{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T22:04:22Z","timestamp":1784066662689,"version":"3.55.0"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T00:00:00Z","timestamp":1631664000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T00:00:00Z","timestamp":1631664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["1R15CA133776-01A1"],"award-info":[{"award-number":["1R15CA133776-01A1"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Chemother Pharmacol"],"published-print":{"date-parts":[[2021,12]]},"DOI":"10.1007\/s00280-021-04352-9","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T10:02:53Z","timestamp":1631700173000},"page":"985-996","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Megestrol acetate is a specific inducer of CYP3A4 mediated by human pregnane X receptor"],"prefix":"10.1007","volume":"88","author":[{"given":"Yakun","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey Z.","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanqin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5239-5663","authenticated-orcid":false,"given":"Daotai","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,15]]},"reference":[{"issue":"2","key":"4352_CR1","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.critrevonc.2005.03.007","volume":"55","author":"P Blower","year":"2005","unstructured":"Blower P et al (2005) Drug-drug interactions in oncology: why are they important and can they be minimized? Crit Rev Oncol Hematol 55(2):117\u2013142","journal-title":"Crit Rev Oncol Hematol"},{"issue":"8","key":"4352_CR2","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/S1470-2045(04)01528-1","volume":"5","author":"JH Beijnen","year":"2004","unstructured":"Beijnen JH, Schellens JH (2004) Drug interactions in oncology. Lancet Oncol 5(8):489\u2013496","journal-title":"Lancet Oncol"},{"issue":"4","key":"4352_CR3","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.ctrv.2007.02.003","volume":"33","author":"S Harmsen","year":"2007","unstructured":"Harmsen S et al (2007) The role of nuclear receptors in pharmacokinetic drug-drug interactions in oncology. Cancer Treat Rev 33(4):369\u2013380","journal-title":"Cancer Treat Rev"},{"issue":"5\u20136","key":"4352_CR4","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1007\/PL00000897","volume":"58","author":"P Anzenbacher","year":"2001","unstructured":"Anzenbacher P, Anzenbacherova E (2001) Cytochromes P450 and metabolism of xenobiotics. Cell Mol Life Sci 58(5\u20136):737\u2013747","journal-title":"Cell Mol Life Sci"},{"issue":"8","key":"4352_CR5","doi-asserted-by":"publisher","first-page":"808","DOI":"10.2174\/1389200216666150223152627","volume":"15","author":"D Tian","year":"2014","unstructured":"Tian D, Hu Z (2014) CYP3A4-mediated pharmacokinetic interactions in cancer therapy. Curr Drug Metab 15(8):808\u2013817","journal-title":"Curr Drug Metab"},{"issue":"16","key":"4352_CR6","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1093\/jnci\/94.16.1247","volume":"94","author":"RH Mathijssen","year":"2002","unstructured":"Mathijssen RH et al (2002) Effects of St. John\u2019s wort on irinotecan metabolism. J Natl Cancer Inst 94(16):1247\u20131249","journal-title":"J Natl Cancer Inst"},{"issue":"3","key":"4352_CR7","first-page":"581","volume":"55","author":"L Chen","year":"1995","unstructured":"Chen L, Waxman DJ (1995) Intratumoral activation and enhanced chemotherapeutic effect of oxazaphosphorines following cytochrome P-450 gene transfer: development of a combined chemotherapy\/cancer gene therapy strategy. Cancer Res 55(3):581\u2013589","journal-title":"Cancer Res"},{"issue":"8","key":"4352_CR8","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1089\/hum.1994.5.8-969","volume":"5","author":"MX Wei","year":"1994","unstructured":"Wei MX et al (1994) Experimental tumor therapy in mice using the cyclophosphamide-activating cytochrome P450 2B1 gene. Hum Gene Ther 5(8):969\u2013978","journal-title":"Hum Gene Ther"},{"key":"4352_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1146\/annurev.pharmtox.39.1.1","volume":"39","author":"FP Guengerich","year":"1999","unstructured":"Guengerich FP (1999) Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol 39:1\u201317","journal-title":"Annu Rev Pharmacol Toxicol"},{"issue":"2","key":"4352_CR10","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1517\/17425255.2.2.171","volume":"2","author":"L Wojnowski","year":"2006","unstructured":"Wojnowski L, Kamdem LK (2006) Clinical