de novo<\/jats:italic>\n            and 30 treatment-related leukemias with a conformation-sensitive gel electrophoresis assay for the presence of the\n            <jats:italic>CYP3A4-V<\/jats:italic>\n            . In all treatment-related cases, there was prior exposure to one or more anticancer drugs metabolized by CYP3A. Nineteen of 99\n            <jats:italic>de novo<\/jats:italic>\n            (19%) and 1 of 30 treatment-related (3%) leukemias carried the\n            <jats:italic>CYP3A4-V<\/jats:italic>\n            (\n            <jats:italic>P<\/jats:italic>\n            = 0.026; Fisher\u2019s Exact Test, FET). Nine of 42\n            <jats:italic>de novo<\/jats:italic>\n            leukemias with\n            <jats:italic>MLL<\/jats:italic>\n            gene translocations (21%), and 0 of 22 treatment-related leukemias with\n            <jats:italic>MLL<\/jats:italic>\n            gene translocations carried the\n            <jats:italic>CYP3A4-V<\/jats:italic>\n            (\n            <jats:italic>P<\/jats:italic>\n            = 0.016, FET). This relationship remained significant when 19 treatment-related leukemias with\n            <jats:italic>MLL<\/jats:italic>\n            gene translocations that followed epipodophyllotoxin exposure were compared with the same 42\n            <jats:italic>de novo<\/jats:italic>\n            cases (\n            <jats:italic>P<\/jats:italic>\n            = 0.026, FET). These data suggest that individuals with\n            <jats:italic>CYP3A4-W<\/jats:italic>\n            genotype may be at increased risk for treatment-related leukemia and that epipodophyllotoxin metabolism by CYP3A4 may contribute to the secondary cancer risk. The\n            <jats:italic>CYP3A4-W<\/jats:italic>\n            genotype may increase production of potentially DNA-damaging reactive intermediates. The variant may decrease production of the epipodophyllotoxin catechol metabolite, which is the precursor of the potentially DNA-damaging quinone.\n          <\/jats:p>","DOI":"10.1073\/pnas.95.22.13176","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T14:42:40Z","timestamp":1027694560000},"page":"13176-13181","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":254,"title":["Association of\n            <i>CYP<\/i>\n            <i>3<\/i>\n            A\n            <i>4<\/i>\n            genotype with treatment-related leukemia"],"prefix":"10.1073","volume":"95","author":[{"given":"Carolyn A.","family":"Felix","sequence":"first","affiliation":[{"name":"Division of Oncology, Children\u2019s Hospital of Philadelphia, Department of Pediatrics, Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Cancer Center, Department of Pathology and Laboratory Medicine, and Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Center for Cancer and Blood Disorders, Children\u2019s Medical Center of Dallas, Dallas, TX 75235; and Department of Pediatrics,..."}]},{"given":"Amy H.","family":"Walker","sequence":"additional","affiliation":[{"name":"Division of Oncology, Children\u2019s Hospital of Philadelphia, Department of Pediatrics, Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Cancer Center, Department of Pathology and Laboratory Medicine, and Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Center for Cancer and Blood Disorders, Children\u2019s Medical Center of Dallas, Dallas, TX 75235; and Department of Pediatrics,..."}]},{"given":"Beverly J.","family":"Lange","sequence":"additional","affiliation":[{"name":"Division of Oncology, Children\u2019s Hospital of Philadelphia, Department of Pediatrics, Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Cancer Center, Department of Pathology and Laboratory Medicine, and Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Center for Cancer and Blood Disorders, Children\u2019s Medical Center of Dallas, Dallas, TX 75235; and Department of Pediatrics,..."}]},{"given":"Terence M.","family":"Williams","sequence":"additional","affiliation":[{"name":"Division of Oncology, Children\u2019s Hospital of Philadelphia, Department of Pediatrics, Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Cancer Center, Department of Pathology and Laboratory Medicine, and Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Center for Cancer and Blood Disorders, Children\u2019s Medical Center of Dallas, Dallas, TX 75235; and Department of Pediatrics,..."}]},{"given":"Naomi J.","family":"Winick","sequence":"additional","affiliation":[{"name":"Division of Oncology, Children\u2019s Hospital of Philadelphia, Department of Pediatrics, Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Cancer Center, Department of Pathology and Laboratory Medicine, and Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Center for Cancer and Blood Disorders, Children\u2019s Medical Center of Dallas, Dallas, TX 75235; and Department of Pediatrics,..."}]},{"given":"Nai-Kong V.","family":"Cheung","sequence":"additional","affiliation":[{"name":"Division of Oncology, Children\u2019s Hospital of Philadelphia, Department of Pediatrics, Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Cancer Center, Department of Pathology and Laboratory Medicine, and Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Center for Cancer and Blood Disorders, Children\u2019s Medical Center of Dallas, Dallas, TX 75235; and Department of Pediatrics,..."}]},{"given":"Brian D.","family":"Lovett","sequence":"additional","affiliation":[{"name":"Division of Oncology, Children\u2019s Hospital of Philadelphia, Department of Pediatrics, Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Cancer Center, Department of Pathology and Laboratory Medicine, and Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Center for Cancer and Blood Disorders, Children\u2019s Medical Center of Dallas, Dallas, TX 75235; and Department of Pediatrics,..."}]},{"given":"Peter C.","family":"Nowell","sequence":"additional","affiliation":[{"name":"Division of Oncology, Children\u2019s Hospital of Philadelphia, Department of Pediatrics, Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Cancer Center, Department of Pathology and Laboratory Medicine, and Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Center for Cancer and Blood Disorders, Children\u2019s Medical Center of Dallas, Dallas, TX 75235; and Department of Pediatrics,..."}]},{"given":"Ian A.","family":"Blair","sequence":"additional","affiliation":[{"name":"Division of Oncology, Children\u2019s Hospital of Philadelphia, Department of Pediatrics, Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Cancer Center, Department of Pathology and Laboratory Medicine, and Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Center for Cancer and Blood Disorders, Children\u2019s Medical Center of Dallas, Dallas, TX 75235; and Department of Pediatrics,..."}]},{"given":"Timothy R.","family":"Rebbeck","sequence":"additional","affiliation":[{"name":"Division of Oncology, Children\u2019s Hospital of Philadelphia, Department of Pediatrics, Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Cancer Center, Department of Pathology and Laboratory Medicine, and Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Center for Cancer and Blood Disorders, Children\u2019s Medical Center of Dallas, Dallas, TX 75235; and Department of Pediatrics,..."}]}],"member":"341","published-online":{"date-parts":[[1998,10,27]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"13","volume":"68","author":"Flannery J T","year":"1985","unstructured":"J T Flannery, J D Boice, S S Devesa, R A Kleinerman, R E Curtis, J F Fraumeni Natl Cancer Inst Monogr 68, 13\u201324 (1985).","journal-title":"Natl Cancer Inst Monogr"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.3109\/02841869009090070"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199603213341210"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1998.16.2.536"},{"key":"e_1_3_3_5_2","first-page":"1564","volume":"56","author":"Travis L B","year":"1996","unstructured":"L B Travis, R E Curtis, J D Boice, C E Platz, B F Hankey, J F Fraumeni Cancer Res 56, 1564\u20131570 (1996).","journal-title":"Cancer Res"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1985.3.4.532"},{"key":"e_1_3_3_7_2","volume-title":"Multiple Primary Cancers: Incidence, Etiology, Diagnosis, and Prevention","author":"Felix C","year":"1998","unstructured":"C Felix Multiple Primary Cancers: Incidence, Etiology, Diagnosis, and Prevention, eds A I Neugut, A T Meadows, E Robinson (Williams & Wilkins, Baltimore, , in press. 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