Factors influencing the cellular accumulation of SN-38 and camptothecin
| Autor: | John F. Smyth, Duncan I. Jodrell, Gillian Smith, Janet S. Macpherson, Helga Wolf, Jeffrey Cummings, Gary Boyd |
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| Rok vydání: | 2002 |
| Předmět: |
Cancer Research
Time Factors Metabolite Adenocarcinoma Irinotecan Toxicology chemistry.chemical_compound Tumor Cells Cultured medicine Humans Pharmacology (medical) Enzyme Inhibitors Ovarian Neoplasms Pharmacology Reverse Transcriptase Polymerase Chain Reaction Chemistry Membrane Transport Proteins Biological Transport Metabolism Membrane transport Drug Resistance Multiple Multidrug Resistance-Associated Protein 2 In vitro Kinetics Oncology Biochemistry Cell culture Colonic Neoplasms Camptothecin Female Genes MDR Multidrug Resistance-Associated Proteins Topoisomerase I Inhibitors Drug metabolism Intracellular medicine.drug |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 49:194-200 |
| ISSN: | 1432-0843 0344-5704 |
| Popis: | Purpose: The influence of biophysical factors (drug metabolism, transport proteins, and chemical stability) on the cellular accumulation of camptothecin (CPT) and SN-38 was examined. Methods: Drug transporter RNA transcript levels were measured by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Intracellular drug accumulation, metabolism, and drug stability studies were all performed by HPLC. Results: A panel of three human cell lines exhibiting different drug resistant phenotypes was investigated. HT29 colon cells glucuronidated SN-38 but did not express P-gp or MRP1 or 2. HCT116 colon cells expressed P-gp and MRP2 but did not catalyse conjugation. A2780 ovarian cells neither catalysed drug metabolism nor contained these drug transporters. In all lines, SN-38 lactone was rapidly taken up achieving peak concentrations at the earliest time point studied (5 min, 3.3–4.1 ng/106 cells). Subsequently, a fall in intracellular lactone concentration occurred, stabilising after 4 h at 0.48–1.18 ng/106 cells. No significant differences in intracellular levels of lactone were observed between the three cell lines with one exception: a twofold increase in HCT116 cells at 24 h. Stability studies in culture medium revealed that SN-38 lactone concentrations disappeared at the same rate regardless of whether cells were present, initially falling to reach equilibrium with the hydroxy acid by 4 h. Indeed, changes in intracellular lactone concentrations followed closely chemical stability profiles in media. Similar patterns of cellular retention and chemical degradation were observed with CPT. Conclusion: The major determinant of drug accumulation in three diverse cell line phenotypes was lactone chemical stability in culture medium. |
| Databáze: | OpenAIRE |
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