implications of CYP3A polymorphisms. Expert Opin Drug Metab Toxicol 2(2):171\u2013182","journal-title":"Expert Opin Drug Metab Toxicol"},{"issue":"5","key":"4352_CR11","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1172\/JCI3703","volume":"102","author":"JM Lehmann","year":"1998","unstructured":"Lehmann JM et al (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 102(5):1016\u20131023","journal-title":"J Clin Invest"},{"issue":"21","key":"4352_CR12","doi-asserted-by":"publisher","first-page":"12208","DOI":"10.1073\/pnas.95.21.12208","volume":"95","author":"G Bertilsson","year":"1998","unstructured":"Bertilsson G et al (1998) Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci U S A 95(21):12208\u201312213","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"4352_CR13","first-page":"1446","volume":"29","author":"P Schmiedlin-Ren","year":"2001","unstructured":"Schmiedlin-Ren P et al (2001) Induction of CYP3A4 by 1 alpha,25-dihydroxyvitamin D3 is human cell line-specific and is unlikely to involve pregnane X receptor. Drug Metab Dispos 29(11):1446\u20131453","journal-title":"Drug Metab Dispos"},{"issue":"2","key":"4352_CR14","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1124\/mol.62.2.359","volume":"62","author":"B Goodwin","year":"2002","unstructured":"Goodwin B et al (2002) Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor. Mol Pharmacol 62(2):359\u2013365","journal-title":"Mol Pharmacol"},{"issue":"9","key":"4352_CR15","doi-asserted-by":"publisher","first-page":"6318","DOI":"10.1128\/MCB.19.9.6318","volume":"19","author":"T Kawamoto","year":"1999","unstructured":"Kawamoto T et al (1999) Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene. Mol Cell Biol 19(9):6318\u20136322","journal-title":"Mol Cell Biol"},{"issue":"1\u20132","key":"4352_CR16","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1080\/03602530600569828","volume":"38","author":"TK Chang","year":"2006","unstructured":"Chang TK, Waxman DJ (2006) Synthetic drugs and natural products as modulators of constitutive androstane receptor (CAR) and pregnane X receptor (PXR). Drug Metab Rev 38(1\u20132):51\u201373","journal-title":"Drug Metab Rev"},{"issue":"5","key":"4352_CR17","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1038\/87912","volume":"7","author":"TW Synold","year":"2001","unstructured":"Synold TW, Dussault I, Forman BM (2001) The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 7(5):584\u2013590","journal-title":"Nat Med"},{"issue":"5","key":"4352_CR18","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1124\/dmd.30.5.608","volume":"30","author":"PB Desai","year":"2002","unstructured":"Desai PB et al (2002) Induction of cytochrome P450 3A4 in primary human hepatocytes and activation of the human pregnane X receptor by tamoxifen and 4-hydroxytamoxifen. Drug Metab Dispos 30(5):608\u2013612","journal-title":"Drug Metab Dispos"},{"issue":"1","key":"4352_CR19","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/0305-7372(89)90004-2","volume":"16","author":"L Schacter","year":"1989","unstructured":"Schacter L et al (1989) Megestrol acetate: clinical experience. Cancer Treat Rev 16(1):49\u201363","journal-title":"Cancer Treat Rev"},{"issue":"4","key":"4352_CR20","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1016\/S0959-8049(98)00398-0","volume":"35","author":"G Westman","year":"1999","unstructured":"Westman G et al (1999) Megestrol acetate in advanced, progressive, hormone-insensitive cancer. Effects on the quality of life: a placebo-controlled, randomised, multicentre trial. Eur J Cancer 35(4):586\u2013595","journal-title":"Eur J Cancer"},{"issue":"6","key":"4352_CR21","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1097\/00000421-200212000-00003","volume":"25","author":"S Markovic","year":"2002","unstructured":"Markovic S et al (2002) Randomized, placebo-controlled, phase III surgical adjuvant clinical trial of megestrol acetate (Megace) in selected patients with malignant melanoma. Am J Clin Oncol 25(6):552\u2013556","journal-title":"Am J Clin Oncol"},{"issue":"8","key":"4352_CR22","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1097\/00001813-199809000-00009","volume":"9","author":"YS Pu","year":"1998","unstructured":"Pu YS et al (1998) Megestrol acetate antagonizes cisplatin cytotoxicity. Anticancer Drugs 9(8):733\u2013738","journal-title":"Anticancer Drugs"},{"issue":"1","key":"4352_CR23","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1053\/j.jrn.2007.10.022","volume":"18","author":"JJ Carrero","year":"2008","unstructured":"Carrero JJ et al (2008) Appetite disorders in uremia. J Ren Nutr 18(1):107\u2013113","journal-title":"J Ren Nutr"},{"issue":"4 Suppl 4","key":"4352_CR24","first-page":"20","volume":"13","author":"NS Tchekmedyian","year":"1986","unstructured":"Tchekmedyian NS, Tait N, Aisner J (1986) High-dose megestrol acetate in the treatment of postmenopausal women with advanced breast cancer. Semin Oncol 13(4 Suppl 4):20\u201325","journal-title":"Semin Oncol"},{"issue":"2 Suppl 1","key":"4352_CR25","first-page":"44","volume":"15","author":"NS Tchekmedyian","year":"1988","unstructured":"Tchekmedyian NS et al (1988) High-dose megestrol acetate in the treatment of advanced breast cancer. Semin Oncol 15(2 Suppl 1):44\u201349","journal-title":"Semin Oncol"},{"issue":"1","key":"4352_CR26","first-page":"23","volume":"31","author":"R Dev","year":"2017","unstructured":"Dev R et al (2017) The evolving approach to management of cancer cachexia. Oncology (Williston Park) 31(1):23\u201332","journal-title":"Oncology (Williston Park)"},{"issue":"2","key":"4352_CR27","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1007\/BF00685925","volume":"34","author":"L Wang","year":"1994","unstructured":"Wang L et al (1994) Reversal of the human and murine multidrug-resistance phenotype with megestrol acetate. Cancer Chemother Pharmacol 34(2):96\u2013102","journal-title":"Cancer Chemother Pharmacol"},{"issue":"6","key":"4352_CR28","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1007\/BF00684845","volume":"29","author":"GF Fleming","year":"1992","unstructured":"Fleming GF et al (1992) Megestrol acetate reverses multidrug resistance and interacts with P-glycoprotein. Cancer Chemother Pharmacol 29(6):445\u2013449","journal-title":"Cancer Chemother Pharmacol"},{"issue":"21","key":"4352_CR29","doi-asserted-by":"publisher","first-page":"10361","DOI":"10.1158\/0008-5472.CAN-06-4758","volume":"67","author":"Y Chen","year":"2007","unstructured":"Chen Y et al (2007) Human pregnane X receptor and resistance to chemotherapy in prostate cancer. Cancer Res 67(21):10361\u201310367","journal-title":"Cancer Res"},{"issue":"6","key":"4352_CR30","doi-asserted-by":"publisher","first-page":"483","DOI":"10.2174\/1389200043335397","volume":"5","author":"G Luo","year":"2004","unstructured":"Luo G et al (2004) CYP3A4 induction by xenobiotics: biochemistry, experimental methods and impact on drug discovery and development. Curr Drug Metab 5(6):483\u2013505","journal-title":"Curr Drug Metab"},{"issue":"2","key":"4352_CR31","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1038\/nm815","volume":"9","author":"RG Tirona","year":"2003","unstructured":"Tirona RG et al (2003) The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nat Med 9(2):220\u2013224","journal-title":"Nat Med"},{"issue":"5","key":"4352_CR32","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1016\/S0006-291X(02)02742-0","volume":"299","author":"PD Thompson","year":"2002","unstructured":"Thompson PD et al (2002) Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements. Biochem Biophys Res Commun 299(5):730\u2013738","journal-title":"Biochem Biophys Res Commun"},{"issue":"6","key":"4352_CR33","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1124\/mol.56.6.1329","volume":"56","author":"B Goodwin","year":"1999","unstructured":"Goodwin B, Hodgson E, Liddle C (1999) The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol Pharmacol 56(6):1329\u20131339","journal-title":"Mol Pharmacol"},{"issue":"47","key":"4352_CR34","doi-asserted-by":"publisher","first-page":"49307","DOI":"10.1074\/jbc.M407281200","volume":"279","author":"EJ Squires","year":"2004","unstructured":"Squires EJ, Sueyoshi T, Negishi M (2004) Cytoplasmic localization of pregnane X receptor and ligand-dependent nuclear translocation in mouse liver. J Biol Chem 279(47):49307\u201349314","journal-title":"J Biol Chem"},{"issue":"12","key":"4352_CR35","doi-asserted-by":"publisher","first-page":"2891","DOI":"10.1210\/me.2005-0156","volume":"19","author":"J Orans","year":"2005","unstructured":"Orans J, Teotico DG, Redinbo MR (2005) The nuclear xenobiotic receptor pregnane X receptor: recent insights and new challenges. Mol Endocrinol 19(12):2891\u20132900","journal-title":"Mol Endocrinol"},{"issue":"12","key":"4352_CR36","first-page":"4875","volume":"42","author":"AH Conney","year":"1982","unstructured":"Conney AH (1982) Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G. H. A. Clowes Memorial Lecture. Cancer Res 42(12):4875\u20134917","journal-title":"Cancer Res"},{"issue":"5","key":"4352_CR37","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1124\/dmd.105.008672","volume":"34","author":"MF Paine","year":"2006","unstructured":"Paine MF et al (2006) The human intestinal cytochrome P450 \u201cpie.