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These tumorspheres are rich in cancer stem\u2010like cells (<jats:styled-content style=\"fixed-case\">CSC<\/jats:styled-content>s), which are resistant to therapy and are a major source of relapse. The purpose of this research was to identify a safe therapeutic approach that could eradicate the peritoneal <jats:styled-content style=\"fixed-case\">CSC<\/jats:styled-content>\u2010rich tumorspheres and inhibit relapse. Highly metastatic ascitic cells (<jats:styled-content style=\"fixed-case\">OVASC<\/jats:styled-content>\u20101) that are resistant to standard\u2010of\u2010care chemotherapy due to upregulation of <jats:styled-content style=\"fixed-case\">MDR<\/jats:styled-content>1 gene were obtained from a patient with ovarian carcinoma and recurrent disease. <jats:styled-content style=\"fixed-case\">CSC<\/jats:styled-content>\u2010rich tumorspheres were generated, characterized, and treated with different chemotherapeutics. The most effective drug combination that could eradicate tumorspheres at nanomolar levels despite upregulation of <jats:styled-content style=\"fixed-case\">MDR<\/jats:styled-content>1 gene was identified. Luciferase\u2010expressing <jats:styled-content style=\"fixed-case\">OVASC<\/jats:styled-content>\u20101 cells were implanted in the peritoneum of nude mice and treated with the identified drug combination. The progression of disease, response to therapy and recurrence were studied by quantitative imaging. Toxicity to abdominal tissues was studied by histopathology. Mice implanted with intraperitoneal (<jats:styled-content style=\"fixed-case\">IP<\/jats:styled-content>) <jats:styled-content style=\"fixed-case\">OVASC<\/jats:styled-content>\u20101 xenografts showed limited response to combination therapy with cisplatin\/paclitaxel at the maximum tolerated dose. Despite overexpression of <jats:styled-content style=\"fixed-case\">MDR<\/jats:styled-content>1 on <jats:styled-content style=\"fixed-case\">OVASC<\/jats:styled-content>\u20101 cells, mice treated with our combination <jats:styled-content style=\"fixed-case\">IP<\/jats:styled-content> low\u2010dose <jats:styled-content style=\"fixed-case\">MMAE<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">SN<\/jats:styled-content>\u201038 chemotherapy showed complete response without relapse. No signs of toxicity to abdominal tissues were observed. While <jats:styled-content style=\"fixed-case\">MMAE<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">SN<\/jats:styled-content>\u201038 are not administered as free drugs due to their high potency and potential for systemic toxicity, our low\u2010dose localized therapy approach effectively restricted the cytotoxic effects to the tumor cells in the peritoneum. Consequently, maximum efficacy with minimal adverse effects was achieved. These remarkable results with <jats:styled-content style=\"fixed-case\">IP<\/jats:styled-content> low\u2010dose combination chemotherapy encourage investigation into its potential clinical application as either first\u2010line therapy or in cases of acquired resistance to cisplatin and paclitaxel.<\/jats:p>","DOI":"10.1002\/cam4.1631","type":"journal-article","created":{"date-parts":[[2018,6,21]],"date-time":"2018-06-21T08:54:01Z","timestamp":1529571241000},"page":"3630-3641","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A novel chemotherapeutic protocol for peritoneal metastasis and inhibition of relapse in drug resistant ovarian cancer"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3694-8915","authenticated-orcid":false,"given":"Siddik","family":"Sarkar","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics Rutgers, The State University of New Jersey  Piscataway NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Obeid M.","family":"Malekshah","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Rutgers, The State University of New Jersey  Piscataway NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alireza","family":"Nomani","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Rutgers, The State University of New Jersey  Piscataway NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niket","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Rutgers, The State University of New Jersey  Piscataway NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4611-7469","authenticated-orcid":false,"given":"Arash","family":"Hatefi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Rutgers, The State University of New Jersey  Piscataway NJ USA"},{"name":"Rutgers Cancer Institute of New Jersey  New Brunswick NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,6,21]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2013.12.001"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2012.02.002"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.61.4776"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa052985"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-1536"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-014-1436-x"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.2174\/1566524013666131118110827"},{"key":"e_1_2_7_9_1","doi-asserted-by":"crossref","first-page":"487","DOI":"10.5962\/bhl.title.7320","volume-title":"Enzyme and metabolic inhibitors","author":"Webb JL","year":"1963"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2015.01.003"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/1479-5876-4-6"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1040-8428(00)00086-X"},{"key":"e_1_2_7_13_1","first-page":"529","article-title":"Antineoplastic agents 337. 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