Abstract
A single cell clonal sub-line A2780/C10B that is 18-fold resistant to oxaliplatin and approximately threefold cross-resistant to cisplatin and exhibiting a metastasis associated cellular phenotype was characterized for mechanisms of resistance. The cell line exhibited a 50% reduction in the accumulation of both oxaliplatin and cisplatin relative to the parent line, while extensive decline in Pt-DNA adduct levels occurred only following oxaliplatin treatment. The basal GSH levels were fivefold higher in A2780/C10B compared to A2780 and had a fivefold elevation in gamma-GT suggesting this may be the mechanism involved in GSH elevation. The basal levels of ERCC-1, XPA and MRP-2 mRNA levels in A2780/C10B were not higher than those in A2780. The highly reduced Pt-DNA adduct formation only for oxaliplatin, but not cisplatin may be a reflection of the fact that at equimolar concentrations oxaliplatin makes fewer Pt-DNA adducts than cisplatin. The data indicate that multiple lesions occur in a single cell to produce the resistant phenotype.
Publication types
- Research Support, N.I.H., Extramural
MeSH terms
- Antineoplastic Agents / metabolism
- Antineoplastic Agents / pharmacology
- Cell Line, Tumor
- Cell Survival / drug effects
- Cisplatin / metabolism
- Cisplatin / pharmacology
- Clone Cells / drug effects
- Clone Cells / metabolism
- DNA Adducts / metabolism
- DNA-Binding Proteins / genetics
- Dose-Response Relationship, Drug
- Drug Resistance, Multiple*
- Drug Resistance, Neoplasm*
- Endonucleases / genetics
- Female
- Glutamate-Cysteine Ligase / genetics
- Glutamate-Cysteine Ligase / metabolism
- Glutathione / metabolism
- Humans
- Membrane Transport Proteins / genetics
- Multidrug Resistance-Associated Protein 2
- Multidrug Resistance-Associated Proteins / genetics
- Organoplatinum Compounds / metabolism
- Organoplatinum Compounds / pharmacology*
- Ovarian Neoplasms / genetics
- Ovarian Neoplasms / metabolism
- Ovarian Neoplasms / pathology
- Oxaliplatin
- RNA, Messenger / genetics
- RNA, Messenger / metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Xeroderma Pigmentosum Group A Protein / genetics
- gamma-Glutamyltransferase / genetics
- gamma-Glutamyltransferase / metabolism
Substances
- ABCC2 protein, human
- Antineoplastic Agents
- DNA Adducts
- DNA-Binding Proteins
- Membrane Transport Proteins
- Multidrug Resistance-Associated Protein 2
- Multidrug Resistance-Associated Proteins
- Organoplatinum Compounds
- RNA, Messenger
- XPA protein, human
- Xeroderma Pigmentosum Group A Protein
- Oxaliplatin
- gamma-Glutamyltransferase
- ERCC1 protein, human
- Endonucleases
- Glutamate-Cysteine Ligase
- Glutathione
- Cisplatin