Cellular pharmacokinetics of carboplatin and cisplatin in relation to their cytotoxic action
| Autor: | Gerrit Los, Hub P.J.M. Noteborn, Els Verdegaal, Daan ten Bokkel Huinink, J. Gordon McVie, Alexander de Graeff, Eelco W. Meesters, Marjan Ruevekamp |
|---|---|
| Rok vydání: | 1991 |
| Předmět: |
inorganic chemicals
Pathology medicine.medical_specialty Cell Survival Pharmacology Biology Biochemistry Carboplatin Cell Line Colony-Forming Units Assay chemistry.chemical_compound Pharmacokinetics Neuroblastoma Tumor Cells Cultured medicine Animals Humans Cytotoxic T cell neoplasms Platinum Cisplatin Spectrophotometry Atomic DNA medicine.disease female genital diseases and pregnancy complications Mechanism of action chemistry Toxicity medicine.symptom Thymidine medicine.drug |
| Zdroj: | Biochemical Pharmacology. 42:357-363 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/0006-2952(91)90723-i |
| Popis: | We have studied the cellular pharmacokinetics of carboplatin (CBDCA), as part of the evaluation of the antitumor activity of CBDCA in cancers limited to the peritoneal cavity in comparison with cisplatin (cDDP). The uptake of CBDCA into L1210 (lymphosarcoma), CC531 (colonic carcinoma), COV413.B (human ovarian carcinoma) and NB1 (human neuroblastoma) cells was 1.5 to 13 times lower than the uptake of cDDP. The uptake of CBDCA into human ovarian carcinoma cells, taken directly from patients, was also 8–20 times lower than cDDP. Platinum concentrations, expressed as a percentage of the total intracellular Pt concentration, were similar for CBDCA and cDDP in cytosol and nucleus/membrane fractions. A second major difference between the drugs was their binding to DNA. Less CBDCA-DNA than cDDP-DNA adducts were formed after incubation at equimolar amounts of drug with isolated salmon sperm DNA (5–25 times less). A 16–69 times higher concentration of CBDCA than cDDP was needed to induce similar changes in cell growth activity (50% [ 3 H]thymidine inhibition) in CC531 and COV413.B cells, indicating that equitoxicity can only be achieved when tumor cells are exposed to higher concentrations of CBDCA than cDDP. Similar toxicity was achieved in CC531 cells after incubation with a 16-fold higher CBDCA dose than cDDP. Comparable intracellular platinum concentrations, however, were obtained with a 10-fold higher CBDCA dose, suggesting that cellular pharmacokinetics of the drugs are different. Regarding drug uptake and pharmacokinetics the mechanism of action of CBDCA differed from cDDP at a cellular level. |
| Databáze: | OpenAIRE |
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