\u201d Drug Metab Dispos 34(5):880\u2013886","journal-title":"Drug Metab Dispos"},{"issue":"1","key":"4352_CR38","first-page":"414","volume":"270","author":"T Shimada","year":"1994","unstructured":"Shimada T et al (1994) Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270(1):414\u2013423","journal-title":"J Pharmacol Exp Ther"},{"key":"4352_CR39","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1146\/annurev.pharmtox.38.1.389","volume":"38","author":"KE Thummel","year":"1998","unstructured":"Thummel KE, Wilkinson GR (1998) In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 38:389\u2013430","journal-title":"Annu Rev Pharmacol Toxicol"},{"issue":"1 Suppl 1","key":"4352_CR40","first-page":"17","volume":"12","author":"RC Gaver","year":"1985","unstructured":"Gaver RC et al (1985) Bioequivalence evaluation of new megestrol acetate formulations in humans. Semin Oncol 12(1 Suppl 1):17\u201319","journal-title":"Semin Oncol"},{"issue":"3","key":"4352_CR41","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1007\/s00280-002-0484-9","volume":"50","author":"K Matin","year":"2002","unstructured":"Matin K et al (2002) Phase I and pharmacokinetic study of vinblastine and high-dose megestrol acetate. Cancer Chemother Pharmacol 50(3):179\u2013185","journal-title":"Cancer Chemother Pharmacol"},{"issue":"10","key":"4352_CR42","doi-asserted-by":"publisher","first-page":"1742","DOI":"10.1124\/dmd.106.010132","volume":"34","author":"SL Ripp","year":"2006","unstructured":"Ripp SL et al (2006) Use of immortalized human hepatocytes to predict the magnitude of clinical drug-drug interactions caused by CYP3A4 induction. Drug Metab Dispos 34(10):1742\u20131748","journal-title":"Drug Metab Dispos"},{"issue":"5","key":"4352_CR43","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1111\/j.1742-7843.2008.00227.x","volume":"102","author":"BH Hellum","year":"2008","unstructured":"Hellum BH, Nilsen OG (2008) In vitro inhibition of CYP3A4 metabolism and P-glycoprotein-mediated transport by trade herbal products. Basic Clin Pharmacol Toxicol 102(5):466\u2013475","journal-title":"Basic Clin Pharmacol Toxicol"},{"issue":"4","key":"4352_CR44","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/S0928-0987(01)00135-X","volume":"13","author":"EL LeCluyse","year":"2001","unstructured":"LeCluyse EL (2001) Human hepatocyte culture systems for the in vitro evaluation of cytochrome P450 expression and regulation. Eur J Pharm Sci 13(4):343\u2013368","journal-title":"Eur J Pharm Sci"}],"container-title":["Cancer Chemotherapy and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00280-021-04352-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00280-021-04352-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00280-021-04352-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T23:22:11Z","timestamp":1635204131000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00280-021-04352-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,15]]},"references-count":44,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["4352"],"URL":"https:\/\/doi.org\/10.1007\/s00280-021-04352-9","relation":{},"ISSN":["0344-5704","1432-0843"],"issn-type":[{"value":"0344-5704","type":"print"},{"value":"1432-0843","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,15]]},"assertion":[{"value":"31 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 September 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"On behalf of all authors, the corresponding author states that there is no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Megestrol acetate specifically induces the expression of cytochrome P450 3A4 (CYP3A4) in human hepatocytes through binding to human PXR and recruitment of cofactors. But it has minimal effects on the expression of other drug metabolizing enzymes and efflux transporters. The study suggests a potential interaction of megestrol acetate with other drugs that are substrates of CYP3A4, as well as the utility of this compound to induce CYP3A4 specifically for pharmacological studies.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Significance statement"}}]}}