PloS one, 2012-09, Vol.7 (9), p.e45248-e45248
2012
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- Autor(en) / Beteiligte
- Titel
- EZN-2208 (PEG-SN38) overcomes ABCG2-mediated topotecan resistance in BRCA1-deficient mouse mammary tumors
- Ist Teil von
- PloS one, 2012-09, Vol.7 (9), p.e45248-e45248
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- BRCA1 dysfunction in hereditary breast cancer causes defective homology-directed DNA repair and sensitivity towards DNA damaging agents like the clinically used topoisomerase I inhibitors topotecan and irinotecan. Using our conditional K14cre;Brca1(F/F);p53(F/F) mouse model, we showed previously that BRCA1;p53-deficient mammary tumors initially respond to topotecan, but frequently acquire resistance by overexpression of the efflux transporter ABCG2. Here, we tested the pegylated SN38 compound EZN-2208 as a novel approach to treat BRCA1-mutated tumors that express ABCG2. We found that EZN-2208 therapy resulted in more pronounced and durable responses of ABCG2-positive tumors than topotecan or irinotecan therapy. We also evaluated tumor-specific ABCG2 inhibition by Ko143 in Abcg2(-/-) host animals that carried tumors with topotecan-induced ABCG2 expression. Addition of Ko143 moderately increased overall survival of these animals, but did not yield tumor responses like those seen after EZN-2208 therapy. Our results suggest that pegylation of Top1 inhibitors may be a useful strategy to circumvent efflux transporter-mediated resistance and to improve their efficacy in the clinic.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0045248Titel-ID: cdi_plos_journals_1344508117
- Format
- –
- Schlagworte
- Adenosine - analogs & derivatives, Adenosine - pharmacology, Adenosine - therapeutic use, Analysis, Animals, Antineoplastic Agents - pharmacology, Antineoplastic Agents - therapeutic use, ATP Binding Cassette Transporter, Sub-Family G, Member 2, ATP-Binding Cassette Transporters - deficiency, ATP-Binding Cassette Transporters - genetics, Biology, BRCA1 protein, BRCA1 Protein - deficiency, BRCA1 Protein - genetics, Breast cancer, Camptothecin - analogs & derivatives, Camptothecin - pharmacology, Camptothecin - therapeutic use, Cancer therapies, Complications and side effects, Deoxyribonucleic acid, Diketopiperazines, DNA, DNA damage, DNA repair, DNA topoisomerase, DNA Topoisomerases, Type I - metabolism, Dosage and administration, Drug dosages, Drug resistance, Drug therapy, Efflux, Female, Gene Expression, Genetic aspects, Health aspects, Heterocyclic Compounds, 4 or More Rings, Homology, Inhibitors, Irinotecan, Lung cancer, Mammary Glands, Animal - drug effects, Mammary Glands, Animal - metabolism, Mammary Glands, Animal - pathology, Mammary Neoplasms, Animal - drug therapy, Mammary Neoplasms, Animal - genetics, Mammary Neoplasms, Animal - mortality, Mammary Neoplasms, Animal - pathology, Medicine, Mice, Mice, Knockout, Mutation, Oncology, p53 Protein, Pharmaceuticals, Poisons, Polyethylene glycol, Polyethylene Glycols - pharmacology, Polyethylene Glycols - therapeutic use, Survival Rate, Therapy, Topoisomerase I Inhibitors - pharmacology, Topoisomerase I Inhibitors - therapeutic use, Topotecan, Topotecan - pharmacology, Topotecan - therapeutic use, Tumors, Vitamin B