{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T16:56:36Z","timestamp":1759683396675,"version":"3.41.2"},"reference-count":48,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2018,9,24]],"date-time":"2018-09-24T00:00:00Z","timestamp":1537747200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA168699"],"award-info":[{"award-number":["CA168699"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Maintenance therapy with 13\u2010cis\u2010retinoic acid and immunotherapy (given after completion of intensive cytotoxic therapy) improves outcome for high\u2010risk neuroblastoma patients. The synthetic retinoid fenretinide (4\u2010HPR) achieved multiple complete responses in relapse\/refractory neuroblastoma in early\u2010phase clinical trials, has low systemic toxicity, and has been considered for maintenance therapy clinical trials. Difluoromethylornithine (DFMO, an irreversible inhibitor of ornithine decarboxylase with minimal single\u2010agent clinical response data) is being used for maintenance therapy of neuroblastoma. We evaluated the cytotoxic activity of DFMO and fenretinide in neuroblastoma cell lines.<\/jats:p><\/jats:sec><jats:sec><jats:title>Procedure<\/jats:title><jats:p>We tested 16 neuroblastoma cell lines in bone marrow\u2010level hypoxia (5% O<jats:sub>2<\/jats:sub>) using the DIMSCAN cytotoxicity assay. Polyamines were measured by HPLC\u2013mass spectrometry and apoptosis by transferase dUTP nick end labeling (TUNEL) using flow cytometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>At clinically achievable levels (100\u00a0\u03bcM), DFMO significantly decreased (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) polyamine putrescine and achieved modest cytotoxicity (&lt;1 log (90% cytotoxicity). Prolonged exposures (7 days) or culture in 2% and 20% O<jats:sub>2<\/jats:sub> did not enhance DFMO cytotoxicity. However, fenretinide (10\u00a0\u03bcM) even at a concentration lower than clinically achievable in neuroblastoma patients (20\u00a0\u03bcM) induced\u00a0\u2265\u00a01 log cell kill in 14 cell lines. The average IC<jats:sub>90<\/jats:sub> and IC<jats:sub>99<\/jats:sub> of fenretinide was 4.7\u00a0\u00b1\u00a01\u00a0\u03bcM and 9.9\u00a0\u00b1\u00a01.8\u00a0\u03bcM, respectively. DFMO did not induce a significant increase (<jats:italic>P<\/jats:italic>\u00a0&gt;\u00a00.05) in apoptosis (TUNEL assay). Apoptosis by fenretinide was significantly higher (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) compared with DFMO or controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>DFMO as a single agent has minimal cytotoxic activity for neuroblastoma cell lines.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.27447","type":"journal-article","created":{"date-parts":[[2018,9,25]],"date-time":"2018-09-25T06:38:41Z","timestamp":1537857521000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Cytotoxic activity of difluoromethylornithine compared with fenretinide in neuroblastoma cell lines"],"prefix":"10.1002","volume":"65","author":[{"given":"Monish R.","family":"Makena","sequence":"first","affiliation":[{"name":"Cancer Center Texas Tech University Health Sciences Center School of Medicine  Lubbock Texas"},{"name":"Department of Cell Biology and Biochemistry Texas Tech University Health Sciences Center School of Medicine  Lubbock Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9220-7225","authenticated-orcid":false,"given":"Hwang Eui","family":"Cho","sequence":"additional","affiliation":[{"name":"Cancer Center Texas Tech University Health Sciences Center School of Medicine  Lubbock Texas"},{"name":"Department of Cell Biology and Biochemistry Texas Tech University Health Sciences Center School of Medicine  Lubbock Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thinh H.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Cancer Center Texas Tech University Health Sciences Center School of Medicine  Lubbock Texas"},{"name":"Department of Pharmacology and Neuroscience Texas Tech University Health Sciences Center School of Medicine  Lubbock Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Balakrishna","family":"Koneru","sequence":"additional","affiliation":[{"name":"Cancer Center Texas Tech University Health Sciences Center School of Medicine  Lubbock Texas"},{"name":"Department of Cell Biology and Biochemistry Texas Tech University Health Sciences Center School of Medicine  Lubbock Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dattesh U.","family":"Verlekar","sequence":"additional","affiliation":[{"name":"Cancer Center Texas Tech University Health Sciences Center School of Medicine  Lubbock Texas"},{"name":"Department of Cell Biology and Biochemistry Texas Tech University Health Sciences Center School of Medicine  Lubbock Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashly","family":"Hindle","sequence":"additional","affiliation":[{"name":"Cancer Center Texas Tech University Health Sciences Center School of Medicine  Lubbock Texas"},{"name":"Department of Cell Biology and Biochemistry Texas Tech University Health Sciences Center School of Medicine  Lubbock Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min H.","family":"Kang","sequence":"additional","affiliation":[{"name":"Cancer Center Texas Tech University Health Sciences Center School of Medicine  Lubbock Texas"},{"name":"Department of Cell Biology and Biochemistry Texas Tech University Health Sciences Center School of Medicine  Lubbock Texas"},{"name":"Department of Pharmacology and Neuroscience Texas Tech University Health Sciences Center School of Medicine  Lubbock Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2827-8536","authenticated-orcid":false,"given":"C. 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