Overcoming cisplatin resistance: design of novel hydrophobic platinum compounds
| Autor: | G, Tallen, C, Mock, S B, Gangopadhyay, B, Kangarloo, B, Krebs, J E, Wolff |
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| Rok vydání: | 2000 |
| Předmět: |
Chemical Phenomena
DNA Repair Molecular Structure Organoplatinum Compounds Brain Neoplasms Chemistry Physical Antineoplastic Agents Glioma Fibroblasts Structure-Activity Relationship Cross-Linking Reagents Drug Resistance Neoplasm Drug Design Tumor Cells Cultured Humans Benzimidazoles Cisplatin Drug Screening Assays Antitumor Medulloblastoma |
| Zdroj: | Anticancer research. 20(1A) |
| ISSN: | 0250-7005 |
| Popis: | The anticancer activity of cisplatin derives from its ability to crosslink DNA. Cisplatin-resistance is partially caused by enhanced nucleotide excision repair (NER). Major 1,2-intrastrand crosslinks can create a hydrophobic notch at the damage site, which can be specifically bound by damage-recognition proteins, thus shielded from NER-activity. We aimed at preventing resistance by enhancing this mechanism using more hydrophobic platinum compounds.We synthesized three platinum analogs with increased hydrophobic characteristics. Performing MTT-assays, the efficacy of cisplatin and the novel agents was compared in a fibroblast and eight brain tumour cell lines.Among the novel compounds, the most hydrophobic molecule, methylpyridineplatinum, was most cytotoxic (LC50 = 5.84 x 10(-5) M), followed by methylpyrazineplatinum, the second most hydrophobic (LC50 = 1.79 x 10(-4) M), and pyridineplatinum (LC50 = 2.76 x 10(-4) M). Overall, cisplatin revealed highest cytotoxicity (LC50 = 8.77 x 10(-6) M).Comparison of the novel compounds supports the hypothesis that increased hydrophobicity contributes to higher antitumour-activity. Other advantageous characteristics of cisplatin might relate to its remaining highest efficacy. |
| Databáze: | OpenAIRE |
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