論文 - 詳細
| RRC ID | 65229 |
|---|---|
| 著者 | Ye FB, Hamza A, Singh T, Flibotte S, Hieter P, O'Neil NJ. |
| タイトル | A Multimodal Genotoxic Anticancer Drug Characterized by Pharmacogenetic Analysis in Caenorhabditis elegans. |
| ジャーナル | Genetics |
| Abstract |
New anticancer therapeutics require extensive in vivo characterization to identify endogenous and exogenous factors affecting efficacy, to measure toxicity and mutagenicity, and to determine genotypes that result in therapeutic sensitivity or resistance. We used Caenorhabditis elegans as a platform with which to characterize properties of the anticancer therapeutic CX-5461. To understand the processes that respond to CX-5461-induced damage, we generated pharmacogenetic profiles for a panel of C. elegans DNA replication and repair mutants with common DNA-damaging agents for comparison with the profile of CX-5461. We found that multiple repair pathways, including homology-directed repair, microhomology-mediated end joining, nucleotide excision repair, and translesion synthesis, were needed for CX-5461 tolerance. To determine the frequency and spectrum of CX-5461-induced mutations, we used a genetic balancer to capture CX-5461-induced mutations. We found that CX-5461 is mutagenic, resulting in both large copy number variations and a high frequency of single-nucleotide variations (SNVs), which are consistent with the pharmacogenetic profile for CX-5461. Whole-genome sequencing of CX-5461-exposed animals found that CX-5461-induced SNVs exhibited a distinct mutational signature. We also phenocopied the CX-5461 photoreactivity observed in clinical trials and demonstrated that CX-5461 generates reactive oxygen species when exposed to UVA radiation. Together, the data from C. elegans demonstrate that CX-5461 is a multimodal DNA-damaging anticancer agent. |
| 巻・号 | 215(3) |
| ページ | 609-621 |
| 公開日 | 2020-7-1 |
| DOI | 10.1534/genetics.120.303169 |
| PII | genetics.120.303169 |
| PMID | 32414869 |
| PMC | PMC7337070 |
| MeSH | Animals Antineoplastic Agents / toxicity* Benzothiazoles / toxicity* Caenorhabditis elegans / drug effects Caenorhabditis elegans / genetics* Carcinogenicity Tests / methods* DNA Repair Drug Resistance, Neoplasm Genome, Helminth Genome-Wide Association Study / methods* Mutagens / toxicity* Mutation Naphthyridines / toxicity* Pharmacogenomic Variants* Polymorphism, Single Nucleotide |
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オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 22 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm5027 tm2026 tm1298 tm423 tm3148 tm1981 tm1937 tm424 tm1866 tm2134 |