Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies
Zebrafish are a major model for chemical genetics, and most studies use embryos when investigating small molecules that cause interesting phenotypes or that can rescue disease models. Limited studies have dosed adults with small molecules by means of water-borne exposure or injection techniques. Cha...
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| Format: | Article |
| Language: | en_US |
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Company of Biologists
2016
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| Online Access: | http://hdl.handle.net/1721.1/105138 |
| _version_ | 1826208595163742208 |
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| author | Henderson, Rachel E. Garraway, Levi A. Zon, Leonard I. Dang, Michelle |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Henderson, Rachel E. Garraway, Levi A. Zon, Leonard I. Dang, Michelle |
| author_sort | Henderson, Rachel E. |
| collection | MIT |
| description | Zebrafish are a major model for chemical genetics, and most studies use embryos when investigating small molecules that cause interesting phenotypes or that can rescue disease models. Limited studies have dosed adults with small molecules by means of water-borne exposure or injection techniques. Challenges in the form of drug delivery-related trauma and anesthesia-related toxicity have excluded the adult zebrafish from long-term drug efficacy studies. Here, we introduce a novel anesthetic combination of MS-222 and isoflurane to an oral gavage technique for a non-toxic, non-invasive and long-term drug administration platform. As a proof of principle, we established drug efficacy of the FDA-approved BRAF [superscript V600E] inhibitor, Vemurafenib, in adult zebrafish harboring BRAF[superscript V600E] melanoma tumors. In the model, adult casper zebrafish intraperitoneally transplanted with a zebrafish melanoma cell line (ZMEL1) and exposed to daily sub-lethal dosing at 100 mg/kg of Vemurafenib for 2 weeks via oral gavage resulted in an average 65% decrease in tumor burden and a 15% mortality rate. In contrast, Vemurafenib-resistant ZMEL1 cell lines, generated in culture from low-dose drug exposure for 4 months, did not respond to the oral gavage treatment regimen. Similarly, this drug treatment regimen can be applied for treatment of primary melanoma tumors in the zebrafish. Taken together, we developed an effective long-term drug treatment system that will allow the adult zebrafish to be used to identify more effective anti-melanoma combination therapies and opens up possibilities for treating adult models of other diseases. |
| first_indexed | 2024-09-23T14:08:06Z |
| format | Article |
| id | mit-1721.1/105138 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:08:06Z |
| publishDate | 2016 |
| publisher | Company of Biologists |
| record_format | dspace |
| spelling | mit-1721.1/1051382022-09-28T18:47:38Z Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies Henderson, Rachel E. Garraway, Levi A. Zon, Leonard I. Dang, Michelle Massachusetts Institute of Technology. Department of Biology Dang, Michelle Zebrafish are a major model for chemical genetics, and most studies use embryos when investigating small molecules that cause interesting phenotypes or that can rescue disease models. Limited studies have dosed adults with small molecules by means of water-borne exposure or injection techniques. Challenges in the form of drug delivery-related trauma and anesthesia-related toxicity have excluded the adult zebrafish from long-term drug efficacy studies. Here, we introduce a novel anesthetic combination of MS-222 and isoflurane to an oral gavage technique for a non-toxic, non-invasive and long-term drug administration platform. As a proof of principle, we established drug efficacy of the FDA-approved BRAF [superscript V600E] inhibitor, Vemurafenib, in adult zebrafish harboring BRAF[superscript V600E] melanoma tumors. In the model, adult casper zebrafish intraperitoneally transplanted with a zebrafish melanoma cell line (ZMEL1) and exposed to daily sub-lethal dosing at 100 mg/kg of Vemurafenib for 2 weeks via oral gavage resulted in an average 65% decrease in tumor burden and a 15% mortality rate. In contrast, Vemurafenib-resistant ZMEL1 cell lines, generated in culture from low-dose drug exposure for 4 months, did not respond to the oral gavage treatment regimen. Similarly, this drug treatment regimen can be applied for treatment of primary melanoma tumors in the zebrafish. Taken together, we developed an effective long-term drug treatment system that will allow the adult zebrafish to be used to identify more effective anti-melanoma combination therapies and opens up possibilities for treating adult models of other diseases. National Institutes of Health (U.S.) National Cancer Institute (U.S.) (grant CA103846-13) 2016-10-28T18:22:36Z 2016-10-28T18:22:36Z 2016-04 2015-11 Article http://purl.org/eprint/type/JournalArticle 1754-8403 1754-8411 http://hdl.handle.net/1721.1/105138 Dang, Michelle, Rachel E. Henderson, Levi A. Garraway, and Leonard I. Zon. “Long-Term Drug Administration in the Adult Zebrafish Using Oral Gavage for Cancer Preclinical Studies.” Disease Models & Mechanisms 9.7, 2016, pp. 811–820. en_US http://dx.doi.org/10.1242/dmm.024166 Disease Models & Mechanisms Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf Company of Biologists Company of Biologists |
| spellingShingle | Henderson, Rachel E. Garraway, Levi A. Zon, Leonard I. Dang, Michelle Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies |
| title | Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies |
| title_full | Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies |
| title_fullStr | Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies |
| title_full_unstemmed | Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies |
| title_short | Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies |
| title_sort | long term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies |
| url | http://hdl.handle.net/1721.1/105138 |
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